CONTEMPORARY PERSPECTIVES IN PUBLIC HEALTH AND PULMONARY DISEASES: FROM MOLECULAR MECHANISMS TO SOCIAL DETERMINANTS

EDITOR
D . Ul iyya JAFAROVA
CONTEMPORARY PERSPECTIVES
IN PUBLIC HEALTH AND
PULMONARY DISEASES:
FROM MOLECULAR
MECHANISMS TO SOCIAL
DETERMINANTS
Published by
BZT TURAN PUBLISHING HOUSE
Ce i ica e Numbe : 202401
Delawa e, Uni ed S a es
www.bz u anpublishinghouse.com
in o@bz u anpublishinghouse.com
EDITOR: D . Ul iyya JAFAROVA
CONTEMPORARY PERSPECTIVES IN PUBLIC HEALTH AND PULMONARY
DISEASES: FROM MOLECULAR MECHANISMS TO SOCIAL DETERMINANTS
OPEN ACCESS
Sugges ed Ci a ion:
Ja a o a, U. (2025). CONTEMPORARY PERSPECTIVES IN PUBLIC HEALTH AND PULMONARY DISEASES:
FROM MOLECULAR MECHANISMS TO SOCIAL DETERMINANTS. BZT TURAN PUBLISHING HOUSE. DOI:
h ps://doi.o g/10.30546/19023.978-9952-8610-4-4.2025.0042
Language: English
Publica ion Da e: Oc obe 2025
Co e Design By Mehme ÇAKIR
P in and digi al e sions ypese by BZT TURAN Media Co. L d.
E-ISBN: 9 7 8 - 9 9 5 2 - 8 6 1 0 - 4 - 4
DOI: h ps://doi.o g/10.30546/19023.978-9952-8610-4-4.2025.0042
iii
PREFACE
The 21s cen u y has wi nessed unp eceden ed challenges in he ield o
heal h sciences, anging om global pandemics o he apid ans o ma ion
o social s uc u es in luencing disease pa e ns. This olume b ings oge he
di e se ye in e connec ed s udies ha aim o shed ligh on bo h he biological
and social de e minan s o heal h in he pos -pandemic e a.
The i s con ibu ion add esses ib o ic lung disease in he pos -
COVID-19 e a, p o iding mechanis ic insigh s in o he pa hophysiology and
discussing eme ging he apeu ic app oaches. As pulmona y ib osis eme ges
as one o he mos c i ical long- e m sequelae o COVID-19, unde s anding
i s molecula pa hways and a ge ed ea men s has become a p essing
p io i y in espi a o y medicine.
Ano he s udy examines he impac o u baniza ion on hy oid cance
incidence by gende in Tu key. This esea ch highligh s how li es yle
changes, en i onmen al exposu es, and u ban li ing condi ions in e sec wi h
gende dynamics o in luence cance epidemiology. By o e ing a gende -
sensi i e analysis, i unde sco es he impo ance o in eg a ing demog aphic
and en i onmen al ac o s in public heal h s a egies.
The hi d s udy ocuses on women’s employmen s a us and i s ole
in applica ions o amily physicians, illus a ing he social dimension o
heal hca e u iliza ion. This pe spec i e d aws a en ion o he ways in which
economic pa icipa ion and gende oles di ec ly shape access o and demand
o p ima y heal hca e se ices, ul ima ely e lec ing he b oade ela ionship
be ween socie y and heal h sys ems.
Finally, he olume includes a discussion o a ge ed he apies and
molecula pa hways in pulmona y diseases, emphasizing he apid ad ances
in p ecision medicine. The in eg a ion o molecula biology in o clinical
p ac ice has no only expanded ea men op ions bu also ans o med he
e y amewo k o espi a o y disease managemen .

i
Taken oge he , hese con ibu ions p o ide a mul idimensional iew o
heal h: om he molecula mechanisms ha d i e pulmona y pa hologies o
he social de e minan s ha shape heal hca e-seeking beha io and disease
incidence. By b idging clinical, molecula , and sociological pe spec i es, he
olume aims o en ich he ongoing dialogue in heal h sciences, o e ing bo h
heo e ical insigh s and p ac ical implica ions o esea che s, clinicians, and
policymake s.
In doing so, his collec ion highligh s he need o in e disciplina y
collabo a ion o add ess he complexi ies o mode n heal h challenges,
ensu ing ha scien i ic p og ess is aligned wi h he eali ies o human li e
and socie al ans o ma ion.
D . Ul iyya Ja a o a is cu en ly
se ing as a Senio Lec u e a
Aze baijan Medical Uni e si y (since
2023). A he Depa men o Human
Ana omy and Medical Te minology, she
eaches he No mal Physiology cou se
h ough bo h lec u es and p ac ical
classes, p epa es cou se ma e ials, and
designs mid e m and inal exam ques ions
o di e en acul ies. Be ween 2016 and
2023, she lec u ed in Human Ana omy
a he same depa men and con ibu ed o
scien i ic esea ch wi hin he S uden Scien i ic Union. F om 2007 o 2016,
she wo ked as a Human Ana omy lec u e a Aze baijan Medical Uni e si y,
and om 2005 o 2007, she se ed as a eache a he Aze baijan Teache s’
Ins i u e, whe e she augh Basics o Medical Knowledge. Ea lie in he
ca ee , om 1993 o 2005, she wo ked as an Eme gency Doc o a Baku
Medical Eme gency S a ion No.1.
D . Ja a o a began he medical educa ion a Aze baijan Medical
Uni e si y, whe e she ea ned he Fi s Deg ee in Pedia ics (Diploma
o Specialis unde he USSR sys em) be ween 1986 and 1992. She hen
comple ed he in e nship in eme gency medicine a Baku Medical
Eme gency S a ion No.6 in 1992–1993.
She is an ac i e membe o he Aze baijan Scien i ic Socie y o
Ana omis s, His ologis s, and Emb yologis s (since 2019). Fo he
con ibu ions o academic and social ac i i ies, she has been ecognized wi h
se e al hono s, including an Awa d o Ac i e Pa icipa ion in Uni e si y’s
Social and Educa ional Ac i i ies (2019) and he i le o Hono a y Doc o
om Mamun Uni e si y and BZT Tu an Academy.
He language p o iciency includes Aze baijani (na i e), Russian ( ull
p o essional), Tu kish ( ull p o essional), and English (limi ed wo king
p o iciency). She has also ecei ed se e al p o essional ce i ica es, including
pa icipa ion in he 12 h In e na ional Is anbul Scien i ic Resea ch
Cong ess on Heal h Sciences (2023), he OIC Minis e ial S anding
Commi ee on Scien i ic and Technological Coope a ion (COMSTECH,
2022–2023), and ea ning 8 CME c edi s a he Scien i ic-P ac ical Webina
on Cu en Issues in Public Heal h (2021).
ii
CONTENTS
PREFACE .................................................................................................................... iii
CHAPTER 1
THE ROLE OF URBANIZATION IN THE CHANGE OF THYROID CANCER
INCIDENCE ACCORDING TO GENDER IN TURKEY ......................................... 1
Mahi COŞKUN
CHAPTER 2
THE ROLE OF WOMEN’S EMPLOYMENT STATUS IN APPLICATIONS TO
FAMILY PHYSICIANS ...............................................................................................11
Tuba Duygu COŞKUN
CHAPTER 3
TARGETED THERAPIES AND MOLECULAR PATHWAYS IN PULMONARY
DISEASES .................................................................................................................21
D . Se ap DÜZGÜNÇINAR
CHAPTER 4
FIBROTIC LUNG DISEASE IN THE POST-COVID-19 ERA: MECHANISTIC
INSIGHTS AND EMERGING TREATMENTS ......................................................41
D . Se ap DÜZGÜNÇINAR
THE ROLE OF URBANIZATION IN THE CHANGE OF THYROID CANCER INCIDENCE ACCORDING
6
Table 2. Resul s o Spea man’s ho co ela ion analysis on he ela ionship
be ween hy oid cance incidence and u baniza ion in men and women
Va iable p
Thy oid cance incidence in men 0.951** 0.000
Thy oid cance incidence in women 0.944** 0.000
Female/Male hy oid cance incidence a io –0.925** 0.000
**p<0.01
Acco ding o he esul s o he yea -con olled pa ial co ela ion analysis
on he ela ionship be ween hy oid cance incidence and u baniza ion in
men and women, s a is ically signi ican associa ions we e ound be ween
u baniza ion and hy oid cance incidence in men ( = 0.951; p < 0.01), in
women ( = 0.944; p < 0.01), and wi h he emale- o-male hy oid cance
incidence a io ( = –0.925; p < 0.01). The di ec ion o he co ela ion was
posi i e o hy oid cance incidence in bo h men and women, and nega i e
o he emale- o-male incidence a io (Table 3).
Table 3. Resul s o yea -con olled pa ial co ela ion analysis on he
ela ionship be ween hy oid cance incidence and u baniza ion in men and
women
Va iable p
Thy oid cance incidence in men 0.951** 0.000
Thy oid cance incidence in women 0.944** 0.000
Female/Male hy oid cance incidence a io –0.925** 0.000
**p<0.01
Acco ding o he esul s o he Gene alized Linea Model (Logi ) analysis
on he e ec o u baniza ion on hy oid cance incidence in men and women,
he e ec s o u baniza ion we e ound o be s a is ically signi ican o bo h
men (B = 0.616; p < 0.01) and women (B = 2.133; p < 0.01) (Table 4).

MAHIR COŞKUN
7
Table 4. Resul s o he Gene alized Linea Model (Logi ) analysis on he e ec o
u baniza ion on hy oid cance incidence in men and women
Pa ame e BS d.
E o
95% Wald Con idence
In e al Hypo hesis Tes
Minimum Maximum Wald X2d p
MEN
(In e cep ) -39.365 3.870 -46.950 -31.779 103.443 10.000
U baniza ion 0.616 0.054 0.511 0.722 132.190 10.000
(Measu emen ) 0.191 0.081 0.083 0.440
WOMEN
(In e cep ) -134.628 11.992 -158.132 -111.125 126.038 10.000
U baniza ion 2.133 0.169 1.801 2.465 158.472 10.000
(Measu emen ) 3.879 1.330 1.980 7.598
B: Reg ession coe icien , d : Deg ees o eedom.
4. Discussion and Conclusion
In his s udy, he ela ionship be ween u baniza ion and he incidence o
hy oid cance in men and women in Tü kiye was examined, and he changes
in hy oid cance incidence and he p opo ion o he u ban popula ion
be ween 2002 and 2018 we e analyzed. The indings indica ed ha wi h
inc easing u baniza ion, hy oid cance incidence ose in bo h gende s, wi h
he e ec being mo e p onounced in women.
P e ious s udies on hy oid cance gene ally demons a e ha he disease
is mo e p e alen in women compa ed o men (13–15). Al hough he e has
been insu icien esea ch on he dis inc ion be ween u ban and u al a eas,
i can gene ally be s a ed ha access o he heal hca e sys em is easie in
u ban se ings, which may con ibu e o highe p e alence and incidence
a es o diseases. In addi ion, en i onmen al ac o s in u ban a eas may also
in luence disease ou comes. In ou s udy, u baniza ion was ound o ha e a
g ea e impac on women han on men. This esul sugges s ha he e ec
is mo e likely ela ed o diagnos ic sc eenings a he han en i onmen al
in luences in u ban a eas.
Acco ding o he esul s ob ained, u baniza ion had a s a is ically signi ican
posi i e e ec —namely, an inc easing e ec —on hy oid cance incidence
in bo h gende s, wi h he e ec being s onge in women. This inding can be
a ibu ed no o en i onmen al condi ions esul ing om u baniza ion, bu
THE ROLE OF URBANIZATION IN THE CHANGE OF THYROID CANCER INCIDENCE ACCORDING
8
a he o imp o ed access o heal hca e ins i u ions ollowing u baniza ion,
leading o g ea e diagnos ic oppo uni ies. Mo e comp ehensi e and c oss-
sec ional s udies compa ing he e ec s o u baniza ion on bo h en i onmen al
condi ions and heal hca e sys em accessibili y could u he cla i y i s impac
on hy oid cance incidence in bo h gende s.
