J. B ea h Res. 11 (2017)047103 h ps://doi.o g/10.1088/1752-7163/aa7957
PAPER
E ec s o g ow h and aging on he e e ence alues o pulmona y
ni ic oxide dynamics in heal hy subjec s
M Högman
1
, A Tho nad sson
1,2
, P Li
2
, T Hua-Huy
3
, A T Dinh-Xuan
3
, E Tu esson
4
, H D essel
5
, C Janson
1
,
K Koskela
6
, P Oksa
6
, R Sauni
6
, J Ui i
6
, E Moilanen
7
and L Leh imäki
8
1
Dep . o Medical Sciences, Respi a o y, Alle gy and Sleep Resea ch, Uppsala Uni e si y, Uppsala, Sweden
2
Cen e o Resea ch and De elopmen , Uppsala Uni e si y/Region Gä lebo g, Sweden
3
Dep . o Respi a o y Physiology, Medical School, Pa is Desca es Uni e si y, Pa is, F ance
4
Dep . o Clinical Sciences Lund, Respi a o y Medicine and Alle gology, Lund Uni e si y, Sweden
5
Epidemiology, Bios a is ics and P e en ion Ins i u e, Di ision o Occupa ional and En i onmen al Medicine, Uni e si y o Zu ich,
Zu ich, Swi ze land
6
The Finnish Ins i u e o Occupa ional Heal h, Tampe e, Finland
7
The Immunopha macology Resea ch G oup, Facul y o Medicine and Biosciences, Uni e si y o Tampe e School o Medicine and
Tampe e Uni e si y Hospi al, Tampe e, Finland
8
Alle gy Cen e, Tampe e Uni e si y Hospi al; and Facul y o Medicine and Biosciences, Uni e si y o Tampe e, Tampe e, Finland
E-mail: [email p o ec ed]
Keywo ds: b ea h es , ni ic oxide, ma hema ical model, heal h, pulmona y gas exchange
Supplemen a y ma e ial o his a icle is a ailable online
Abs ac
The lung jus like all o he o gans is a ec ed by age. The lung ma u es by he age o 20 and age- ela ed
changes s a a ound middle age, a 40–50 yea s. Exhaled ni ic oxide (F
E
NO)has been shown o be
age, heigh and gende dependen . We hypo hesize ha he ni ic oxide (NO)pa ame e s al eola NO
(C
A
NO), ai way flux (J
aw
NO), ai way di using capaci y (D
aw
NO)and ai way wall con en (C
aw
NO)
will also demons a e his dependence. Da a om heal hy subjec s we e ga he ed by he cu en
au ho s om hei ea lie publica ions in which heal hy indi iduals we e included as con ol subjec s.
Heal hy subjec s (n=433) anged in age om 7 o 78 yea s. Age-s a ified e e ence alues o he NO
pa ame e s we e significan ly di e en . Gende di e ences we e only obse ed in he 20–49 age g oup.
The esul s om he mul iple eg ession models in subjec s olde han 20 yea s e ealed ha age,
heigh and gende in e ac ion oge he explained 6% o a ia ion in F
E
NO a 50 ml s
−1
(F
E
NO
50
),4%
in J
aw
NO, 16% in C
aw
NO, 8% in D
aw
NO and 12% in C
A
NO. In conclusion, in his s udy we ha e
gene a ed e e ence alues o NO pa ame e s om an ex ended NO analysis o heal hy subjec s. This
is impo an in o de o be able o use hese pa ame e s in clinical p ac ice.
In oduc ion
The use o non-in asi e me hods o diagnose espi a-
o y diseases and moni o ea men is ad an ageous
o bo h pa ien s and heal hca e p o essionals. Exhaled
ni ic oxide (F
E
NO)has been used ex ensi ely since i s
disco e y in human b ea h [1], especially in as hma
whe e clinical p ac ice guidelines ha e al eady been
published [2]. The pulmona y ni ic oxide dynamics
models ha e he ad an age o being a mo e p ecise
assessmen o ni ic oxide (NO)dynamics, bu hei
applica ion has been limi ed [3]. The echnical de elop-
men has apidly e ol ed and oday we ha e NO
analyse s adop ed o clinical use, bo h in specialized
espi a o y medicine andp ima y ca e [4,5].
