asthma

CH 1;:;;.Vf'\K J('

r~U1)/' · 1 ;: "

http://informahealthcare.com/jas ISSN: 0277-0903 (print), 1532-4303 (electronic)

.lnunrnl of

ASTHMA

J Asthma, Early Online: 1-8 (è; 2014 Informa Healthcare USA, lnc. DOI: 10.3109/02770903.2014.882934

informa healthcare

ORIGINAL ARTICLE

High sputum total adiponectin is associated with low odds for asthma Akshay Sood, MD, MPH 1 , JeanClare Seagrave, PhD 2 , Guy Herbert, BS 2 , Michelle Harkins, MD 1, Yasir Alam, MBBS 3, Annalisa Chiavaroli 4 , Rugia Shohreh 4 , Paolo Montuschi, MD 5, Matthew Campen, PhD 6 , Molly Harmon, MS 6 , 1 Clifford Qualls, PhD1, Marianne Berwick, Pho1, and Mark Schuyler, MD 1

'School of Medicine, University of New Mexico, A/buquerque, NM, USA, Lovelace Respiratory Research /nstitute, Albuquerque, NM, USA, 3

4

Shifa College of Medicine, Islamabad, Pakistan, Faculty of Pharmacy, University G. D'Annunzio, Chieti, Jta/y, 5 Catho/ic Unlversity of the 6

Sacred Heart, Rame, /taly, and Coflege of Pharmacy, University of New Mexico Hea/th Sciences Center, Albuquerque, NM, USA

Abstract

Keywords

e:

Objective: Adipose tissue prodlices adiponectin, an anti-inflammatory protein. High systemic

o

tota! adiponectin is associateci with a low risk for incident asthma but the association with lung adiponectin is not known. Our objective was to evaluate the association between sputum total adiponectin and asthma. Methods: This case·control study included 44 cases with objectively-confirmed asthma and an equa! number of body mass index (BMI) and sex-matched controls. Serum and sputum adiponectin were estimateci by ELISA and Western Blot technique, respectively. While Fisher's exact test, r-test and Spearman's correlatìons were used for univariate analyses, Spearman and regression analyses were performed for multivariable analyses. Results: While high-molecular-weight adiponectin was the domi11ant isoform in serum, medium·rnolecular·-weight isoform was dominant in sputum, Sputum total adiponectin was not correlateci with serum adiponec.tin or BMI. Sputum tota! adiponectin was lower among asthmatics than controls (p ..... 0.03), although individuai sputum isoforms were not similarly associateci. High sputum total adiponectin was associateci with lower odds for asthma (OR 0.33, 95% C.I. 0.12, 0.91 ), even after adjustment for systemic adiposity measures including serum adiponectin. Conclusions: High sputum tota I adiponectin predicted lower odds for asthma, even after adjustment for serum adiponectin. Although not studied, it is possible that pharmacological modulation of sputum adiponectin may suggest new ways to prevent and/or treat asthma.

Adiponectin, adiposity, airway inflammation, asthma, obesity, oxidant stress

e

e:

·e:

o ;-

History Received 18 June 2013 Revised 20 December 2013 Accepted 8 January 2014 Published online 11 February 2014

:::

o ·!::