MAHIR COŞKUN
9
Re e ences
1. Ulisse, S., Baldini, E., Lau o, A., Pi oni, D., T ipodi, D., Lo i, E., ... & So en i, S. (2021).
Papilla y hy oid cance p ognosis: An e ol ing ield. Cance s, 13(21), 5567.
2. Chen, D. W., Lang, B. H., McLeod, D. S., Newbold, K., & Hayma , M. R. (2023). Thy oid
cance . The Lance , 401(10387), 1531-1544.
3. A aque, K. A., Gubbi, S., & Klubo-Gwiezdzinska, J. (2020). Upda es on he managemen
o hy oid cance . Ho mone and Me abolic Resea ch, 52(08), 562-577.
4. C nčić, T. B., Tomaš, M. I., Gi o o, N., & I anko ić, S. G. (2020). Risk ac o s o hy oid
cance : wha do we know so a ?. Ac a Clinica C oa ica, 59(Suppl 1), 66.
5. Pe ei a, M., Williams, V. L., Hallange Johnson, J., & Valde abano, P. (2020). Thy oid
cance incidence ends in he Uni ed S a es: associa ion wi h changes in p o essional
guideline ecommenda ions. Thy oid, 30(8), 1132-1140.
6. Kim, J., Gosnell, J. E., & Roman, S. A. (2020). Geog aphic in luences in he global ise o
hy oid cance . Na u e Re iews Endoc inology, 16(1), 17-29.
7. Wang, J., Yu, F., Shang, Y., Ping, Z., & Liu, L. (2020). Thy oid cance : incidence and mo -
ali y ends in China, 2005–2015. Endoc ine, 68, 163-173.
8. Lincango-Na anjo, E., Solis-Pazmino, P., El Kawkgi, O., Salaza -Vega, J., Ga cia, C., Le-
desma, T., ... & B i o, J. P. (2021). T igge s o hy oid cance diagnosis: a sys ema ic
e iew and me a-analysis. Endoc ine, 72, 644-659.
9. She y, S. S., Deep hi, D., Ha shi ha, S., Sonkusa e, S., Naik, P. B., & Madhyas ha, H.
(2023). En i onmen al pollu an s and hei e ec s on human heal h. Heliyon, 9(9).
10. Manisalidis, I., S a opoulou, E., S a opoulos, A., & Bezi zoglou, E. (2020). En i on-
men al and heal h impac s o ai pollu ion: a e iew. F on ie s in public heal h, 8, 14.
11. Yılmaz K, Tu anlı M. A (2023). Mul i-disciplina y In es iga ion o Linea iza ion De i-
a ions in Di e en Reg ession Models. Asian Jou nal o P obabili y and S a is ics,
29;22(3):15-9.
12. Yilmaz K, Tu anlı M. (2022). A mul i-disciplina y in es iga ion on minimizing linea i-
za ion de ia ions in di e en eg ession models. Change & Shaping The Fu u e, IV.
ASC-2022/Fall Cong ess, ISBN 978-625-8048-99-5
13. Shobab, L., Bu man, K. D., & Wa o sky, L. (2022). Sex di e ences in di e en ia ed hy-
oid cance . Thy oid, 32(3), 224-235.
14. Li, M., Dal Maso, L., & Vacca ella, S. (2020). Global ends in hy oid cance incidence
and he impac o o e diagnosis. The lance Diabe es & endoc inology, 8(6), 468-470.
15. Boucai, L., Za e eo, M., & Cabanillas, M. E. (2024). Thy oid cance : a e iew. Jama, 331(5),
425-435.
11
CHAPTER 2
THE ROLE OF WOMEN’S EMPLOYMENT
STATUS IN APPLICATIONS TO FAMILY
PHYSICIANS
Tuba Duygu COŞKUN1
Abs ac
Objec i e: The aim o his s udy was o examine he ela ionship be ween
applica ions o amily medicine uni s and women’s employmen s a us.
Me hod: In he s udy, da a on applica ions o amily physicians be ween
2008 and 2019 we e ob ained om he Minis y o Heal h S a is ical
Yea books, while da a on emale unemploymen and o e all unemploymen
a es we e ob ained om he Wo ld Bank Coun y Repo s. Co ela ions
be ween he a iables we e analyzed using he co ela ional su ey model.
Resul s: In 2008, he yea amily medicine was i s in oduced, he e
we e 45,111,103 applica ions, which inc eased o 332,907,540 by 2022.
Du ing he same pe iod, he emale unemploymen a e ose om 11.60% in
2008 o 13.42% in 2022. O e all unemploymen , which was 10.97% in 2008,
was 10.43% in 2022, displaying a luc ua ing pa e n. While he numbe o
applica ions o amily physicians inc eased apidly om 2008 un il 2011, i
ollowed a mo e s able cou se om 2012 onwa d. The unemploymen a e
among women o wo king age also showed a luc ua ing end. Resul s o he
1 D ., Minis y o Heal h Van Family Medicine, Van, Tü kiye.
E-mail: [email p o ec ed] | ORCID: 0000-0003-1212-5786

THE ROLE OF WOMEN’S EMPLOYMENT STATUS IN APPLICATIONS TO FAMILY PHYSICIANS
12
Spea man’s ho co ela ion analysis indica ed ha he e was no s a is ically
signi ican ela ionship be ween applica ions o amily physicians and emale
o o e all unemploymen (p > 0.05). Howe e , esul s o he yea -con olled
pa ial co ela ion analysis showed a s a is ically signi ican nega i e
ela ionship be ween applica ion a es o amily physicians and emale
unemploymen ( = –0.595; p < 0.05) as well as o e all unemploymen ( =
–0.643; p < 0.05). Acco ding o he esul s o he Gene alized Linea Model
analysis, emale unemploymen had a s a is ically signi ican and nega i e
e ec on applica ions o amily physicians (B = –2.093; p < 0.05).
Conclusion: Acco ding o he indings, al hough ising emale
unemploymen appea s o educe applica ions o amily physicians, i can
be in e ed ha employed women a e mo e heal h-conscious. Fo ea ly
diagnosis o diseases, imp o ed public heal h, and he e ec i e unc ioning
o amily medicine uni s, i is impo an o each unemployed women and o
p omo e emale employmen .
Keywo ds: Family medicine, applica ions, women’s employmen .
1. In oduc ion
The amily medicine uni is a heal hca e p ac ice ha was i s in oduced
in Tü kiye in 2007 in se en p o inces, and hen implemen ed na ionwide in
2008 (1). Acco ding o he Gene al Di ec o a e o Public Heal h o he Minis y
o Heal h, amily medicine is de ined as uni s p o iding indi idualized
p e en i e heal h se ices, p ima y heal hca e se ices, ehabili a i e heal h
se ices, and, pa icula ly in diagnosis and ea men , add essing all amily
membe s and hei en i onmen (2). Applica ions o amily physicians no
only allow indi iduals o ecei e heal h- ela ed se ices bu also signi ican ly
a ec he p ocess o ea ly diagnosis and ea men o diseases. F om a ional
d ug use (3,4) o adop ing heal hy li es yles (5), and especially in a eas such
as psychological diso de s (6,7), amily medicine plays a c i ical ole in
many impo an heal h- ela ed issues (8).
One o he mos impo an condi ions o amily physicians o ul ill
hei key oles wi hin he heal hca e sys em is he applica ions made o
hese uni s. Conside ing ha he majo i y o socie y belongs o he lowe -
middle income g oup, women’s employmen s a us may play an impo an
ole in de e mining he likelihood o applying o amily physicians. Al hough
s udies ha e been conduc ed on amily medicine, he e is a lack o esea ch
examining he impac o women’s employmen s a us on such applica ions.
The e o e, he aim o his s udy was o in es iga e he ela ionship be ween
applica ions o amily medicine uni s and women’s employmen s a us.
TUBA DUYGU COŞKUN
13
2. Me hods
2.1. Resea ch Model
The esea ch was designed using desc ip i e and co ela ional su ey
models. In his mixed model, he phenomenon is i s desc ibed using
quan i a i e and quali a i e da a, ollowed by an analysis o he ela ionships
be ween a iables (9). In his s udy, he implemen a ion o amily medicine
in Tü kiye and women’s employmen le els o e he yea s we e desc ibed,
and hei ela ionships we e s a is ically analyzed.
2.2. Da a Se
In he s udy, da a on applica ions o amily physicians be ween 2008
and 2019 we e ob ained om he Minis y o Heal h S a is ical Yea books,
while emale unemploymen and o e all unemploymen a es we e e ie ed
om he Wo ld Bank Coun y Repo s. In Tü kiye, amily medicine was
i s pilo ed in he p o ince o Düzce in 2005. In 2006, i was in oduced in
se en p o inces, and in 2008 i was implemen ed na ionwide. The e o e, he
ime se ies o he s udy co e s he pe iod be ween 2008 and 2022, which
co esponds o he mos ecen da a a ailable om he Minis y o Heal h.
The Wo ld Bank unemploymen da a we e ob ained om he da ase s i led
“Unemploymen , emale (% o emale labo o ce) (modeled ILO es ima e)”
and “Unemploymen , o al (% o o al labo o ce) (modeled ILO es ima e).”
2.3. S a is ical Me hod
SPSS 25.0 o Windows was used o da a analysis, and all analyses
we e conduc ed a a 95% con idence in e al wi h a signi icance le el o
0.05. Changes in amily medicine applica ions and unemploymen a es o e
he yea s we e e alua ed using pa i y analysis. In he co ela ional su ey
analysis, due o de ia ions in linea iza ion (10,11), nonpa ame ic es s such
as Spea man’s ho and Gene alized Linea Model (Logi ) analyses we e
employed. To assess he e ec o ime, yea -con olled pa ial co ela ion
analysis was pe o med.
3. Resul
In 2008, he i s yea o amily medicine implemen a ion, he e we e
45,111,103 applica ions, while by 2022 his igu e had inc eased o
332,907,540. Du ing he same pe iod, he emale unemploymen a e ose
om 11.60% in 2008 o 13.42% in 2022. O e all unemploymen , which
THE ROLE OF WOMEN’S EMPLOYMENT STATUS IN APPLICATIONS TO FAMILY PHYSICIANS
14
was 10.97% in 2008, s ood a 10.43% in 2022, wi h unemploymen a es
ollowing a luc ua ing end (Table 1).
Table 1. Numbe o applica ions o amily physicians, emale unemploymen
a e, and o al unemploymen a e by yea
Yea Numbe o applica ions
Female unemploymen
a eᵃ
To al unemploymen
a eᵇ
2008 45.111.103,00 11,60 10,97
2009 65.716.898,00 14,32 14,03
2010 108.976.049,00 13,00 11,88
2011 240.298.753,00 11,29 9,79
2012 221.672.029,00 10,80 9,21
2013 212.318.024,00 11,93 9,71
2014 214.120.750,00 11,91 9,90
2015 208.538.951,00 12,67 10,30
2016 205.549.931,00 13,75 10,90
2017 228.098.527,00 14,11 10,92
2018 258.436.607,00 13,90 10,96
2019 278.043.149,00 16,51 13,73
2020 247.273.830,00 14,98 13,15
2021 239.053.780,00 14,72 11,97
2022 332.907.540,00 13,42 10,43
a. Pe cen age wi hin he emale labo o ce, b. Pe cen age wi hin he o al labo
o ce.
F om 2008 o 2011, he numbe o applica ions o amily physicians
inc eased apidly, while om 2012 onwa d i ollowed a mo e s able cou se.
The unemploymen a e among women o wo king age, on he o he hand,
displayed a luc ua ing end (Figu e 1).
TUBA DUYGU COŞKUN
15
Figu e 1. Change in applica ions o amily physicians and emale
unemploymen le els by yea
The esul s o he Spea man’s ho co ela ion analysis examining he
ela ionship be ween applica ions o amily physicians and emale and o e all
unemploymen le els indica ed ha he e was no s a is ically signi ican
ela ionship be ween applica ions o amily physicians and ei he emale
unemploymen o o al unemploymen (p > 0.05) (Table 2).
TARGETED THERAPIES AND MOLECULAR PATHWAYS IN PULMONARY DISEASES
22
he apeu ic e icacy, while challenges like d ug esis ance, high cos s, and
access dispa i ies pe sis . Fu u e di ec ions emphasize mul i-omic p o iling,
nex -gene a ion he apies, and global heal h equi y o ensu e accessible,
pe sonalized pulmona y ca e.