F
E
NO om one single exhala ion will gi e a mea-
su ed alue o NO p oduc ion om he en i e espi a-
o y sys em. A mo e de ailed insigh can be gained
h ough he use o he ma hema ical wo-compa men
model (2CM)o pulmona y NO dynamics, which di -
e en ia es he NO exchange o he pe iphe al and cen-
al pa s o he lung and explains he flow dependence
o F
E
NO [6,7].Inb ie , he2CMconsis so anal eola
compa men comp ising he pe iphe al gas exchanging
pa s o he lung ( espi a o y b onchioles and al eoli)
and an ai way compa men comp ising he conduc i e
OPEN ACCESS
RECEIVED
1 May 2017
REVISED
13 June 2017
ACCEPTED FOR PUBLICATION
14 June 2017
PUBLISHED
13 Sep embe 2017
O iginal con en om his
wo k may be used unde
he e ms o he C ea i e
Commons A ibu ion 3.0
licence.
Any u he dis ibu ion o
his wo k mus main ain
a ibu ion o he
au ho (s)and he i le o
he wo k, jou nal ci a ion
and DOI.
© 2017 IOP Publishing L d
ai ways la ge han espi a o y b onchioles. Gas in he
al eola compa men holds a ce ain concen a ion o
NO (C
A
NO). Du ing exhala ion, al eola gas a els
h ough he b onchial compa men and mo e NO di -
uses om he b onchial wall in o he luminal gas (ai -
way NO flux, J
aw
NO)[8].C
A
NO and J
aw
NO can be
es ima ed based on a linea model i F
E
NO is measu ed
a h ee flow a es a o leas 100 ml s
−1
[9].I aflow a e
less han 30 ml s
−1
is used oge he wi h a median and a
high flow a e,i.e.100and300mls
−1
, hen a non-linea
model can be applied which also es ima es he ai way
wall concen a ion o NO (C
aw
NO)and he di using
capaci y o NO om he ai way wall o he gas s eam
(D
aw
NO)[8,10]. In es iga ions ha e used he 2CM wi h
in e es ing esul s, especially o C
A
NO whe e inc eased
alues ha e been ound in se e e as hma [11], al eoli is
[12], and ch onic obs uc i e pulmona y disease [10,13]
and ea ly scle ode ma [14].C
A
NO has been specifically
used o iden i y scle ode ma pa ien s a high isk o
lung unc ion de e io a ion and ad ancing disease, wi h
5.3 ppb being sugges ed as he cu o alue [15].
Re e ence alues a e necessa y o any new
me hod o be accep ed in clinical p ac ice, and e e -
ence alues o F
E
NO a he ecommended flow o
50 ml s
−1
(F
E
NO
50
)ha e been published [16,17].
Heigh , age and gende ha e been shown o influence
F
E
NO
50
. Re e ence alues o NO pa ame e s om
ex ended NO analysis a e limi ed o wo publica-
ions, one wi h 89 adul s [18]and one wi h 66
child en [19]. The lung ma u es by he age o 20 in
ega d o closing olume [20]and in olde age he
di using capaci y declines in a linea ashion wi h
inc easing age [21], and hese changes in pulmona y
physiology migh also a ec NO pa ame e s. The
aimo hiss udywas oes ablish e e ence alues o
NO pa ame e s in heal hy subjec s anging om
young o old age.
Me hods
Subjec s
Da a om heal hy non-smoking subjec s we e ga he ed
by he cu en au ho s om hei ea lie publica ions in
which heal hy indi iduals we e included as con ol
subjec s [10,14,18,19,22–30]. In he majo i y o hese
s udies measu emen s o lung unc ion and symp om
ques ionnai es e ified he heal h s a us. Gende , age
and heigh we e no ed. The exhaled flow oge he wi h
co esponding exhaled NOle elswe e collec ed.
NO analysis
F
E
NO
50
and F
E
NO alues om exhala ion wi h flows o
5–500 ml s
−1
o he ex ended NO analysis we e ga h-
e ed. All da a we e ecalcula ed ei he wi h he linea
model (Tsoukias & Geo ge, TG)[9]using h ee flow
a es o a leas 100 ml s
−1
o wi h he non-linea model
(Högman-Me iläinen Algo i hm, HMA)[10,22]using a
low flow a e o 5, 10 o 20, a median a e o 100 and a
high flow a e o 300, 400 o 500 ml s
−1
. Da a we e ed
in o an algo i hm in a s anda d Mic oso ® Excel
en i onmen , a ailable as supplemen a y in o ma ion,
o he es ima ion o he NO pa ame e s (s acks.iop.
o g/JBR/11/047103/mmedia). When gene a ing NO
pa ame e s om he linea model [9],Pea son’s - alue
was no ed. Wi h he use o NO pa ame e s om he
non-linea model [10,22]aplo o flow wi h co esp-
onding NO alues can be gene a ed; a a flow o
50 ml s
−1
, a NO alue was no ed and compa ed o he
measu ed F
E
NO
50
o a quali y con ol o he es ima ion
o he NO pa ame e s. Wi h he non-linea model he e
is also a buil -in quali y es o he cu e [10].Thisisin
line wi h he fi s guidelines o he ex ended NO
analysis [31].
S a is ical analysis
Due o aging o he lung, he subjec s we e di ided in o
h ee age g oups, <20 yea s, 20–49 yea s and 50
yea s. Desc ip i e da a o he subjec s a e p esen ed as
equency o as medians and qua iles whe e app o-
p ia e. The dis ibu ions o he NO pa ame e s,
s a ified by age g oups, a e p esen ed as an a i hme-
ical mean o geome ical mean ( o skewed dis ibu-
ed da a)and as 2.5 h, 5 h, 25 h, 50 h, 75 h, 95 h,
97.5 h pe cen iles. A K uskal-Wallis es and one-way
ANOVA we e used o es o di e ences in he
dis ibu ion o NO pa ame e s be ween he age
g oups. In he case o significan di e ence be ween
age g oups, pos -hoc es s we e pe o med using a
pai wise Mann-Whi ney U- es . Pea son Co ela ion
was used o es co ela ions o C
A
NO. Spea man’s
ank o de co ela ion was used o he o he NO
pa ame e s.
Gende -s a ified simple eg ession models we e
fi ed wi h he loga i hms o F
E
NO
50
,C
aw
NO, D
aw
NO,
and J
aw
NO, espec i ely, as he dependen a iable,
and wi h age as an independen a iable. Loga i h-
mically scaled eg ession lines we e e ans o med
back in o na u al scale and all eg ession lines we e
hen plo ed along wi h hei co esponding 95%
e e ence in e als.
Mul iple eg ession modelling was pe o med on
da a whe e subjec s younge han 20 yea s we e exclu-
ded, as child en di e om adul s in ega ds o he
ela ionship be ween age and heigh , which made i
di ficul o fi obus s a is ical models. The models
we e specified wi h he C
A
NO in na u al scale, he
loga i hms o F
E
NO
50
,C
aw
NO, D
aw
NO, and J
aw
NO,
espec i ely, as he dependen a iable, and wi h age,
heigh and gende , including in e ac ion e ms
be ween gende
*
heigh and gende
*
age, as indepen-
den a iables. Fo all he models, ANOVA chunk es s
we e pe o med, join ly es ing i he wo in e ac ion
e ms con ibu ed significan ly o he models as com-
pa ed o omi ing hem om he model. As his was
no he case o any o he NO pa ame e s, he models
we e efi ed wi hou he in e ac ion e ms. To
2
J. B ea h Res. 11 (2017)047103 M Högman e al
accoun o a po en ial clus e e ec in he da a, we
also con olled o s udy cen e and es ima ion
me hod (TG e sus HMA). To help he in e p e abili y
o eg ession coe ficien s, he a iables age and heigh
we e cen ed and age was scaled o a uni o 10 yea s
and 10 cm espec i ely [32]. Fo he ac o gende , B
ep esen s he expec ed a io in geome ical means
be ween a male and a emale, keeping all o he a i-
ables fixed. Fo he loga i hmically ans o med pa a-
me e s, eg ession coe ficien s ha e been
e ans o med o na u al scale using he exponen ial
unc ion. The boo s ap p ocedu e p oduces op i-
mism-co ec ed es ima es o R
2
, wi h a co ec ion ac-
o based on he a e age di e ence, in o e 5000
boo s ap samples, be ween he R
2
o he model fi o
he boo s ap da a and he R
2
o he boo s ap model
applied o he o iginal da a.
Model assump ions o no mali y and homo-
scedas ici y o esiduals we e assessed om g aphs. A
p- alue <0.05 was conside ed s a is ically significan .
Excel (Mic oso
R
O fice 2011)was used o calcula-
ions o he NO pa ame e s. S a is ical analyses we e
pe o med using SPSS, . 22 (SPSS Inc., Chicago, MI,
USA), and R [33]using he ms package [34].
Resul s
Heal hy subjec s (n=433)aged be ween 7–78 yea s
we e analysed. The e we e mo e men (n=268) han
women (n=165)( able 1). The e was no di e ence in
F
E
NO
50
be ween he s udy cen es (p=0.37).
The NO pa ame e s we e es ima ed using he lin-
ea model TG (n=87)wi h an - alue om 0.90 o
1.0, and wi h a median alue o 1.0 (0.99, 1.0). In he
non-linea model HMA (n=346), all passed he buil -
in quali y es . The di e ence in measu ed and es i-
ma ed F
E
NO
50
anged om −5.0 o 5.0, wi h a median
alue o 0.3 (−0.6, 1.3)ppb.
NO pa ame e s in he di e en age g oups
The e we e s a is ically significan di e ences in he
dis ibu ion o he NO pa ame e s be ween he young,
middle and olde age g oups ( able 2).F
E
NO
50
was
highe in he olde age g oup compa ed o he young
age g oup (p<0.001)and he middle age g oup
(p=0.001), and F
E
NO
50
was highe in he middle age
g oup han he younge age g oup (p<0.001).J
aw
NO
was lowe in he young age g oup compa ed o he
middle age (p<0.001)as well as he olde age g oup
(p<0.001).C
aw
NO was highe in he olde age g oup
compa ed o he young age g oup (p<0.001)and he
middle age g oup (p<0.001), and C
aw
NO was highe
in he middle age g oup han in he younge age g oup
(p<0.001).D
aw
NO was lowe in he olde age g oup
compa ed o he young age g oup (p=0.023)and he
middle age g oup (p=0.001).C
A
NO was lowe in he
middle age g oup compa ed o he young age g oup
(p=0.001)and he olde age g oup (p<0.001).
NO pa ame e s in he di e en age g oups by gende
The e was only a di e ence be ween gende s in he
middle age g oup in F
E
NO
50
(p<0.001),J
aw
NO
(p<0.001),C
aw
NO (p<0.001)and C
A
NO
(p=0.027)bu no in D
aw
NO ( able 3).
Reg ession analyses
Rela ionships be ween age and he NO pa ame e s
(J
aw
NO, C
A
NO, D
aw
NO and C
aw
NO), wi h uni a ia e
eg ession lines and es ima ed 95% e e ence in e als,
a e shown in figu e 1.F
E
NO
50
is shown in he
supplemen a y ma e ial, a ailable online.
The mul iple eg ession analyses, wi h he boo -
s ap alida ion s ep, showed in he age g oups abo e
20 yea s ha age, heigh and gende in e ac ions oge-
he explained 6% o a ia ion in F
E
NO
50,
4% in
J
aw
NO, 16% in C
aw
NO, 8% in D
aw
NO and 12% in
C
A
NO ( able 4). Age was a significan p edic o in all
models (p<0.001)excep o J
aw
NO (p=0.18)
( able 4). The associa ion was posi i e o F
E
NO
50
and
all NO pa ame e s. Gende con ibu ed as a significan
main e ec o C
aw
NO and C
A
NO only. Mul iple lin-
ea eg ession models poo ly p edic ed he la ge a ia-
ions in F
E
NO
50
and NO pa ame e s.
In he age g oup <20 yea s he e we e only 83 sub-
jec s and he e o e mul iple eg ession models we e no
applied. Age co ela ed posi i ely o F
E
NO
50
( =0.31,
p=0.005)and o J
aw
NO ( =0.32, p =0.003).The e
we e s onge co ela ions be ween heigh and F
E
NO
50
( =0.45, p <0.001),andheigh andJ
aw
NO ( =0.41,
p=0.001), while no co ela ions we e ound be ween
heigh and C
A
NO, C
aw
NO and D
aw
NO.
Table 1. Subjec cha ac e is ics in he di e en age g oups p esen ed by gende .
Age g oup
<20 y s 20–49 y s 50 y s
Gende Female Male Female Male Female Male
Subjec s, n 41 42 82 113 42 113
Age, yea s 10 (9, 11)10 (8, 12)33 (26, 40)39 (30, 44)53 (52, 60)56 (52, 65)
Heigh , m 1.39 (1.32, 1.47)1.37 (1.31, 1.49)1.68 (1.64, 1.71)1.81 (1.75, 1.85)1.67 (1.63, 1.69)1.76 (1.72, 1.80)
Weigh , kg 34 (30, 38)32 (28, 39)60 (55, 68)80 (73, 87)70 (61, 76)79 (73, 88)
BMI, kg/m
2
17 (16, 19)17 (16, 19)22 (20, 23)25 (23, 26)25 (23, 27)26 (24, 28)
Da a a e gi en in median (25, 75 pe cen ile).
3
J. B ea h Res. 11 (2017)047103 M Högman e al
Discussion
In his s udy we ha e gene a ed e e ence alues o
NO pa ame e s om an ex ended NO analysis o
heal hy subjec s. By pooling he heal hy subjec s’da a
om ea lie published da a he alues o NO pa a-
me e s o a la ge g oup o subjec s can be p esen ed.
We ha e ound ha age influences F
E
NO and all he
NO pa ame e s, while gende a ec s NO pa ame e s
only in he middle age g oup. Mul iple linea eg es-
sion models poo ly p edic ed he la ge a ia ions in
F
E
NO
50
and NO pa ame e s. In he See e al pape
(n=13.275)abou 10% o he a ia ion in F
E
NO was
explained by a a ie y o a iables [35], and his is in
line wi h he cu en esul s (n=433)whe e abou 6%
o he a ia ion in F
E
NO
50
was explained by age,
heigh , gende , NO model and s udy cen e.
Lung de elopmen
In he <20 age g oup, F
E
NO
50
and he ai way NO
pa ame e s J
aw
NO and C
aw
NO we e lowe han in he
o he age g oups. This could possibly eflec an inc eas-
ing mucosal su ace a ea wi h inc easing heigh and
g owing lung olumes. This was also p esen in he s udy
by Jacin o e al whe e he F
E
NO
50
inc ease b eakpoin
appea ed a ound 14 yea s in gi ls and 16 yea s in boys
[17]. This is in line wi h he g ow h o he body, and
mo e specifically he de elopmen o he b onchial ee.
Ageing
In he middle and olde age g oups pulmona y aging
seems o inc ease C
A
NO. This possibly eflec s
dec eased di usi i y o gases in he dis al po ion o
he lung, as C
A
NO is de e mined no only by ac o s
p oducing NO in he lung pe iphe y bu also by how
much al eola NO can di use in o he pulmona y
ci cula ion whe e i is apidly sca enged by haemoglo-
bin. In olde age, he di using capaci y declines in a
linea ashion wi h inc easing age [21]and in elde ly
heal hy subjec s he e is a dec ease in s eady-s a e
ans e capaci y o ca bon monoxide (CO)[36]and
NO [37]. The e is also an inc ease in esidual olume
Table 2. Mean alues and pe cen ile dis ibu ion o F
E
NO
50
and NO pa ame e s in he h ee age g oups.
Pe cen ile dis ibu ion
Age g oups Mean p- alue
*
2.5 5 25 50 75 95 97.5
1
F
E
NO
50
, ppb
<20 y s 10.8 <0.001 4.7 4.9 7.1 10.5 15.9 25.6 27.0
20–49 y s 16.0 6.6 7.4 12.0 15.3 20.9 38.0 45.5
50 y s 18.2 7.7 8.5 13.2 18.2 25.3 36.5 44.9
1
J
aw
NO, nl/s
<20 y s 0.40 <0.001 0.08 0.10 0.26 0.38 0.66 1.36 1.60
20–49 y s 0.76 0.31 0.34 0.53 0.70 1.08 2.01 2.51
50 y s 0.81 0.27 0.31 0.52 0.83 1.23 2.00 2.23
1
C
aw
NO, ppb
<20 y s 64 <0.001 19 21 34 58 123 208 439
20–49 y s 105 30 35 65 105 160 309 441
50 y s 155 40 51 89 150 267 491 535
1
D
aw
NO, ml/s
<20 y s 7.5 0.002 0.9 1.3 4.8 8.7 13.1 25.6 26.9
20–49 y s 7.8 1.3 2.5 5.3 8.3 12.7 19.1 21.6
50 y s 5.7 1.0 1.2 3.5 6.2 10.3 17.1 20.8
C
A
NO, ppb
<20 y s 2.07 <0.001 0.11 0.61 1.52 2.05 2.73 3.59 3.88
20–49 y s 1.72 0.21 0.29 1.13 1.61 2.23 3.66 3.93
50 y s 2.2 0.33 0.51 1.48 2.25 2.85 3.77 3.88
1
Da a wi h skewed dis ibu ion a e gi en in geome ical mean,
*
K uskal-Wallis es o di e ence in mean alues be ween
age g oups.
Table 3. F
E
NO
50
and NO pa ame e s in he di e en age g oups p esen ed by gende .
Age g oup
<20 y s 20–49 y s 50 y s
Gende Female Male Female Male Female Male
1
F
E
NO
50
, ppb 11 (8, 16)10 (7, 15)13 (10, 17)18 (13, 23)
*
17 (12, 23)19 (14, 26)
1
J
aw
NO, nL/s 0.43 (0.28, 0.66)0.37 (0.23, 0.66)0.63 (0.44, 0.83)0.87 (0.60, 1.25)
*
0.75 (0.49, 1.14)0.84 (0.54, 1.26)
1
C
aw
NO, ppb 76 (48, 130)54 (30, 84)77 (54, 115)126 (77, 211)
*
121 (71, 173)163 (100, 288)
1
D
aw
NO, ml/s 6.5 (4.0, 10.9)8.7 (5.5, 17, 4)8.8 (6.2, 12.8)7.3 (4.8, 12.7)7.1 (4.8, 11.4)5.4 (3.2, 9.8)
C
A
NO, ppb 2.12 (1.78, 2.39)1.98 (1.25, 2.33)1.99 (1.22, 2.39)1.52 (1.07, 2.06)
*
2.44 (1.25, 2.92)2.20 (1.45, 2.83)
Da a a e gi en in median (25,75 pe cen ile).
1
Geome ical mean. Mann-Whi ney U- es o gende di e ences,
*
p<0.05.
4
J. B ea h Res. 11 (2017)047103 M Högman e al
Figu e 1. Rela ionship be ween age and he NO pa ame e s, ai way NO flux (J
aw
NO), al eola NO (C
A
NO), ai way di using capaci y
(D
aw
NO)and ai way wall con en (C
aw
NO), wi h uni a ia e eg ession lines and es ima ed 95% e e ence in e als. Since child en
di e ma kedly om adul s, in pa icula ega ding he associa ions be ween heigh and age, he young age g oup was ea ed
sepa a ely.
5
J. B ea h Res. 11 (2017)047103 M Högman e al

[38] eflec ing obs uc ion o he dis al pa o he
ai ways ha could possibly con ibu e o he inc ease
in C
A
NO seen in his s udy. Thus, he e is an
accumula ion o NO om he al eola egion oge he
wi h he inhaled NO om he ai ways ha inc eases
wi h age, and bo h can con ibu e o he inc ease o
C
A
NO. Howe e , he up ake o NO in pulmona y
capilla ies is e y high [39], and he inc ease in C
A
NO
could also be due o o he causes. One o hese o he
causes a ec ing C
A
NO may be ha clinically heal hy
olde subjec s ha e an al e ed inflamma o y cell p ofile
and can ac ually ha e a low-g ade inflamma ion in he
lowe espi a o y ac [40]. This could be due o he
mac ophages becoming less e ficien in sca enging
in ading mic oo ganisms in olde age g oups [41,42].
This could be an explana ion o he inc eased exhaled
F
E
NO
50
and NO pa ame e s, i.e. J
aw
NO, C
aw
NO and
C
A
NO, in ou olde subjec s.
In s udies wi h olde unheal hy pa ien s, i is impo -
an ha he con ol subjec s be ma ched o hem by age
un il he e is enough da a o his age g oup. The e o e,
he inc eased C
A
NO ha has been ound in COPD
pa ien s should be e-e alua ed since hey ha e been
compa ed in some s udies o younge indi iduals
[10,13]. Howe e , in o he s udies, e.g. in cases o sys-
emic scle osis o al eoli is, he C
A
NO alues a e su ely
inc eased since he e we e no age di e ences be ween
he pa ien s and con ol subjec s [12,14,43].Ma ching
by gende should also be aken in o accoun o he mid-
dle age g oup, since C
A
NO inc eases ea lie in emales.
This is possibly explained by a dec ease in he capilla y
blood olume o he lung [44]causing an impai ed gas
exchange in women in he middle age g oup.