lntroduction

Adiponcctin. a protcin produced primarily by adipose tissuc. has a largely anli-inflammatory role that involves inhihition of pro-inflammatory mcdiators such as Lumor nccrosis factoralpha (TNF-'.'1) and interleukin OLJ-6 and prornotinn of antiinflarnmatory mediators (IL· IO and IL .. I receptor antagonist). Despite being produced by adipose tissue. systemic adiponcctin rnnccntrations m«:: invcrscly correlateti wilh body mass intlcx (BMI) 11 J. An c.,.planation for this rinding is that adipose tissue in the obese produces less adiponectin due to the paracrine inhihition by excess TNF-'1 and IL-6 [2]. Additionally. impaired mitochondrial function in thc obese induce:, an endoplasmic reticulum stre.,s responsc. resulting in inadcquatc proccssing of thc mature adìponcctin protcin in adipocylcs 1-'J. Circulating adiponcctin includcs thrcc distinct isoforms - low-molccular wcight (l ,MW) (trimcrs); mcdium-molccular wcight (MMW) (hcxamcrs); and Corrcspondcnce: 1\kshay Sood. MD. MPH. Associate Pnife"nr. Dcpartrncnt of Medicine, Division of Pulrnonary and Cril'ical Care :Vlcdicinc. Health Sciences Centcr, School of Medicine. Unh-ersity of '.'Jcw :V1cxico. I l.lniversitv of Nl'w Mexico, MSC I O 5550, ACC 5. i\lbuquerquc. NM 87131, ·LISA. Tcl: (505 J 2ì2-·:1751. Fax: (505 J 2T!.· 87 two months: (4) prcgnancy and nursing state: (5) presence of lung diseases other than asthma: (6) stroke ì.n prior 3 month~: (7) aortìc aneurysm; and (8) failure to expcctoratc adequate-quality sputum in response to induction. Tn addition. ali tests \Vere dclaycd in the cvent of an acute infcction within thc prior 4 weeks :md rcspiratory tract infix-tions or asthma cxacerbations within thc prior 8 weeks. For menstruating women. testing wa:.; done within 3 14 days following the cessation of menstrual flnw (a period 1Jf high estrogen ami low progesterone) to standardize the effeet of :;ex burmones on test variables. None of the subjects in thc study wcrc on systcmic corticosteroids at thc time of thc study. Questionnaires

Standardizcd qUL'stionnaircs wcre administcred hy thc sank' trained intervicwcr to obtain information on smoking history. respiratory health [ 171. asthma ~everity [ 18]. gastroesophageal reflux [ 19] ami habitual physical activity [20]. Detaib of' thcse questionnaìrcs are available in the Online Supplemcntary data.

Tabk I. Unadjustcd Ctlmparison of characteristics betwecn subject> with a:>thma and eontmls. Asthma (11 Characteristic Agc (in ycars) remale sex White racc tfopank ethnidty lf woman. prcmcnopausal scatu, Formcr srnokcrs Cum.mt envimnmental tnhacco smoke exposure :\topic state by skin pri.9±9.5 205±11.2 26.3± .13.U 31.8± 165 28.5 ± 11.4 36.5 ± 12.3 38.1±13.1 33.5±155 39.2± 14.2 40.6± 12.9 39.7 ± 19.0 42.5 ± 13.5 57.7 ± 12.6

0.95 0.92 0.67 0.66 0.62 0.77 IU6 0.33 0.22 0.21 0.42 0.50 0.77 O.ì:I

0.73 0.79 0.26

0.66 0.80

::::

e e

DEXA: Dual encrgy X-ray ah,orptiomctry. Gray 1989 rcfercnce equatiom wcrc

l1'Cd to calculutc pcrccnt body fat u'inµ bioelec:trical Ìlllpt

0.03 0.57 0.30 0.4'.l 0.91

0.03

0.89

4180.6 .± 2671.l 4426. l ± 2742.2

±·'I 06.0

0.76

0.61

3689.1 ± 2586.4

34 0.12.8 ± 27 597 .8

33 26~.4 ± '::.7 874.9

0.20 0.90

0.13 O.X)

HMW: high-molccular wcight isoform; rvt!\1W: mid-molccular weight isoform: LMW: Jow-molecular wcight isoli1rm.Studcrll's 1-tcst was u~d for analy;,ing all variabk,. Anrong asthnmlic>. mcan serum HMW adiponcuin conccntratir the relmionship of aslhma status on sputum tolal adiponectin (p-0.03. O..