Keywo ds: Ta ge ed he apies, Molecula pa hways, Pulmona y diseases,
As hma, COPD.
1. In oduc ion
Pas successes in molecula biology, high- h oughpu genomics and
indi idual medicine ha e made i possible o model disease-speci ic
bioma ke s and d uggable a ge s [1]. The esul o hese ools has been
biologic agen s and small-molecule oncology- a ge ed inhibi o s wi h
pa ien speci ici y ha a e mo e e icacious and less oxic [2]. Also, d ug
de elopmen , pa ien s a i ica ion and p edic ion o pa ien he apeu ic
esponse in pulmona y diseases a e being ad anced by a i icial in elligence
(AI), and compu a ional modeling [3, 25]. Wi h such ad ances, howe e ,
pulmona y diseases con inue o exe a la ge heal h bu den wo ldwide, wi h
hund eds o millions o he global popula ion a lic ed and causing a high
le el o mo bidi y and mo ali y as well as spending associa ed wi h ea ing
he illness [4]. As hma, ch onic obs uc i e pulmona y disease (COPD),
idiopa hic pulmona y ib osis (IPF), pulmona y a e ial hype ension (PAH)
and se e al ypes o lung cance (pa icula ly non-small cell lung cance
(NSCLC)) a e he mos common and se ious o hem. Al hough hey a e
dissimila in e iology and clinical mani es a ions, hese condi ions ha e a
common se o pa hological mechanisms: ch onic in lamma ion, issue
emodelling, immune egula ion, and cellula signalling diso de s [4,5].
In he pas , he ea men o pulmona y diseases was dependen on he use
o he b oad-spec um mechanisms such as co icos e oids, b onchodila o s,
and sys em-wide chemo he apy. These op ions ha e been success ul a
con olling symp oms and p olonging su i al, bu in many cases, hese did
no co ec he p oblema ic molecula de ec s ha had mani es ed hemsel es
in o disease p og ession [5,6]. In addi ion, sys emic side e ec s, widely
anging pa ien esponses, and ising esis ance, especially in ch onic and
malignan lung diso de s, a e linked o adi ional he apies [6].
Wi h he ad en o a ge ed he apies, i is possible o change pulmona y
medicine h ough p o iding p ecision-media ed ea men ha would
in e e e wi h a gi en pa h o a pa hogen. Among examples, he e is
monoclonal an ibody di ec ed agains in e leukin (IL)-5 in eosinophilic
as hma [3], y osine-kinase-inhibi o s (TKIs) aimed a EGFR mu a ions in

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NSCLC [6,12] and an i ib o ic agen s ha block ib oblas ac ion in IPF
[4]. Rela i e newcome s including JAK inhibi o s in in lamma o y lung
disease, KRAS G12C inhibi o s like so o asib in lung cance , and inhaled
biologics o deli e d ugs in a mo e ai way-speci ic way a e now in clinical
use [8,10,20,21]. Bu he e a e a numbe o cons ain s ha emain such as
pa ien he e ogenei y in esponse o ea men , cos , poo accessibili y in low-
esou ce a eas, and poo long- e m sa e y da a [11]. I is also impo an o
make he exis ing ange o e ec i e a ge ed he apies bigge by conduc ing
con inuous esea ch in o molecula mechanisms and signalling pa hways
and hus enhancing pa ien ou comes [22].
He e, he e is a de ailed desc ip ion o he molecula pa hways in ol ed
in key lung diseases and a ge ed medicine ha a emp s o media e hese
pa hways. I in es iga es he molecula pa hways speci ic o he disease,
he mechanism o ac ion o he d ug, he e ec i eness o he cu en ly used
ea men , he challenges in ea men , and he esea ch possibili ies ha will
esul in p ecision medica ion in he ield o espi a o y ca e.
2. Unde s anding Pulmona y Molecula Pa hways
Pulmona y pa hologies esul in a complex in e play o in lamma o y
media o s, p o ib o ic signals, immune checkpoin s, and mu a ions in
gene exp ession leading o he occu ence o a disease. These molecula
ne wo ks play impo an oles in he p ecision he apies and he apeu ic
a ge de elopmen s. In his sec ion, a summa y o he ou mos impo an
classes o molecula pa hways in he majo espi a o y diseases includes
in lamma o y signalling, ib o ic emodelling, immune e asion in cance ,
and oncogenic mu a ions.
2.1 In lamma o y Pa hways o Pulmona y Diseases
Ch onic in lamma ion is he basis o such diseases as as hma, COPD, and
in e s i ial lung diseases. Summa izing he key cy okines, he e a e in e leukins
(IL)-4, IL-5, IL-13 and umo nec osis ac o -alpha (TNF-alpha) ha lead
o immune cell in il a ion, mucus sec e ion, ai way hype esponsi eness
and issue des uc ion [1]. Th2 cells p oduce IL-4 and IL-13, whe e IL-4
leads o class change IgE and IL-13 causes goble cell me aplasia and he
emodelling o ai ways [2]. The wo cy okines sha e a common signalling
pa hway h ough he IL-4 ecep o alpha (IL-4R alpha), which is a con i med
a ge o dupilumab since i ge s app o ed o se e e pheno ypes o ype 2
as hma [3]. The IL-5 main ains eosinophil ma u a ion and su i al and
plays a pi o al ole in eosinophilic as hma and exace ba ion. Mepolizumab,
TARGETED THERAPIES AND MOLECULAR PATHWAYS IN PULMONARY DISEASES
24
eslizumab and ben alizumab a e monoclonal IL-5-binding (o ecep o -
blocking) an ibodies ha dec ease a es o exace ba ion and he amoun
o o al co icos e oids [4,5]. In neu ophilic COPD ai ways in lamma ion,
TNF - alpha (TNF- alpha) is also in ol ed, bu an i-TNF ea men s did
no demons a e consis en ou comes ac oss pulmona y condi ions and a e
equen ly abandoned because o ad e se eac ions [6]. Pa hway speci ic
an i-in lamma o y ac ion The e is on-going esea ch on he iden i ica ion o
CXCR2 an agonis s and phosphodies e ase-4 inhibi o s such as o lumilas ,
which a e d ugs which can posi i ely in luence he ou come o COPD [7,
21]. Recen esea ch indica es ha ea men o ups eam ala mins, such as
TSLP (e.g., ezepelumab), can be o wide use han a ge ing downs eam
signals (IL-4/IL-13, IL-5, and IL-5 ecep o , e c.) [8, 22].
2.2. Pulmona y ib osis mani es ed in IPF and in pos -
COVID-19
In e s i ial lung disease shows dis o ed epai p ocesses, ac i a es he
ib oblas popula ion, and excessi ely p oduces he ex acellula ma ix
(ECM). Fib ogenesis is media ed by ans o ming g ow h ac o -be a (TGF-β)
and Wn /B-ca enin signalling [9]. As a mas e egula o , TGF -be a s imula es
epi helial- mesenchymal ansi ion (EMT), myo ib oblas di e en ia ion and
collagen p oduc ion h ough SMAD signalling. An i ib o ic d ugs such as
pi enidone and esolimumab ha e been p oduced o a ge TGF- app oaches
ha we e de eloped o inhibi TGF- his p ocess [10]. Concu en ly, Wn /
be a-ca enin signalling mechanism, which in he no mal adul lung is
quiescen , ge s eac i a ed in an inju ed lung and con ols he p oli e a ion
and cell ma ix syn hesis ansc ip ion. Pa hological Wn signalling is ela ed
o he disease p og ession, which indica es he po en ial o Wn inhibi o y
me hods in he con ex o ib o ic lung diso de s [11]. New ea men s a e
in de elopmen modi ying hese pa hways in o de o s abilize o e e se
ib osis [12, 23], including zil i ekimab and pam e lumab [23].
2.3 Lung Cance Immune Checkpoin s
The immuno he apy has ans o med he he apy o NSCLC. Cance s
la gely a oid immune su eillance h ough he use o he PD-1/PD-L1
pa hway and CTLA-4 pa hways. The exp essed PD-L1 on umou cells
in e ac s wi h PD-1 on ac i a ed T- cell, disabling he T-cell. The monoclonal
an ibodies, including ni olumab, pemb olizumab, and a ezolizumab,
can e e se an i umo ac i i y and exhibi ed signi ican su i al e ec ,
especially in a umou wi h high PD-L1 exp ession [13]. Inhibi o y ecep o s
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Ano he example o checkpoin ecep o , CTLA-4 inhibi s ea ly T-cell
ac i a ion. Added o PD-1 inhibi o s, he immune s imula o y cha ac e is ics
o ipilimumab (an i-CTLA-4) boos immune eac ions and a e ce i ied in
limi ed NSCLC pa ien s [14]. The combina ional app oach is unde ial
wi h chemo he apy, new agen s o ex end he immuno he apy co e age [15].
Checkpoin inhibi o s ha e become he key ac o s in he he apy o NSCLC
and a e cons an ly imp o ing wi h he u he p og ess (IMpowe 110,
CheckMa e 227, and KEYNOTE-189) [16, 24].
2.4 Molecula Mu a ions Resul ing in Lung Cance s
Ac ionable d i e mu a ions in NSCLC ha e been iden i ied using
molecula p o iling hus being ea ed on a ge . The EGFR, ALK
ea angemen s and KRAS mu a ions a e he mos impo an ones.
• EGFR mu a ions a e seen in ~ 20 pe cen o NSCLC cases (pa icula ly,
non-smoke s). Fi s , a hi d-gene a ion TKI, Osime inib, has been able o
eplace such p e ious d ugs as e lo inib and ge i inib because o inc eased
an i- esis ance ac i i y on T790M change [17].
• In ~5 pe cen o he cases, he e is ea angemen o ALK, which is
usually used wi h EML4. Such ac o s as c izo inib, alec inib, and lo la inib
a e d ugs ha inhibi ALK and p olong li e, enhancing ou comes o
p og ession- ee su i al [18].
• KRAS is no longe ega ded as und uggable because he KRAS G12C
inhibi o s, such as so o asib and adag asib can a ge he p e iously un ea able
subpopula ion due o KRAS mu a ions [19, 25]. Cu ing-edge diagnos ic
me hods like nex -gene a ion sequencing (NGS) and liquid biopsies a e now
becoming s anda d in guiding a a ge ed he apy and de ec ing de elopmen
o esis ance [20].
3. Ta ge ed The apies in Speci ic Pulmona y
Diseases
E olu ion o molecula biology and pha macogenomics has changed
he ea men o pulmona y diseases. As an al e na i e o an inde ini e
compensa o y ac o in he o m o nonspeci ically ac ing an i-in lamma o y
d ugs and symp oma ic agen s, mode n pulmonology implemen s p ecision
medicine in he o m o a a ge ed ea men agen complica ing speci ic
molecula mechanisms o he pa hogenesis o he disease. The usage o such
he apies is desc ibed in ela ion o as hma, ch onic obs uc i e pulmona y
TARGETED THERAPIES AND MOLECULAR PATHWAYS IN PULMONARY DISEASES
26
diseases (COPD), idiopa hic pulmona y ib osis (IPF), lung cance , and
pulmona y a e ial hype ension (PAH).
3.1. As hma and COPD: Biologic and An i-In lamma o y
Ta ge s
3.1.1 As hma
IL-4, IL-5 and IL-13-d i en ype 2 in lamma ion de ines he eosinophilic
and alle gic o ms o as hma. Biologic agen s a e now an indi idualized
choice o pa ien s who a e no esponsi e o inhaled co icos e oids and
b onchodila o s.
• Omalizumab is a monoclonal IgG an ibody agains IgE and by so doing
blocks he a achmen o IgE o mas cell. I is licensed o mode a e-and
se e e alle gic as hma and lowe s exace ba ions wi hou inc easing quali y
o li e [1].
• Mepolizumab and eslizumab block IL-5 connec ion, cu ing down
eosinophil ec ui men and su i al. Thei use is ecommended in se e e
eosinophilic as hma as a way o educing he numbe o exace ba ions and
co icos e oid equi emen s [2].
• Ben alizumab is a ecep o -blocking agen speci ic o he alpha-chain
o he in e leukin-5 (IL-5) ecep o and wi hou in e naliza ion, causing
apop osis o eosinophil h ough an an ibody-dependen cell-media ed
cy o oxici y (ADCC), which leads o sus ained and apid emo al o
eosinophil [3]. These d ugs ha e also ans o med he issue o as hma
owa ds pheno ype and endo ype di ec ed app oaches [20].
3.1.2. COPD
Al hough COPD is gene ally cha ac e ized by neu ophil dominance, i
has he subg oup o pa ien s wi h eosinophilic cha ac e is ics who espond
o biologics.
• Mepolizumab has demons a ed small imp o emen s in eosinophilic
subg oups o COPD, especially minimizing he numbe o exace ba ions [4].
• Phosphodies e ase-4 (PDE4) inhibi o s, e.g. o lumilas , ha e no only
shown an i-in lamma o y and an i- emodeling e ec s in se e e COPD wi h
ch onic b onchi is [5], bu also held he ad an age ha o lumilas showed
signi ican e ec s on imp o ing exe cise pe o mance [6]. Agen s unde
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clinical ial (such as CXCR2 an agonis s and IL-33 inhibi o s) a e a ge ed
mechanisms o in lamma o y modula ion in COPD [6, 21].
3.2 Idiopa hic Pulmona y Fib osis (IPF): An i-Fib o ic
The apy
IPF e e s o a p og essi e, incu able in e s i ial lung disease cha ac e ized
by he de elopmen o ib oblas s, ECM and pe manen sca ing o he lungs.
• Nin edanib is a y osine kinase inhibi o and p e en s PDGF, FGF and
VEGF signals. When used as pa o clinical ials like INPULSIS, i has
been demons a ed o educe he loss o FVC by up o 50 pe cen [7].
• Pi enidone down egula es TGF-b exp ession, ib oblas ac i i y and
has shown o be e ec i e in disease p og ession and longe p og ession ee
su i al in ASCEND and CAPACITY ials [8].
Nei he o he d ugs es o es ib osis, bu hey signi y a pa adigm
ex ension o IPF ansla ion. Clinically-de eloped new an i- ib o ic agen s,
including pam e lumab (an i-CTGF), zil i ekimab (an i-IL-6 signaling), and
BG00011 (an i-in eg in ea men ) ha e been de eloped and indica e hope o
a wide impac on ib osis and he achie abili y o a mo e a o able sa e y
p o ile [9, 22].
3.3 P ecision Oncology in Ac ion: Lung Cance
Molecula p o iling and a ge ed ea men has ans o med he ea men
o lung cance , especially non-small cell lung cance (NSCLC).
• Oncogenic signaling is igge ed by EGFR mu a ions, which a e
cha ac e is ic o non-smoke s. TKIs o he hi d gene a ion, including
osime inib, ha e been adop ed as supe io al e na i es o ea lie TKIs,
including e lo inib and ge i inib, because hey pene a e he CNS be e and
a e e ec i e agains T790M esis ance mu a ion [10].
• The p e alence o he ALK ea angemen s is app oxima ely 5 pe cen
o he NSCLC pa ien s. Speci ic TKIs such as alec inib, lo la inib, and
ce i inib a e a majo boos o su i al [11].
• KRAS mu a ions, o me ly no ac ionable, a e ac ionable. Inhibi o s o
KRAS G12C such as so o asib and adag asib ha e success ully been pu in o
clinical applica ions wi h p omising esul s on speci ic pa ien s [12, 23].
• The immune checkpoin inhibi o s, pemb olizumab (PD-1),
a ezolizumab (PD-L1) o ipilimumab (CTLA-4) ha e become he i s -
line s anda d ea men o ad anced NSCLC and especially in high PD-L1

TARGETED THERAPIES AND MOLECULAR PATHWAYS IN PULMONARY DISEASES
28
exp essing umo s. Combina ion he apies e en inc ease he e ec i eness
u he [13, 24].
These he apies a e guided by nex -gene a ion sequencing (NGS) and
liquid biopsies, enabling p ecision- a ge ed ea men s a egies.
3.4 Vasodila o -Ta ge ed The apy in PAHPAH
PAH is an endo helial dys unc ion, ascula emodeling and inc eased
esis ance o he pulmona y ascula u e condi ion. Ta ge ed asodila o
he apies in end o achie e ascula balance.
• Endo helin ecep o an agonis (ERA), including Bosen an,
Amb isen an, and Maci en an, p e en s he p oli e a ion and con ac ion
e ec o endo helin-1 [14].
• Phosphodies e ase-5 (PDE5) inhibi o s sildena il and adala il enhance
he ni ic oxide pa hway h ough cyclic GMP o be e asodila ion and
espi a o y ole ance [15].
• P os acyclin analogs and ecep o agonis s epop os enol, ep os inil
and selexipag es o e asodila ion and block ascula smoo h muscle
p oli e a ion [16].
• Di ec s imula o s o cGMP p oduc ion using soluble guanyla e cyclase
(sGC), e.g. iocigua , a e app o ed in he ea men o PAH as well as ch onic
h omboembolic pulmona y hype ension (CTEPH) [17].
These ea men s enhance hemodynamics, unc ional class, and su i al,
bu p olonged esponse and consis ency plus a ailabili y a e pe sis en
challenges in he clinical p ac ice [25].
4. D ug Deli e y and P ecision Medicine
P ecision medicine is ans o ming he pa adigm o pulmona y
medicine by abandoning symp om-based gene alized ea men s in a o o
pe sonalized ea men s ha ake in o conside a ion genomic, molecula and
pheno yping a ibu es. A he cen e o his ansi ion a e enhanced pla o ms
o d ug deli e y and companion diagnos ics ha imp o e he p ecision o
ea men s, he oxici y and he clinical bene i s [1].
4.1 Biologics and Nanopa icles ia Inhala ion
Con en ional sys emic ea men o any pulmona y disease is usually
hampe ed by inadequa e d ug le els in he lung, sys emic oxici y and low
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e ec i eness. D ugs deli e ed by inhaling each he speci ic a ea o he lung
a ec ed by he pa hology di ec ly and in an o - a ge manne .
4.1.1. Inhaled Biologics
Elsewhe e, RNA he apeu ics and deli e ed monoclonal an ibodies
(mAbs) a e being de eloped o ea diseases such as as hma, idiopa hic
pulmona y ib osis (IPF) and lung cance . The e a e a ew ad an ages o
inhaled biologics:
The local d ug concen a ion is enhanced; he e is less sys emic side e ec s
and acu e ac ion. Tocilizumab is an immune p o ein (in e leukin-6 ecep o -
blocking) which is being es ed in clinical ials agains in lamma o y lung
disease when used by inhala ion. Isola ed ib o ic lungs may ha e a be e
al e na i e adminis a ion ou e, in a enous o subcu aneous adminis a ion
o he d ug, ia inhala ion [2, 16].
Such p oblems encoun e ed wi h ega d o inhaled biologics a e p o ein
s abili y unde nebuliza ion p ocess, immunogenici y educ ion, and pa icle
deposi ion in he sca ed o obs uc ed lung issue [2].
4.1.2. Deli e y Sys em using Nanopa icles
Nanomedicines Nanopa icle (NP) o mula ions exe high p ecision
and con olled deli e y o he apeu ic agen s as liposomes and polyme ic
micelles, solid lipid nanopa icles.
In he case o NSCLC, he o mula ions in oduce nanopa icles con aining
y osine inhibi o s in kinase ecep o s, siRNA, and chemo he apeu ic
p epa a ions, which ha e been ailo ed o imp o e umo speci ici y and
educe side e ec s [3].
In he IPF, inhaled in es iga ional pi enidone-loaded nanogels ci cum en
hepa ic clea ance o a ge he lungs and augmen bioa ailabili y in he lung
[3, 18].
4.1.3. Sma Nanopa icles
The cu en gene a ion o hese nano agen s is able o espond o
mic oen i onmen a ia ions, such as change in pH and oxida i e s ess, o
a pa icula enzyme ac i i y, o a ge hei payload o in lamed o ib o ic
issue selec i ely [3].
TARGETED THERAPIES AND MOLECULAR PATHWAYS IN PULMONARY DISEASES
30
The wo echnologies show he po en ial o enhancing d ug bio-
a ailabili y, inc easing ea men adhe ence and also con ol cos s associa ed
wi h he managemen o ch onic lung diseases.
4.2 Companion Diagnos ics and Genomic P o iling
The in eg a ion o genomic medicine has e olu ionized clinical
decision-making in pulmona y disease, enabling ea men selec ion based
on molecula signa u es.
4.2.1. Genomic P o iling in Lung Cance
Nex -gene a ion sequencing (NGS) is now s anda d in NSCLC o
de ec ing ac ionable d i e mu a ions in EGFR, ALK, ROS1, BRAF, MET,
and RET genes [4].
These bioma ke s guide he use o a ge ed agen s such as TKIs and
immune checkpoin inhibi o s [4].
Liquid biopsies, which de ec ci cula ing umo DNA (c DNA), p o ide
non-in asi e ools o moni o ing umo dynamics, de ec ing esis ance
mu a ions, and adap ing he apy in eal ime [5, 22].
4.2.2. Companion Diagnos ics (CDx)
CDx a e FDA-app o ed es s ha p edic a pa ien ’s likelihood o
esponding o speci ic a ge ed he apies.
EGFR mu a ion es ing is equi ed be o e ini ia ing osime inib.
PD-L1 exp ession sco ing helps assess eligibili y o pemb olizumab and
o he immune checkpoin inhibi o s.
KRAS G12C mu a ion es ing in o ms he use o so o asib o adag asib
[6].
In IPF, bioma ke s p edic ing esponse o nin edanib o pi enidone a e
unde in es iga ion bu no ye s anda dized.
In as hma and COPD, bioma ke s such as blood eosinophil coun s, FeNO
( ac ional exhaled ni ic oxide), and IgE le els suppo s a i ica ion o
biologic he apies like an i-IL-5 o an i-IgE agen s [6].
4.2.3. Fu u e o P ecision Deli e y
Eme ging echnologies a e d i ing he nex e olu ion o pe sonalized
pulmona y ea men :
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AI-powe ed algo i hms in eg a e imaging, clinical, and genomic da a o
p edic ea men esponse and disease p og ession [6, 28].
Gene-edi ing pla o ms like CRISPR-Cas9, deli e ed h ough inhalable
i al o non- i al ec o s, a e being explo ed o co ec disease-causing
mu a ions di ec ly in lung issues.
Wea able senso s and sma inhale s a e enabling eal- ime moni o ing o
lung unc ion, adhe ence, and he apeu ic impac —ushe ing in a new age o
da a-in o med, esponsi e ca e [6, 26].
5. Clinical T ials And Real-Wo ld Da a
A s ong and g owing e idence base consis ing o andomized con olled
ials (RCTs), me a-analyses and eal-wo ld da a (RWD) exis s o suppo
a ge ed he apies in pulmona y diseases. Whe eas RCTs supply egula o y
endo semen and ule-based guidance, he e a e eal-wo ld examina ions
which gi e complimen a y in o ma ion abou long- e m secu i y, indi idual
a iance o pa ien s as well as accessibili y in b oade clinical con ex [1].
5.1. Landma k T ials and Clinical E idence
These ex ensi e and la ge ials ha e esul ed in egula o y app o al and
p ac ice ans o ming sugges ions o se e al pulmona y condi ions:
5.1.1 Idiopa hic Pulmona y Fib osis (IPF)
• INPULSIS-1 and 2 (NCT01335464, NCT01335477): These pi o al
Phase III s udies demons a ed ha nin edanib signi ican ly educed he
annual a e o o ced i al capaci y (FVC) decline in pa ien s wi h IPF,
leading o global app o al [2].
• ASCEND T ial (NCT01366209): Con i med he e icacy o pi enidone
in educing FVC decline and imp o ing p og ession- ee su i al in IPF [2].
5.1.2 Non-Small Cell Lung Cance (NSCLC)
• FLAURA (NCT02296125): Demons a ed ha osime inib, a hi d-
gene a ion EGFR y osine kinase inhibi o (TKI), signi ican ly imp o ed
bo h p og ession- ee su i al and o e all su i al in EGFR-mu a ed
NSCLC compa ed o olde TKIs [2].
• IMpowe 110 (NCT02409342) and KEYNOTE-024 (NCT02142738):
Showed ha a ezolizumab and pemb olizumab, espec i ely, signi ican ly
imp o ed ou comes in ad anced NSCLC wi h high PD-L1 exp ession [2].
TARGETED THERAPIES AND MOLECULAR PATHWAYS IN PULMONARY DISEASES
38
The dawn o biological unde s anding and echnological c ea i i y is
ushe ing in a new age when pulmona y ca e is no only mo e e ec i e, bu
indi idualized. As clinicians, esea che s, policy make s and echnology
de elope s con inue o pa ne oge he in he e o o p o ide all pa ien s
wi h pe son-cen e ed, accessible, and e idence-based espi a o y ca e, he
ou come becomes no me ely achie able, bu una oidable.

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Re e ences:
1. Wenzel SE. As hma: cha ac e izing he ch onic adul pheno ypes. Lance .
2012;380(9851):1033–42.
2. Bel EH, Wenzel S, Thompson PJ, e al. O al glucoco icoid–spa ing e ec o mepoli-
zumab in eosinophilic as hma. N Engl J Med. 2014;371(13):1189–97.
3. Fi zGe ald JM, Bleecke ER, Nai P, e al. Ben alizumab, an an i–in e leukin-5 ecep-
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41
CHAPTER 4
FIBROTIC LUNG DISEASE IN THE POST-
COVID-19 ERA: MECHANISTIC INSIGHTS
AND EMERGING TREATMENTS
D . Se ap DÜZGÜNÇINAR1
Abs ac
COVID-19, caused by SARS-CoV-2, has g ea ly a ec ed he heal h o he
lungs and con inues o lea e a long-las ing impac . Though acu e espi a o y
ailu e and i al pneumonia we e gi en he mos a en ion ini ially, some
pa ien s la e de elop pe sis en in lamma ion, damage o lung s uc u es,
and sca ing in hei lungs. Pos -COVID ib o ic lung disease has become a
mo e widely ecognized condi ion ha can se iously a ec a pe son’s heal h.
When pulmona y ib osis occu s, i causes he lung issue o hicken and sca ,
which can educe he exchange o oxygen and wo sen b ea hing p oblems.
Fib osis is commonly seen in idiopa hic in e s i ial lung diseases (ILDs),
bu i is now hough ha SARS-CoV-2 in ec ion may ini ia e o speed up
ib o ic changes in he lungs h ough a pa icula pa hway in ol ing immune
p oblems, inju y o blood essels, ongoing elease o cy okines, and imp ope
issue epai . Age, p e ious lung disease, a amily his o y o lung p oblems,
and using mechanical en ila ion o a long ime seem o be impo an ac o s
in he de elopmen and p og ession o ib osis a e COVID-19.
1 A Li e Hospi al Kuzey Anka a Has anesi, Anka a, Tu kiye,
[email p o ec ed], ORCID: 0009-0003-3769-7104
FIBROTIC LUNG DISEASE IN THE POST-COVID-19 ERA: MECHANISTIC INSIGHTS AND EMERGING
42
The chap e explo es in de ail he ac o s and e en s ha cause ib o ic
disease o he lungs a e COVID-19. Ini ially, we analyze he sp ead
o ib osis and he people who ha e been mos a ec ed a e an in ec ion
wi h SARS-CoV-2. A e wa d, we explo e he main pa hways in ib osis,
including hose in ol ing TGF-β, ib oblas s imula ion, myo ib oblas
de elopmen , and changes in he ex acellula ma ix. Va ious ools used o
examine and diagnose pa ien s, such as HRCT, pulmona y unc ion es ing,
and bioma ke s, a e desc ibed as ways o ell pos -COVID ib osis apa
om o he ILDs. The chap e co e s he main ways o ea ing pulmona y
ib osis, such as co icos e oids, an i- ib o ic d ugs, and ehabili a ion o
oxygen he apy. Meanwhile, we s udy new and upcoming ea men s such as
hose based on s em cells, an i ib o ic d ugs, and medicine ha uses a i icial
in elligence and genomics.
This s udy also discusses he impac o long- e m lung ib osis on public
and heal hca e sys ems in people who had COVID-19. We e iew a eas
whe e knowledge is missing, sugges u u e opics o clinical s udies and
desc ibe how o spo , isk assess and manage hea disease ea ly, combined
wi h a ious medical eams. The chap e aims o gi e clinicians, esea che s
and policy-make s a clea and p ac ical amewo k by combining knowledge
o disease pa hways wi h new e idence on ib o ic pulmona y complica ions
a e he pandemic.
Keywo ds: Ta ge ed he apies, Molecula pa hways, Pulmona y diseases,
As hma, COPD.
1. In oduc ion
Because o he COVID-19 pandemic, global in ec ious diseases a e now
di e en and he disease can lead o se ious heal h issues ha las o a long
ime (1,2). A i s , medical p o essionals ocused on ARDS, in ensi e ca e
ea men and how he i us sp eads, bu i is now ob ious ha SARS-CoV-2
in ec ion may esul in ch onic lung p oblems (3,4). Fib o ic lung disease
esul s in sca ing, educed abili y o he lungs o expand and con ac , and
poo gas exchange (5).
In mos cases, pulmona y ib osis occu s when abno mal collagen and
o he ma e ials a e deposi ed in he spaces be ween he ai sacs in he lungs
(6). Such changes esul in pe manen damage o he lung s uc u e, loss
o i s uni s and a g adual ailu e o exchange oxygen (7). While ib osis is
a ypical ea u e o ILDs such as IPF, sys emic scle osis-associa ed ILD
and hype sensi i i y pneumoni is, i appea ing a e SARS-CoV-2 in ec ion
ep esen s an inno a i e and esh medical challenge (8,9).
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43
In he beginning o he pandemic, doc o s obse ed g ound-glass
opaci ies, o ganizing pneumonia pa e ns and hickening inside he lungs
in pa ien s wi h mode a e o se e e COVID-19 (10,11). Following ini ial
s udies, i has been ound ha some pa ien s s ill ha e hese abno mali ies
o hey may de elop in o ib osis mon hs a e ge ing be e (12–14). The
p ecise p ocesses a e no ye comple ely unde s ood, bu hey a e belie ed
o in ol e p oblems wi h he immune sys em, “cy okine s o ms” (mainly
in ol ing in e leukin-6, TNF-α and TGF-β), ha m o epi helial cells in he
lungs and ine ec i e healing o wounds in he lungs (15,16). They can be
u he inc eased by ac o s like being e y old, ha ing a high amoun o
he i us, a his o y o smoking, diabe es, and using in asi e mechanical
en ila ion (17,18).
I is challenging o doc o s o ecognize and diagnose pos -COVID
ib o ic lung disease. Some imes, exe ional dyspnea, d y cough, ell pos -
COVID ib osis apa om o he ongoing lung diseases, doc o s ely on he
pa ien ’s his o y, de ailed images, lung unc ion es s and some imes examine
issue samples (19,20). As a esul , i is essen ial o indi iduals wi h lung
diseases o be ca ed o by pulmonologis s, adiologis s, in ec ious disease
specialis s, and ehabili a ion p o essionals (21,22). Managing he apy is
also a challenging p ocess.
Co icos e oids ha e helped in he ea ly s ages o COVID-19, bu i is s ill
unclea i hey a e use ul in managing o p e en ing ib osis in he long un
(23,24). Nin edanib and pi enidone which we e designed o IPF, a e being
s udied in people su e ing om pos -COVID condi ions (25,26). Ye , he
success a e o ea men s, he iming o hei use, who should ecei e hem
and in o ma ion on hei long- e m sa e y a e s ill lacking (27,28). In addi ion,
esea che s a e explo ing me hods such as s em cell he apy, epigene ic
echniques and AI o add ess he sho comings in ea men (29,30).
This means ha he consequences o pos -COVID ib osis impac mo e
han jus he heal h o indi idual pa ien s. As many people a ound he wo ld
eco e om COVID-19, heal hca e sys ems a e now dealing wi h he
combined e ec o long- e m lung p oblems (31). Thus, pa ien s mus ge
long- e m ea men , isi specialized doc o s when need, use pulmona y
ehabili a ion and ecei e ai access o ea men s whe e esou ces a e
low (32,33). This chap e aims o ho oughly e iew ib o ic lung disease
as one o he pos -COVID complica ions. We will examine he sp ead o
he disease, he body p ocesses in ol ed, i s symp oms, how o diagnose i
and a ailable ea men s. In addi ion, we will examine ongoing expe imen al
ea men s and poin ou some impo an ques ions ha scien is s ha e ye o

FIBROTIC LUNG DISEASE IN THE POST-COVID-19 ERA: MECHANISTIC INSIGHTS AND EMERGING
44
answe . We aim o gi e clinicians, scien is s and heal hca e policymake s he
unde s anding needed o de ec , manage and lessen he long- e m e ec s o
COVID-19 on he lungs.
2. Unde s anding Epidemiology and I s Clinical
Signi icance
Fib o ic lung disease has ecen ly become a signi ican conce n o people
dealing wi h COVID-19. Pulmona y ib osis was p e iously ied o ILDs,
en i onmen al exposu es, immune sys em dys egula ion, and medica ions
wi h po en ial pulmona y oxici y (e.g., chemo he apeu ic agen s like
bleomycin, amioda one, ni o u an oin, and me ho exa e) (9,10); howe e ,
he SARS-CoV-2 i us has added a new eason (1,2,5). This has equi ed us
o conside ib o ic disease epidemiology once again, conside ing he global
sp ead o he i us, he di e en se e i y o he disease, and how people om
di e en g oups handle i .
2.1 How common is his disease?
I is di icul o es ima e he impac o COVID-19 on pulmona y ib osis
because he pandemic’s dynamics con inue o e ol e, some people do no
ha e equal access o heal hca e, and he e a e no common guidelines o
diagnosing pos - i al ib osis (1,3,4). E en so, s udies and egis y indings
sugges ha many pa ien s who had mode a e o se e e COVID-19 now show
in e s i ial changes in hei lungs, and some o hese changes may become
ib o ic (6,7). Repo s di e , bu be ween 10% and 30% o COVID-19
pa ien s who a e hospi alized de elop ib osis on adiology images wi hin 3
o 6 mon hs o being discha ged (6).
The s udy in Wuhan, China, e ealed ha 29% o pa ien s who le he
hospi al a e eco e ing om COVID-19 showed ib o-like changes on
ollow-up HRCT images (6). The e ha e been cases in Eu ope and No h
Ame ica whe e olde pa ien s and hose ecei ing in ensi e ca e o en ila ion
showed ac ion b onchiec asis, e icula opaci ies, and pa enchymal bands
on imaging (3,6,7). You should also ell apa ansien ib o ic-like changes
om p og essi e ib osis. Some lung p oblems may clea up as ime goes
on, bu in hose wi h p io lung disease, a weak immune sys em, o who had
se e e ARDS, some issues may no imp o e o may e en wo sen (1,4,5).
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2.2 Risk Fac o s A ec ing he Whole Popula ion
Acco ding o esea ch, ce ain ac o s make i mo e likely o SARS-
CoV-2 in ec ion o esul in ib o ic lung disease (3,5,6,8).
• Being olde han 60 inc eases he isk o in ec ion because olde people
ha e less abili y o eco e om damage, highe le els o in lamma ion, and
less lung capaci y. Se e e COVID-19 ha equi es ICU, special en ila ion,
o needs oxygen o a long ime o en esul s in long- e m changes in he
lungs.
• Ha ing ch onic obs uc i e pulmona y disease, as hma, hea disease,
obesi y, diabe es melli us, and au oimmune illnesses can inc ease he isk o
COVID-19 (5,6).
• Some esea che s belie e ha gene ic ac o s such as hose in he MUC5B
and TERT genes could in luence he de elopmen o ib o ic changes a e
COVID-19 (11).
• Sex and E hnici y: Acco ding o some s udies, males and indi iduals
o ce ain e hnici ies seem o ha e mo e cases o ib osis, al hough he
easons may be ela ed o unequal access o heal hca e. Addi ionally, ac o s
such as high i al load du ing he disease, his o y o in ensi e ca e uni
admission and in asi e mechanical en ila ion, p olonged hospi al s ay,
como bid condi ions (e.g., hype ension, ca dio ascula diseases), ad anced
age, diabe es, and smoking his o y signi ican ly con ibu e o he isk o
de eloping pos -COVID ib o ic lung disease (1,5,6).
2.3. How he Disease Impac s Pa ien s and Thei
Quali y o Li e?
When a pe son de elops ib osis a e COVID-19, i is o en a majo
heal h p oblem. Those wi h pos -COVID ib o ic lung disease end o
con inue expe iencing symp oms such as:
• Di icul y in b ea hing due o physical ac i i y
• A cough ha does no lead o he emo al o mucus
• Pain in he ches
• Fa igue
• A dec ease in he amoun o exe cise a pe son can do
They may con inue o a long ime, and in some si ua ions, hey can ge
wo se as ime passes (1,6,7). In many cases, pulmona y unc ion es s indica e
FIBROTIC LUNG DISEASE IN THE POST-COVID-19 ERA: MECHANISTIC INSIGHTS AND EMERGING
46
a es ic i e b ea hing pa e n, dec eased abili y o abso b oxygen om he
lungs (DLCO), and d opping oxygen sa u a ion as indi iduals exe cise (3,6).
HRCT imaging plays a key ole in iden i ying and measu ing he ib osis
in a pa ien . The indings may consis o :
• T ac ion b onchiec asis
• Re icula ions
• Honeycombing (when he cance is ad anced)
• The e is ib osis a ound he lungs
• F equen a eas o g ound-glass opaci y ha g adually de elop in o
ib osis.
In addi ion, some o hese changes can appea like hose in o he ib osing
ILDs, so i ’s necessa y o diagnose he disease and obse e i s p og ession
accu a ely (4,6). Pos -COVID pulmona y ib osis can g ea ly impac a
pe son’s quali y o li e (1,5,6).
Many people wi h COVID-19 may ha e las ing p oblems wi h hei
heal h, eel dis essed psychologically, and a e unable o go back o wo k o
lead a egula daily li e. I becomes mo e di icul o people in hese g oups
since ollow-up, ehabili a ion, and access o long- e m medicine may no be
a ailable (8,12).
2.4 Heal h Challenges Faced by People in Di e en
Coun ies
E en a small isk o ib osis in COVID-19 su i o s means a signi ican
p oblem o he wo ld. The e is a isk ha millions o people wo ldwide,
who we e in ec ed ea ly in he pandemic wi hou access o accines and
be e he apies, could su e om long- e m b ea hing issues (1,6,8). Now,
heal hca e sys ems ha e o deal wi h bo h immedia e COVID-19 and u u e
complica ions om COVID-19 and ib osis. This includes:
• Se ing up clinics ha ocus on pa ien s a e COVID and de eloping
ollow-up plans
• C ea ing guidelines o sc een indi iduals who a e mo e likely o ge
COVID-19
• S eng hening he aining and equipmen used o bo h lung images and
es ing
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• Inc easing he chances o people o ecei e an i- ib o ic d ugs and
ehabili a ion se ices (3,8,12)
The e ec o pos -COVID ib o ic lung disease could be e en s onge
and longe o people in low- and middle-income coun ies, whe e heal hca e
is no as widesp ead (1,12,13). As a esul , public heal h app oaches should
i he needs o each egion and be a ailable wi h he esou ces on hand
(12,13).
3. Wha Happens in he Lungs wi h Pos -Co id
Pulmona y Fib osis?
Lung sca ing a e ge ing SARS-CoV-2 in ol es ongoing in lamma ion,
changes in he immune sys em, ha m o he ai sacs, and pe manen changes
in he connec i e issue suppo ing he lungs. Al hough ib osis is no a
common p oblem o all COVID-19 pa ien s, i occu s o en in people who
ha e a se e e o c i ical in ec ion. To imp o e ea men and p edic he
ou come o pos -COVID ib ogenesis, we mus i s unde s and he biology
and chemis y behind i in ulne able indi iduals. The sec ion discusses he
di e en biological p ocesses ha can lead o ib osis a e in ec ion wi h
COVID-19. I co e s he immune-in lamma o y p ocess, damage o bo h
epi helial and endo helial cells, signalling pa hways ha p oduce ib osis,
and ac o s ha in luence a pe son’s isk (6,11,13).
3.1 The p oblem wi h Cy okine S o m and Immune
Dys egula ion
Expe iencing a se e e o m o COVID-19 o en leads o a “cy okine
s o m,” which is a hype in lamma o y s a e. The phenomenon is de ined
by a ise in he blood le els o p o-in lamma o y cy okines, including IL-6,
IL-1β, TNF-α, and GM-CSF. They ini ia e and boos a se e e in lamma o y
eac ion in he body ha upse s he balance o he immune sys em in he
lungs (6,9,11).
High le els o cy okines in he lungs lead o damage o he al eola
epi helium, inc eased leakage o luids om blood essels, and he a i al o
neu ophils and mac ophages in o he al eoli. As a esul , damage occu s in
he lungs’ small ai sacs (DAD), hyaline memb anes o m, and i epai ails,
ib op oli e a ion occu s (6,9). Ce ain ypes o monocy es and mac ophages
wi h p o- ib o ic p ope ies elease TGF-β, IL-13, and pla ele -de i ed
g ow h ac o (PDGF), encou aging ib oblas s o become ac i e and deposi
collagen (6,11).
FIBROTIC LUNG DISEASE IN THE POST-COVID-19 ERA: MECHANISTIC INSIGHTS AND EMERGING
54
By s udying clinical pheno ypes, doc o s can adjus ea men and es ima e
how he disease will de elop (25). New ypes o ib o ic diseases appea ing
a e COVID a e:
• Wi h he ib oin lamma o y pheno ype, he e is ac i e in lamma ion
along wi h ib osis, which co icos e oids o immunomodula o s may help
o e e se (26)
• Fib o ic p og ession: The condi ion con inues o wo sen wi h ime, e en
wi h ea men , and may bene i om an i- ib o ic agen s (27)
• Residual ib osis ha does no ge wo se and does no cause any decline
in unc ion—should be managed conse a i ely(28)
Such amewo ks will play a bigge ole as pe sonalized medicine
de elops in ca ing o pa ien s wi h lung diseases.
In sho , de ec ing pos -COVID ib o ic lung disease as soon as possible
can g ea ly imp o e ou comes. Clinicians should be on he lookou o
lung complica ions in pa ien s wi h ongoing b ea hing di icul ies a e
COVID-19(2,6,9). By using de ailed imaging, pulmona y unc ion es s,
analyzing bioma ke s and including di e en specialis s, a comple e
app oach o diagnosis is ollowed. When we be e unde s and pos - i al
ib o ic condi ions, we can de elop in e en ions and ools ha i each
pa ien ’s needs.
5. How T ea men Wo ks Today?
T ea ing ib o ic lung disease a e COVID-19 b ings many p oblems o
heal hca e p o ide s. Unlike IPF, whe e an i- ib o ic d ugs ha e shown some
success in slowing de elopmen (6), he ib osis ha ollows COVID-19 is
mo e di e se and usually in ol es con inuous in lamma ion, ongoing illness
om he i us, and di e en pa e ns o eco e y (10,18). Consequen ly,
he apies should change wi h he pa ien , ocus on hei needs, and ely
on bo h how hings unc ion and wha is seen in p ac ice. In his sec ion,
we ake a close look a he a ious d ug ea men s, suppo i e ca e, and
ecen indings om he eal wo ld abou managing pos -COVID pulmona y
ib osis.
5.1. Co icos e oids and An i-in lamma o y Medicines
Co icos e oids a e s ill widely used o ea he lung in lamma ion seen
in COVID-19, mainly in he i s and second s ages. They help educe he
damaging e ec s o cy okines on he lungs, lessen he amoun o luid in

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he al eoli, and p o ec issue om damage by he immune sys em (3,11).
Co icos e oids can help speed up eco e y in pa ien s wi h o ganizing
pneumonia o mixed in lamma o y in e s i ial pa e ns a e COVID (12).
Pa ien s who ecei e 6 mg o dexame hasone each day o up o 10 days
and a e hospi alized wi h COVID-19 show be e su i al a es i hey
need oxygen o mechanical en ila ion (2). S ill, i ’s no clea how much i
con ibu es o long- e m ib o ic complica ions.
The e idence o co icos e oids in he ea ly ib o ic s age a e COVID is
s ill de eloping and unce ain, mainly o pa ien s wi h ongoing in lamma ion
o o ganizing pneumonia (12,17). Unde hese ci cums ances, a doc o migh
gi e p ednisone, beginning wi h 0.5–1 mg/kg each day, depending on he
HRCT esul s and bioma ke s.
S ill, aking co icos e oids o a long ime can cause p oblems such as
weakened immuni y, changes in glucose le els, bone hinning, and emo ional
issues. Tha ’s why i ’s impo an o use clinical judgmen and wa ch he
pa ien closely. A his ime, no ag eemen exis s on whe he o use s e oids
in pa ien s wi h ad anced, non-in lamma o y ib osis o UIP-like pa e ns
(6).
The use o mac olide an ibio ics ( o example, azi h omycin), colchicine,
and TNF-α inhibi o s in ea ing pos -COVID in lamma o y lung disease is
being explo ed, bu he e isn’ enough in o ma ion ye (13). T ials ahead will
be impo an o unde s anding hei place, especially in pa ien s wi h a mix
o in lamma o y and ib o ic changes.
5.2 An i- ib o ic Medica ions
Because o hei success in ea ing idiopa hic pulmona y ib osis, an i-
ib o ic he apies a e now ou inely used in p og essing ib o ic in e s i ial
lung diseases (PF-ILDs), including pos -COVID ib osis (6,14).
Pi enidone and nin edanib, which a e cu en ly used in he ea men
o IPF, a e being s udied in people su e ing om pos -COVID condi ions
(14,15).
Since he pandemic, se e al clinical ials ha e been examining how well
i wo ks. I seems ha pi enidone could help main ain lung capaci y and
slow down any adiological damage in hose wi h lung ib osis, and dec ease
DLCO (15,16). This medicine may cause an upse s omach, ash, i edness,
and changes in li e enzymes, so people ecei ing i mus be ca e ully
obse ed (6).
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Nin edanib blocks y osine kinases ha con ol he pa hways linked o
ib oblas ac i a ion, including hose in ol ing PDGF, FGF, and VEGF
(6,18). The d ug is also app o ed o IPF and non-IPF ib osing ILDs ha
p og essi ely wo sen.
In 2022, esea che s began looking a how INBUILD migh be applied o
people wi h ib o ic lung disease a e COVID-19 (19). Ini ial esul s sugges
ha lung unc ion may be s abilizing, mainly in people wi h NSIP-like o
UIP-like HRCT pa e ns (18).
Pa ien s may expe ience dia hea, changes in li e enzyme le els, nausea,
and an inc eased isk o bleeding due o nin edanib, especially i hey a e on
an icoagulan s (6).
Though hese d ugs a e exci ing, hey a e no o icially app o ed o use
in ib osis a e COVID-19 in mos pa s o he wo ld (14,19). A his poin ,
no andomized con olled ials ha e shown ha hese medica ions wo k
well in his popula ion. As a esul , hey should be ese ed o pa ien s who
ha e wo sening ib o ic disease despi e aking co icos e oids o who canno
ole a e p olonged s e oid ea men (15).
D ug choices should be chosen o each pa ien sepa a ely, and i is bes i
ILD specialis s a e pa o he decision-making eam.
5.3 Suppo i e The apies
Owing o he unce ain p og ess o pos -COVID pulmona y ib osis,
suppo i e ca e is impo an o sus aining a good quali y o li e, p e en ing
isks, and imp o ing how pa ien s manage daily ac i i ies (10,20).
Pulmona y ehabili a ion is a key ea men o people wi h ch onic
espi a o y diseases (21). Typically, ailo ed p og ams consis o he
ollowing:
• Exe cises done wi h he guidance o a aine , p ac icing b ea hing
exe cises
• Ad iso y se ices o ea ing a well-balanced die
• Help wi h men al heal h.
Fo pos -COVID pa ien s, ehabili a ion esul s in be e abili y o
exe cise, use oxygen, s eng hen muscles, and eel be e emo ionally (21,22).
P og ams a e bes s a ed 4–8 weeks a e in ec ion and should con inue o
6–12 weeks, wi h egula checks (21).
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Many indi iduals wi h ib o ic lung disease o en need o use oxygen
he apy, whe he hey a e mo ing o es ing (10). Indica ions include:
• A es o when walking, SpO₂ d ops below 88%
• Hypoxemia ha occu s du ing sleep
• Fading colo sa u a ion du ing he 6-minu e walk es .
People who ecei e long- e m oxygen he apy because o low oxygen
le els o en li e longe and unc ion be e each day, bu some may ind ha
i causes hem o mo e less and eel less happy (20).
Mos pa ien s wi h pos -COVID ib osis ha e been diagnosed wi h
ca dio ascula disease, diabe es, anxie y, dep ession, and decondi ioning
(23). I is impo an o ac i ely con ol hese como bidi ies o imp o e a
pa ien ’s lung unc ion.
Recei ing accina ions ( o lu, pneumonia, and COVID-19) is impo an
o help s op u he in ec ions ha can wo sen sca ing in he lungs (24).
5.4 P oblems wi h Da a and T ea men
Al hough mo e a en ion is being gi en o pos -COVID pulmona y
ib osis, he e a e s ill no many la ge-scale, long- e m s udies abou i (25).
• No e e y pa ien wi h ib osis p og esses; i is ha d o ell which pa ien s
will s ay s able and which will ge wo se.
• The e a e no s anda d ules o ea ing hese condi ions: T ea men
plans di e g ea ly om one place o ano he (26).
• An i- ib o ic d ugs a e o en oo expensi e o pa ien s and a e a ely
co e ed by insu ance when used o o he diseases (27).
• I is possible ha people’s symp oms a e w ongly associa ed wi h
gene al a igue o anxie y, which may pos pone he co ec diagnosis and
ea men (10).
The e is a lack o pos -COVID ib osis pa ien s om low- and middle-
income coun ies in esea ch, which educes how well he indings can be
applied o o he s (28).
A numbe o ials, including NCT04607928 and NCT04541680, a e
in es iga ing an i- ib o ic, immunomodula o y, and new biologic d ugs o
ib osis a e COVID-19 (15,19). Regis ies like he UK In e s i ial Lung
Disease COVID-19 egis y a e gi ing us use ul in o ma ion on ea men s
and ou comes (18).
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All in all, doc o s use he same app oach as o ILD, bu mus also
conside he unique way pos -COVID pulmona y ib osis a ec s pa ien s.
T ea men wi h co icos e oids may imp o e in lamma o y o ms o he
disease, bu u he s udies a e needed o de e mine i an i- ib o ic agen s
can help wi h ib osis (6,14,15). Using suppo i e he apies is impo an o
bo h main aining unc ions and imp o ing li e quali y (20,21). Nex , well-
designed clinical s udies and he addi ion o eal-wo ld da a will play an
impo an ole in shaping use ul guidelines o his complex pulmona y issue
(25–28).
6. Looks a New and Expe imen al Fo ms o
The apy
The medical ield is unde p essu e o c ea e new and eliable ea men s
o pos -COVID pulmona y ib osis. Since co icos e oids and epu posed
an i- ib o ic agen s ha e hei own limi a ions, he e is a need o new
app oaches ha mo e p ecisely add ess he main ib ogenic pa hways and
ha e ewe side e ec s (3,5).
This chap e explo es he p og ess o new and expe imen al
ea men s, co e ing nex -gene a ion an i- ib o ics, s em cell he apies,
immunomodula o s, biologics and imp o emen s in pe sonalized and
p ecision medicine (6,14,22).
O e all, hese he apies he ald a new app oach o handling ib o ic lung
disease a e he pandemic.
6.1 An i-Fib o ic Compounds A e Being Tes ed in T ials
The e a e se e al in es iga ional d ugs being es ed, bo h in labs and in
humans, o see i hey can a ge ib o ic pa hways wi h mo e p ecision han
he i s an i- ib o ic d ugs (6,17,22).
PBI-4050, a no el d ug o G-p o ein coupled ecep o s (GPR40,
GPR84), dec eases in lamma ion and ib osis in animal es s by blocking he
ac i a ion o ib oblas s and he p oduc ion o collagen (17). The esul s om
ea ly human ials in IPF sugges ha he ea men is sa e and may be use ul
o ea ing pos -COVID ib osis (17,22).
O iginally in oduced o IPF, PRM-151 is a ecombinan human
pen axin-2 p o ein ha plays a ole in con olling mac ophage ac ion and
emodeling issue (17). I helps keep epai p ocesses no mal and p e en s
excessi e ib osis by adjus ing monocy e- o- ib ocy e di e en ia ion. Ea ly
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esul s om Phase 2 ials sugges ha ib o ic ILD ea men could be use ul
and u u e s udies a e planning o look a i s use a e COVID-19 (17).
Mac ophages and ib oblas s can exp ess galec in-3 which encou ages
bo h in lamma ion and ib osis. Some inhibi o s such as belapec in and
TD139 (GB0139) ha e been shown o limi he exp ession o genes ha
p omo e sca ing in he lungs and ea ly es s on hese d ugs a e being ca ied
ou in people wi h lung ib osis (18).
LOXL2 is a p o ein ha encou ages he s i ening o issues by helping
collagen c oss-link. In lab animals, sim uzumab has been ound o slow
ib osis, bu in he ea ly es ing on people, he esul s ha e no been consis en .
Mo e wo k is being done in pos - i al ib o ic models (17).
6.2 The apy using S em Cells
One o he mos exci ing pa hs in egene a i e pulmona y medicine is
using MSCs o help epai he lungs and con ol he immune esponse (19,22).
MSCs possess:
• The abili y o educe he ac ion o in lamma o y cy okines
• Pa ac ine signaling, which helps issues epai by eleasing g ow h
ac o s
• Sa e o al eola epi helial and endo helial cells, p e en ing hem om
cell dea h.
You can ge hese cells om bone ma ow, adipose issue, o he umbilical
co d, and hey a e mos o en injec ed in o he ein. Upon eaching inju ed
lung issue, hey elease exosomes and in e ac wi h nea by cells o wo k
(19,20).
Doc o s a e es ing COVID-19 ea men s in clinical ials. In ea ly-
phase s udies (like NCT04276987 and NCT04333368), MSCs we e used
on pa ien s wi h se e e COVID-19 and i was ound ha hey imp o ed
oxygena ion, lowe ed in lamma o y ma ke s and allowed pa ien s o lea e
he ICU soone (19,20).
Mos o he s udies we e on acu e lung inju y, bu hei esul s can be used
o pos -COVID ib osis ea men s (19,22). A majo p oblem is inc easing
p oduc ion, keeping cells consis en and igu ing ou he bes imes, amoun s
and ways o deli e ea men s. E en so, MSC he apy may ha e he po en ial
o change he cou se o ib o ic lung disease.

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6.3 Immunomodula o y The apies
T ea men s ha con ol he immune sys em may help p e en pos -
COVID ib ogenesis (14,21).
Janus Kinase (JAK) inhibi o s in e e e wi h he in e nal signalling o
di e en p o-in lamma o y cy okines such as IL-6, IFN-γ and GM-CSF.
Thus, hese d ugs can help educe he ea ly swelling ha causes ib osis (21).
Ba ici inib is being used o hospi alized COVID-19 pa ien s and migh
help p e en las ing heal h p oblems. Long- e m an i ib o ic e ec s o
pi enidone a e being s udied in animal models wi h pos - i al ILD (5,14).
IL-6 is impo an in causing COVID-19 cy okine s o ms and may help
c ea e a ib o ic en i onmen . Tocilizumab which a ge s IL-6, has been
b oadly used o ea acu e COVID-19 (3,14). I is s ill unce ain whe he
supp essing IL-6 o a long ime can s op ib osis, bu s udies a e being done
o ind ou (14).
Al hough esul s wi h TNF-α inhibi o s in ib o ic diseases a e inconsis en ,
new agen s ha a ge TGF-β, such as esolimumab and SB-525334, a e
cu en ly being s udied (17,21). TGF-β is in ol ed in many issue epai
p ocesses, so di ec ly blocking i is isky, bu using i locally o unde con ol
may imp o e bo h sa e y and success.
6.4 Biologics and Monoclonal An ibodies
Biologic he apies can a ge ib osis p ecisely and migh s op i om
s a ing a i s beginning (6,14,17).
In pa icula , in eg in α β6 p omo es he ac ion o la en TGF-β and
becomes mo e ac i e in he lungs du ing ib osis. BG00011, which a ge s
α β6, is cu en ly being in es iga ed in IPF and may be used o ea pos -
COVID ib osis. An i-CTGF is he name gi en o his d ug (17).
T ea men wi h pam e lumab, which a ge s CTGF, may lead o slowe
a es o FVC loss in IPF. Since i wo ks in andem wi h TGF-β blockade, i
could be use ul in he i s s ages o ib osis (17).
New he apies ha ocus on FAP, a sign o ac i a ed ib oblas s, may help
des oy only ib ogenic cells while lea ing no mal lung unc ion in ac . We
ha e no eached clinical ials wi h his s a egy ye , bu i could be use ul
in he u u e (18).
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6.5 Pe sonalized and P ecision Medicine Me hods
Because pos -COVID ib osis is so di e en om case o case, p ecision
medicine is becoming mo e impo an o ea men (22,23,24).
Because o ad ances in genomics, ansc ip omics, and p o eomics,
scien is s can now iden i y di e en molecula sub ypes o ib o ic disease. A
high le el o p o- ib o ic genes (such as COL1A1 o ACTA2) o ib ogenic
miRNAs (such as miR-21 o miR-199a) could help choose he bes he apy
and iden i y pa ien s a highe isk (23,24).
AI-based adiomics can measu e how se e e ib osis is, guess how i will
wo sen, and ell apa ib o ic om in lamma o y changes seen on HRCT
(25). Resea che s a e building machine lea ning models using huge imaging
collec ions o help c ea e pe sonalized ea men schedules and check how
well pa ien s a e esponding (25).
The combina ion o se um bioma ke s like KL-6, MMP-7 and YKL-40
wi h clinical symp oms may one day help clinicians choose pa ien s who will
bene i om an i-in lamma o y, an i- ib o ic o egene a i e ea men s (26).
E en hough hese new he apies hold p omise, mos a e s ill in he ea ly
s ages and mus be es ed u he by RCTs and be in eg a ed wi h eal pa ien
da a (3,17,22). The ields o e hics, cos , scalabili y and long- e m sa e y a e
always opics o conce n. S ill, he as pace o inno a ion due o COVID-19
has made pulmona y ib osis esea ch mo e impo an .
Now, i is mo e impo an han e e o pulmonologis s, immunologis s,
bioenginee s and da a scien is s o collabo a e. O e all, he bes app oach
o pos -COVID ib o ic lung disease will be h ough combining inno a ion,
pe sonaliza ion and p ecision (6,23,26). The ield o he apeu ics is g owing
quickly due o new small molecules, biologics, s em cell he apy and AI-
d i en es s. As we change ou app oach o ca e, hese new ools may be
able o s op ib osis and help millions o people eco e hei lung heal h
wo ldwide.
7. Wha Can Happen A e T ea men , Risks, and
Las ing Ca e?
Pos -COVID pulmona y ib osis pa ien s a e s ill being s udied long- e m,
as he e is ongoing unce ain y abou hei ou look. While ce ain pa ien s ge
be e slowly o emain s able, o he s con inue o ha e wo sening symp oms,
mo e ib ous sca ing, and issues in mul iple sys ems ha a ec hei li es and
use mo e esou ces (16,17). Now, he main goals in pos -COVID espi a o y
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ca e a e o p edic ou comes, de ec high- isk pa ien s ea ly, and use planned
ollow-up s a egies (17).
He e, we examine he esul s and p og ession seen in pa ien s, how
common i is o hem o ha e addi ional diseases and wha is ecommended
o hei ongoing ca e. I also looks a he e ec s hese indings ha e on he
heal hca e sys em dealing wi h long- e m COVID-19 issues (17).
7.1 P og ess Made and Resul s
Because o di e en ways o de ining he disease, a mix o pa ien s, and
a lack o long- e m s udies, i is di icul o ully g asp he na u al his o y o
pos -COVID ib osis ully (18). E en so, ecen obse a ional s udies and
ini ial coho analysis a e now e ealing pa e ns in he da a (18).
In some cases, pa ien s ha e HRCT indings including g ound-glass
opaci ies and e icula ions ha disappea wi hin 3–12 mon hs (4,8,13). These
esul s may sugges o ganizing pneumonia, sca ing a e in lamma ion, o
incomple e eco e y om ARDS, a he han ue ib osis. Some pa ien s
expe ience s able ib o ic changes ha do no p og ess u he and usually
esul in mild o mode a e disabili y (13,16).
In some cases, ib osis wo sens, as seen by wo sening images, dec easing
lung unc ion, g ea e need o oxygen, and less abili y o exe cise. This
ype o issue change esembles idiopa hic pulmona y ib osis and o he PF-
ILDs (13,15,16).
Es ima es om la es esea ch:
• Be ween 25% and 30% o people who spend ime in he hospi al wi h
COVID-19 show abno mali ies sugges ing ib osis on imaging 6 mon hs
a e in ec ion (15,18).
• Abou 10–15% o hese pa ien s may expe ience wo sening ib osis,
esul ing in ongoing unc ional p oblems a e 12 mon hs (13,15).
• The chance o p og ession inc eases o people who needed mechanical
b ea hing suppo , su e ed om mul iple o gan ailu e, o had a lung disease
be o e ea men (17,18).
To make hese es ima es, esea che s use da a om he UKILD Pos -
COVID S udy, COMEBAC S udy, and analyses o ea ly COVID cases in
China (13,18).
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7.2 Complica ions in he Body
Pos -COVID pulmona y ib osis is uncommon by i sel . People wi h hese
condi ions also o en deal wi h addi ional medical p oblems ha make he
disease wo se, speed up hei decline, and inc ease hei isk o dying (16,17).
Respi a o y Como bidi ies:
• Ch onic Obs uc i e Pulmona y Disease (COPD): People wi h COPD
may de elop ib osis in hei lungs a e COVID-19, which makes i ha de
o hem o b ea he and exchange gases (10,15).
• Obs uc i e Sleep Apnea (OSA) is common among obese and pos -
COVID indi iduals, which can esul in mo e hypoxemia a nigh , mo e
i edness, and make ea men mo e di icul (10,16).
Ca dio ascula Complica ions:
• Pulmona y Hype ension (PH): Na owing and sca ing o blood essels
in he lungs, along wi h hypoxic cons ic ion, can cause high p essu e in he
a e ies, esul ing in igh hea s ain ha may ail wi hou ea men (12,14).
• Fib osis can be ound wi h o make wo se pos -COVID condi ions
such as myoca di is, a hy hmias, and hea ailu e. Dyspnea and a igue,
which a e seen in bo h diseases, mus be ca e ully dis inguished by di e en
specialis s (12,16).
B ain og, dep ession, anxie y, and PTSD a e o en seen in people
eco e ing om se e e COVID-19 (6,9,16). They in luence how well
ea men is ollowed, how much someone can do, and how good hei li e is.
Au onomic dys unc ion, especially POTS, can make i ha de o ib o ic
pa ien s o s ay ac i e (6,9).
Acu e kidney inju y (AKI) ha occu s du ing hospi aliza ion aises
he isk o ch onic kidney disease (CKD) la e on, and his CKD p oblem
in e ac s wi h ib osis by making i di icul o ake medica ions such as
an i ib o ics and diu e ics (6,10,14).
• In lamma ion and wo se ou comes o en happen because diabe es and
insulin esis ance, which COVID-19 and co icos e oid use can cause o
wo sen, a e in ol ed (6,11,14).
Add essing all hese issues oge he is e y impo an o helping ib o ic
pa ien s li e be e and longe (16,17).
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8.4.5 Imp o e Resea ch, Moni o ing, and Da a Technology
• In oduce na ional egis ies o moni o he sp ead, de elopmen , and
esul s o ib osis a e COVID
• Hold unding o s udies ha las se e al yea s and include RCTs o
add ess pos - i al ib o ic ILDs
I is impo an o p omo e he sha ing o global da a and use common
epo ing o shape policies in e na ionally (19,20,21)
8.4.6 Encou age Coope a ion Among Coun ies and Collec
Funds
• Team up wi h g oups such as he WHO, UNICEF, and he Global Fund
o ackle pos -COVID ib osis wi hin eco e y plans o he pandemic
• Encou age help om in e na ional dono s o se ing up ch onic disease
p og ams in weak heal h sys ems
• P omo e esea ch cen e s wo ldwide ha wo k on bo h pulmona y
ib osis and egene a i e lung medicine (19,21)
8.5 Wo king Towa d a Fai App oach o Heal h A e he
Pandemic
The las ing e ec s o COVID-19 a e changing wha public heal h
ocuses on. Jus as he i s wa e o COVID-19 equi ed a s ong esponse,
pos -COVID pulmona y ib osis dese es he same conside a ion (6,8).
Neglec ing ch onic espi a o y ca e may esul in people expe iencing se ious
disabili ies, a he han he clea e ec s o a i al pandemic. A c ucial pa o
his p ocess is accep ing ha COVID-19 su i o s will need li elong sys ems
o suppo and manage hei heal h and possibly help e e se damage caused
by he disease. I is impo an o go e nmen s o ex end heal h co e age o
co e ch onic espi a o y illnesses, gi e inancial help o equi ed ea men s
and o m communi y suppo s. Sys ems o heal h ca e should change om
eac ing o eme gencies o handling bo h sudden and ongoing h ea s while
s ill looking a e a - isk popula ions. Because pulmona y ib osis is a global
issue, jus like COVID-19, he solu ions should be sha ed, e ec i e ac oss
coun ies, and in ol e e e yone (6,21,28).

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9. Conclusion
COVID-19 has deeply changed ou knowledge o in ec ious diseases and
he long- e m ou comes o people wi h lung disease. Fib o ic lung disease
is one o he many se ious esul s o SARS-CoV-2 in ec ion and is di icul
o ea since i can cause many heal h issues h oughou he body (1,6,11).
As he chap e explained, he e a e many di e en o ms o pos -COVID
pulmona y ib osis. I co e s a ange om changes ha can be e e sed o
hose ha become pe manen and look simila o well-known in e s i ial
lung diseases (6,7,10). Vi al damage o cells, p oblems wi h he immune
sys em, damage o cells lining blood essels and he lungs, poo healing,
and o e ac i e TGF-β and ib oblas s all play a ole in he disease (4,12,13).
A pa ien ’s ou comes a e also in luenced by hei own gene ics, any o he
heal h p oblems and sys emic di icul ies (6,15).
When managing pos -COVID ib osis, clinicians ely on de ailed imaging,
assessmen s o unc ion and ca e ul classi ica ion o ell apa linge ing
in lamma ion om ac ual ib osis (7,17). Doc o s ely on co icos e oids and
agen s ha we e o iginally made o ea ing ib osis, bu i is impo an o
use hem wisely, based on e idence and acco ding o each pa ien ’s needs
(18,19). Ha ing pulmona y ehabili a ion, oxygen he apy and psychosocial
ca e is key o keeping people heal hy and happy (20). The chap e has also
poin ed ou ha he e a e now a wide ange o expe imen al he apies being
de eloped, including an i- ib o ic d ugs, in e en ions wi h s em cells,
immunomodula o s, and monoclonal an ibodies (21–23). These me hods
seem p omising, ye mos a e s ill in he ea ly s ages and mus be es ed
ca e ully using adap i e clinical ials, egis ies and ansla ional esea ch
(24).
In addi ion o medical ea men , pos -COVID ib osis has se ious
public heal h e ec s. Because o he pandemic, many heal h sys ems a e
managing a high numbe o pa ien s who need long- e m ca e o espi a o y
illnesses, and his is happening amid p essu ed esou ces and a ying access
(1,9,25). In low- esou ce a eas, many people canno ge access o he ools
and ea men s hey need (25). Fo his eason, global heal h policy should
apidly add pos -COVID ib osis o i s policies o ch onic diseases, unding,
medicines, and ehabili a ion (26).
As we look o wa d, he bigges di icul y is o ill he esea ch gaps ha
s op us om p edic ing, p e en ing and ea ing pos -COVID ib o ic lung
disease. P io i ies include:
FIBROTIC LUNG DISEASE IN THE POST-COVID-19 ERA: MECHANISTIC INSIGHTS AND EMERGING
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• Expe imen s ha explain disease p ocesses h ough molecula and
cellula app oaches
• Following pa ien s o e ime o lea n abou hei disease and how hey
espond o ea men
• Looking o bioma ke s o de ec disease ea ly and ailo ea men o
each pe son
• Technology ha helps wi h diagnosis, p edic ion o ou comes, and
ea men decisions
• Adding people om di e en pa s o he wo ld o ials o ensu e
e e yone is ep esen ed (24,26,27)
We need o ely on esh ideas, eamwo k and kindness o mo e ahead.
Expe s in pulmonology, in ec ious diseases, ehabili a ion, da a science, and
policymaking should uni e o design ca e models ha add ess bo h science
and wha COVID-19 su i o s go h ough (9,11,23).
Pos -COVID pulmona y ib osis may emain a long- e m e ec o he
pandemic, ye i can also lead o p og ess. We ha e a chance o eno a e he
way ch onic diseases a e ea ed, build be e in as uc u e o espi a o y
heal h and ensu e ha all pa ien s a e ca ed o du ing a global eme gency
(24,26). I we join o ces, ca y ou ocused s udies and a e dedica ed o
equal heal h ca e, we can change his p oblem and ensu e he su i o s a e
no de ined by hei sca s om he pandemic.
Impo an ly, pos -COVID pulmona y ib osis is no limi ed o i al damage
and lung sca ing; i highligh s he way biological isk, heal hca e a ailabili y,
scien i ic adap abili y, and unequal socie y in luence he disease (6,25,26). I
demons a es ha a single disease can poin ou he s eng hs and weaknesses
in ou in e na ional heal hca e and esea ch sys ems (25). This condi ion
calls o doc o s o adjus hei way o diagnosing. Now, any symp oms ha
doc o s once hough we e only i edness o psychological should igge
comp ehensi e checks, eam e alua ions and p omp ac ions (9,19). Because
o pos -COVID ib osis, physicians mus use hei expe ience while also
welcoming new disco e ies and s anda ds o ca e (13,20). This momen is
e y impo an o esea che s. Because pos -COVID complica ions a e so
u gen , scien is s om many ields such as immunology, molecula biology,
AI and da a science a e now collabo a ing mo e han e e (21,22,27). Wha
we ha e achie ed so a mus no be was ed; i should be used o help ede ine
ch onic lung disease esea ch going o wa d. Go e nmen agencies, medical
jou nals and uni e si ies should keep suppo ing esea ch in his ield o
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add ess he a e ma h o COVID-19 and o de elop ools o handling u u e
espi a o y h ea s (24,27,28).
Fo hose who lead and decide in public heal h, pos -COVID pulmona y
ib osis poin s o he need o heal h equi y. This condi ion will no a ec
e e yone in he same way. Unless we ac , hose who cu en ly lack HRCT,
medicine, o ehabili a ion will su e he mos (25,26). The pandemic should
lead o new ways o p o iding, unding, and making a ailable ch onic
espi a o y ca e in places whe e heal h sys ems a e weak (25). Su i o s
should be included, lis ened o, and gi en he powe o make decisions in
hei ongoing igh . Wha indi iduals wi h men al illness go h ough and how
hey communica e should guide he way esea ch, ea men , and suppo
a e planned (26,28). They a e pa ne s in seeking ou be e solu ions o
ongoing heal h conce ns.
All in all, he appea ance o ib o ic lung disease in he pe iod a e
COVID-19 p esen s a ough clinical p oblem and a one-o -a-kind chance
o s udy and ea i . A no el lung disease is eme ging all a ound us, in
many di e en places, ields, and heal hca e sys ems. The way we eac
will in luence he heal h o COVID-19 su i o s and p o e he s eng h and
compassion o doc o s wo ldwide (1,6,10). This chap e is mean o inspi e
us o keep lea ning, ca ing mo e, building be e sys ems, and making su e
we s ay commi ed o healing a e he i us is gone (28).
FIBROTIC LUNG DISEASE IN THE POST-COVID-19 ERA: MECHANISTIC INSIGHTS AND EMERGING
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