D
aw
NO dec eased wi h inc easing age. This is
in e es ing, as D
aw
NO is he o al di usi i y o NO
om b onchial mucosa o luminal ai , and i can be
assumed o eflec bo h he o al su ace a ea a ailable
o di usion and also he physical p ope ies o he
mucosa a ec ing he di usi i y o gases. As indi iduals
g ow so do hei b onchial ees, and one would
assume ha D
aw
NO inc eases wi h inc easing heigh ,
bu we did no see his. Ins ead, we ound ha C
aw
NO
inc eased and his explained he inc ease in J
aw
NO and
F
E
NO
50
du ing he g ow h pe iod. The dec ease o
D
aw
NO ound in olde age migh eflec he physical
changes occu ing in he b onchial mucosa o he
aging lung.
Gende
I was only in he middle age g oup whe e a gende
di e ence could be ound in F
E
NO
50
,J
aw
NO, C
aw
NO
and C
A
NO. In he eg ession model only he a ia ions
in C
aw
NO and C
A
NO we e significan o gende .
Olin e al ound F
E
NO
50
o be highe in men han
in women a ound 50 yea s o age wi h 18 esp. 15 ppb
espec i ely, bu when compa ing F
E
NO
50
be ween
he sexes wi h simila heigh s and ages no di e ence
was ound [16]. Jacin o e al ha e shown a gende di -
e ence in he same age g oup wi h men sligh ly abo e
15 ppb and women a ound 12 ppb [17]. The co esp-
onding alues o F
E
NO
50
in he p esen s udy wi h he
young age g oup excluded a e 16 ppb o men and
15 ppb o women, which a e in line wi h he alues
ob ained by Olin e al using he same analysing
me hod, namely chemiluminescence.
A limi a ion in his s udy is ha da a we e pooled,
which esul ed in mo e men han women, especially in
he old age g oup. In addi ion, he c oss-sec ional
design o he s udy is no op imal o assess he ela ion
be ween age and NO pa ame e s. Howe e , long
enough longi udinal s udies would equi e decades o
ollow-up. I would be in e es ing o pu lung unc ion
in ela ion o he NO pa ame e s, bu un o una ely
we did no ha e lung unc ion da a om all o he sub-
jec s. We did check ha he e was no significan di e -
ence in he mean F
E
NO
50
alues be ween he di e en
cen es, which sugges s ha he me hodology was
simila enough o allow o he pooling o he da a.
In conclusion, in his s udy we ha e gene a ed
e e ence alues o NO pa ame e s om an ex ended
NO analysis o heal hy subjec s. This is impo an in
o de o be able o use hese pa ame e s in clinical
p ac ice. We ound ha pulmona y aging seems o
inc ease C
A
NO, which is possibly a eflec ion o a
dec eased di usi i y o gases in he gas exchange a ea.
The impai ed immune de ence sys em ha occu s
wi h old age could also explain he inc ease in all NO
pa ame e s excep D
aw
NO ha was dec eased in his
g oup. Fu he s udies o addi ional pooling o da a
a e needed be o e we can p o ide e en be e age- ela-
ed e e ence alues o he NO pa ame e s and
Table 4. Reg ession coe ficen s (B)and p- alues o he mul iple eg ession models o NO- a iables. The R
2
is he unadjus ed
coe ficien o de e mina ion o he models and R2boo is he co esponding op imism-co ec ed R
2
alues as es ima ed by
boo s apping.
In e cep Age Heigh Gende (male)
B B p- alue B p- alue B p- alue R
2
R
2
boo
F
E
NO
50
ppb 15.8 1.07 <0.001 1.04 0.29 1.12 0.13 0.08 0.06
J
aw
NO nl/s 0.77 1.03 0.18 1.05 0.33 1.10 0.26 0.07 0.04
C
aw
NO ppb 86.6 1.16 <0.001 0.87 0.04 1.70 <0.001 0.19 0.16
D
aw
NO ml/s 8.6 0.88 <0.001 1.21 0.01 0.69 0.01 0.11 0.08
C
A
NO ppb 1.95 0.2 <0.001 −0.03 0.68 −0.24 0.09 0.15 0.12
6
J. B ea h Res. 11 (2017)047103 M Högman e al
possibly c ea e eliable e e ence equa ions. Howe e ,
his is cu en ly he la ges da ase o NO pa ame e s
ha can be used as a basis o compa isons in u u e
s udies ega ding heal h and disease.
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