w'"

reduction intervention may favorably influcnce asthma severity nutcomes [40]. Like mice, the systernic adiponectin-asthrna relationshìp is bidirectional in humans but the primary direction of this as~ocìation is that adiponcctin affccts asthma, cxcept in severe conditions whcn thc rcvcrsc dircction is also truc. Thus, prcvalcnt asthma hm no chronic cffocts on scrum adiponcctin [IO] and transicnt bronchoprovocation from cxpcrimcntal allergen inhalation does not acutely affect serum adiponectin conccntrations among subjects with asthma [411. Yet. severe asthma exacerbations requiring hnspìtalization result in a lransicnt decrcase in serum adiponcctin [38]. lt is possiblc that systemic spill-ovcr of intense locai inflammation in a severe asthma exacerbation inhibits the secretìon of adiponectin from adipose tissue [38]. In order to minimize the confounding cflcct of asthma cxaccrbation on adiponcctin, wc dclayed tcsting in our study by at lcast 8 wecks following any asthma cxaccrbatìon, none of which rcquìrcd hospitalization. Wc dcmonstratc that sputum total adiponcctin may bcttcr predict asthma status than other adiposity variablcs such as serum total adiponcctin. scrum lcptin or DEXA mcasurcs of fai and lcan mass. Aif\vay adiponcctin was not correlatt:d with systcmic adiponectin. as also dcscribcd by others [39.42]. Pot(:ntial cxplanations for this finding are that adiponcctin may be dcgradcd within thc Jung itsclf and/or diffcrent isomers may be tran~ported at difforenl rntcs from blm>d into the airway. It is also possible that adiponectin produced by intrathoracìc viscera] fat or by various cells in the Jung such as airway cpithelium 1121 rnay have paracrinc effects that may be ~tronger than thc endocrine effccts of systcrnic adiponectin. While ìt may ~eem surprbing to find group differences in sputum total adiponectin but no differences in individuai isoforms, thìs may be explained by thc larger variancc of the isoform concentrations.

Although thc published data are limitcd and confusing. high serum adiponectin i' as~ociated with less clinica! asthma severity and high lung function measures among boys and women [38.43-45] but surprisingly as~ociated with more clinica! scverity among men 1431. On thc eontrary, >crum adiponcctin is nol associated with cosinophilic inflammatory asthma measurcs in any populatìon group [42]. In our ;,tudy. wc did not find sputum tota! adiponcctìn to be associateci with physiological, eosinophilic ìnflammatory or oxìdant ~tre;,s measures of asthma scverity (Table 6). On the other hand. the non-dorninant isoforms 0f sputum adiponectin (i.e. HMW ancl LMW isoforms) were associateci with low systcrnic oxidant stress among subjccts with asthma. It ìs possiblc thai low HMW and LMW adiponectin isofonns in asthma are associatcd with non-eosinophìlic airway inflammation potcntiated by systemic oxidant stress. The strengths of our study include an innovative and topica! rcsearch question, a we\1-charactcrizcd study population. focu~ on airway adiponcctin and its isofonm. ability to contro! for ~ystcmic ami regional adiposity measurcs, and study of physiologicaL inl'lammatory and oxidant stressrclatcd asthma outcomes. lhe of sclf-rcport or questionnaircs may result in information bias which was minimizcd by che use of standard questionnaires administcred by thc same intcrviewer. lnformation bìas was further minimi1cd by the use of trained study personncl. standard test prnl\x·ols. strict quality contro! for assays and blinding of study personnel towards case status of study subjects. Selection hias a.rise' from the recruitment process hut was minimized by recruit1m:nl from tbc communìty. instcad of thc hospital. Sclf-reporl of physician diagnosis of a~tluna is subject to misclassirication bias [46] and was therefore minimized by confirmatnry use of tbc methacholinc challcnge test. Since cigarctte srnoke exposure ìncreases lung acliponectin in mice [471 but reduce-; RIGH1S

S1mrw11 tota! adipmu'ciùt

lung adiponcctin in 01hc1;wisc hcalthy l'.Urrcnt smokcrs 112]. wc minimizcd thc variablc and confounding cffoct of cigarettc smoke hy uremcnt of inflnmmalory indices in inJuced 'Plltum: cffccts of o;election of sputum to mìnimìz.c 'lllivary conlamination. Eur Respir J 19%;9:1174--1180. Kirn CK. Callaw:iy 7. Kim DW, Kita H. Eo,ìnophìl dei!ranulation i> more irnportant than ensinophìlia in identifying asthma in d1ronic congh. J A'thma 20 I 1:48: