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Am J Physiol Lung Cell Mol Physiol 303: L729 –L732, 2012;
doi:10.1152/ajplung.00305.2012.
Editorial
Pulmonary research in 2013 and beyond: a National Heart, Lung, and Blood
Institute perspective
James P. Kiley1 and Robert M. Senior1,2
1
Division of Lung Diseases, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland;
and 2Division of Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School
of Medicine, St. Louis, Missouri
Submitted 5 September 2012; accepted in final form 6 September 2012
resources and avoid duplication. From this broad perspective,
we highlight a number of topics in pulmonary research and
several areas of investigation that show promise for advancing
the prevention, treatment, and cure of lung diseases.
Innovations in Disease Prevention
Avoidance of tobacco products, known occupational respiratory hazards, and contagious pulmonary infections and vaccination for influenza and Streptococcus pneumoniae, are currently the principal means of preserving lung health. On a
worldwide scale, obstructive lung disease secondary to indoor
air pollution is a major problem (19). Accordingly, prevention
of this COPD-like disease should be a goal of lung researchers.
Simple stoves that replace open indoor fires in developing
countries can reduce indoor air pollution, but so far the reductions achieved do not appear to be enough to reduce disease (7).
Much has been learned about early origins of lung disease
(13, 26), which opens the opportunity to study the developing
lung in the context of both primary prevention strategies and
promotion of healthy lungs, similar to what is underway for
cardiovascular disease (18, 33). Looking beyond the traditional
exposures and risk factors for lung disease, has progress been
sufficient to identify lung diseases for which there are nearterm opportunities for testing primary preventative interventions? If not, what resources are required to accelerate development and testing of such interventions?
The extent to which viral infections are a precursor of
chronic lung disease is an area that merits further study. The
possibility that viruses alter lung biology permanently has
experimental support (2, 11, 16). Indeed, the repertoire of
respiratory viruses keeps increasing. Human rhinovirus C exemplifies discovery of a new human viral pathogen whose late
consequences, if any, are not known (4). An important related,
but poorly understood, issue is the interplay between viruses
and cigarette smoke (15). The relationship of viral infections to
asthma has long been a challenge that continues (27). The role
of viruses, including HIV, in pathogenesis of pulmonary arterial hypertension (3) or herpes viruses in pulmonary fibrosis
(28) is not understood. Finding connections between viruses
and lung disease should stimulate development of new vaccines and other forms of antiviral therapy. The role of the
microbiome in disease prevention, development, progression,
and treatment is new territory just now being explored.
Innovations in Understanding Lung Disease Pathogenesis
Address for reprint requests and other correspondence: J. P. Kiley, Division
of Lung Diseases, National Heart, Lung, and Blood Institute, National Institutes of Health, Two Rockledge Centre, Suite 10042, 6701 Rockledge Dr.,
MSC 7952, Bethesda, MD 20892 (e-mail: [email protected]).
http://www.ajplung.org
Alpha-1 antitrypsin (A1AT) deficiency exemplifies the complexity of understanding the pathogenetic mechanisms of
chronic lung diseases. In A1AT the genetic defect and princiL729
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is always perilous, particularly regarding
trends in biomedical research. With no scientific analog of a
crystal ball, we probably prognosticate best by simply observing trends — noting areas of research and approaches that have
recently developed or are moving forward rapidly. Several
general predictions follow immediately from such an approach.
Studies on pulmonary health and disease will be increasingly
multidisciplinary, involving experts in fields beyond the lung
and even beyond the biological sciences, including engineering, physics, informatics, and other physical sciences. Partnerships among academia, government, industry, and patient advocacy organizations will be essential to provide the needed
expertise and support and to maximize efficiency. Research
teams will be bigger and less defined by geography. And, very
importantly, data will be increasingly abundant as a result of
the burgeoning of “omics,” making data analysis, informatics,
and computational methods a challenge for the research community.
Predictions can also be made regarding specific areas of
research that are likely to expand and be fruitful over the next
5–10 years. This perspective identifies a number of these
promising areas. It is written from the viewpoint of the Division of Lung Diseases (DLD) of National Heart, Lung, and
Blood Institute (NHLBI), which supports a wide range of
basic, clinical, and applied research in pulmonary, critical care,
and sleep, most of which is investigator initiated. The DLD
portfolio encompasses research on the fundamental mechanisms of how the lungs work in health and common lung
conditions — chronic obstructive pulmonary disease (COPD),
asthma, pulmonary fibrosis, and acute lung injury — and less
frequent conditions, such as cystic fibrosis, pulmonary arterial
hypertension, primary ciliary dyskinesia, and lymphangiomyomatosis (LAM), as well as lung disease secondary to systemic
diseases such as sickle cell anemia and human immunodeficiency virus (HIV) infection. The research is supported
through single-site awards and multisite clinical projects to
evaluate questions such as the role of statins in attenuating
acute lung injury or COPD exacerbations, and the characterization of diseases such as sarcoidosis. The portfolio also
includes the development of research resources, such as repositories of biological samples obtained from human subjects and
production of rodents with genetic alterations to help model
human diseases. In addition, DLD is engaged with voluntary,
professional, and private sector organizations to leverage its
PREDICTING THE FUTURE
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PULMONARY RESEARCH IN 2013 AND BEYOND: AN NHLBI PERSPECTIVE
appears to improve the prognostication strength of BODE
alone (6). An index derived from clinical data and serum
MMP7 concentration can predict mortality in IPF patients (23).
Prognostication tools may influence clinical decisions, such as
early referral for lung transplant consideration.
In recent years, measurable factors linking to specific lung
conditions have been reported: for example, serum VEGF D
for LAM (34), and pulmonary vascular endothelial microparticles for emphysema (10). What makes these recent tests
exciting is they derived from insights into disease pathogenesis. Circulating lymphocytes may carry molecular signatures of
inflammatory conditions. Accelerated efforts are needed to
discover other relevant origins/preclinical markers of lung
disease susceptibility in peripheral blood leukocytes and lung
cells that reflect the activity and prognosis of pulmonary
diseases.
With rapid whole genome sequencing on the immediate
horizon, identifying individuals with risk for a particular lung
condition may become available. Using existing diagnostic
tools with advanced molecular profiling of the lung may
provide new paradigms to understand the earliest manifestations of lung pathology that will lead to more precise tailored
interventions. At the same time, it remains critical to heighten
awareness of lung conditions and the importance of early
diagnosis using tools already available.
Innovations in Early Disease Detection
Except for the skin, the lungs are the only directly accessible
organ. Accordingly, lung cells can be reached without passage
through the circulation or by a surgical procedure. Although
such access has enabled direct instillation into the lungs of
medications such as surfactant replacement for neonatal respiratory distress syndrome, bronchodilators for COPD, and
asthma and antibiotics for cystic fibrosis, recent studies demonstrate the possibility of altering lung gene expression by
safely putting reagents into the lungs via the airways. An
example of this approach is instilling vectors into the airways
of mice designed to infect lung macrophages with the human
A1AT gene, leading to production of human A1AT by mouse
alveolar macrophages (32).
The capacity of the gut microbiome to process ingested
molecules into bioactive forms might be an intriguing way to
treat the lungs and to determine differences between individuals in the efficacy of drugs. A gut cardiovascular axis has been
identified by which small molecules ingested are modified by
gut organisms into agents that affect the development of
atherosclerosis (14, 31). Ingestion of microbial products alters
respiratory inflammatory cells consistent with the idea that the
gut microbiome affects the lung (22). The relationship of the
gut microbiome to the lung will be an exciting area for
investigation to be developed along with studies of the lung
microbiome itself. Clearly, as with the cardiovascular system,
there is a lung-gut microbiome axis that has broad effects on
the lung, including the response to drugs for lung diseases. This
nascent area of research as it applies to lung health and disease
needs further study.
Lung regeneration and stem cell therapy are the holy grail of
treatment for advanced forms of lung disease. If this is going to
happen much needs to be learned about populating the lungs
with proliferative cells capable of differentiating into the vari-
The goal of detecting a disease at an early stage is to begin
treatment to prevent progression and ideally to achieve cure.
Successful early detection occurs before symptoms or obvious
physical manifestations, and, in the case of infections, before
the infectious agent spreads to other individuals. Tuberculosis
(TB) skin testing and chest radiographs to identify TB infections are the classic examples of tests for early detection of a
lung disease. A recent example is low-dose chest computed
tomography scans to detect lesions suspicious for lung cancer
among middle-aged smokers (1).
Early detection may not benefit everyone for every condition. Early detection is rational only selectively, when applied
to individuals at increased risk for a treatable or preventable
pulmonary condition or disorder. Increased risk may be suspected from personal habit (cigarette smoking), familial association (A1AT deficiency, idiopathic pulmonary fibrosis), environmental circumstances (premature birth, coal mining), use
of medication with pulmonary side effects (amiodarone), and
body size (massive obesity). So-called subclinical interstitial
pneumonias are an example of a recently described condition
detectable without clinical disease (8). The implications of
identifying this condition and whether it is a precursor of
clinical disease need to be determined.
Classically, biomarkers of lung diseases for identification of
disease or as prognosticators have been nonspecific, such as
arterial blood gases and indicators of inflammation like the
erythrocyte sedimentation rate. Use of diagnostic panels of
multiple factors already identified may be an innovative approach to monitor disease activity and generate prognoses. For
example, coupling the BODE index for COPD with a battery of
factors associated with inflammation, especially IL-6 levels,
Innovations in Therapy
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pal function of the deficient protein are known, but it remains
a mystery why some individuals with the deficiency develop
COPD and others do not. Clearly, chronic lung diseases such as
COPD have complex pathogenesis. As such, gene-gene, geneepigene, and gene-environment analyses, along with improved
phenotypic, molecular, and genomic characterization, will be
necessary to unravel the pathogenesis of these conditions.
Despite impressive steps forward, molecular characterization of lung diseases has only moved description of these
conditions to a more sophisticated level. Still missing in the
discoveries are mechanisms linking these findings to function
and disease etiology; how abnormalities of the MUC5B gene
(25) relate to idiopathic pulmonary fibrosis (IPF) is an example. Another is understanding how penetrance and expression
of BMPR2 are dysregulated in pulmonary arterial hypertension. An important impediment to progress on mechanisms of
chronic lung conditions is lack of good animal models of
human conditions. Studies of individuals and families with
heritable, uncommon forms of lung disease may yield opportunities for biological samples from which subtle abnormalities
of physical properties and function can be investigated. For
example, studying individuals with familial pulmonary fibrosis
due to a mutation in surfactant protein C may provide valuable
insights into early events in pulmonary fibrosis pathogenesis
(29). Recent findings about effects of nicotine on vascular
remodeling point to the importance of continuously integrating
new and emerging concepts (30).
Editorial
PULMONARY RESEARCH IN 2013 AND BEYOND: AN NHLBI PERSPECTIVE
Conclusions
We are in an era of remarkable advances in diagnosis,
understanding, and treatment of lung diseases and conditions.
Areas ripe for research now include development of molecular
signatures for risk and monitoring lung diseases such as sarcoidosis, techniques of safely altering gene expression by lung
cells in vivo, uncovering the late consequences of lung infections, especially viral, on lung immunity and inflammatory
responses, and the interplay between the lungs and other parts
of the human body such as the gut microbiome. The explosion
of knowledge in recent years has shown that attaining better
lung health for the country is possible and desirable given the
very high prevalence and burden of lung disease (21). Progress
has also taught us that the lungs and the respiratory system
overall have incredible complexity, so the potential for generating new knowledge about the respiratory system appears
inexhaustible. Our goal at NHLBI is to facilitate research and
press the frontier of this exciting science to improve public
health. At the same time, an important priority is to train the
next generation of clinician/scientists to discover more about
human lung biology in health and disease.
ACKNOWLEDGMENTS
The authors thank Thomas P. Croxton, MD, PhD; Dorothy Gail, PhD;
Michael Twery, PhD; and Gail Weinmann, MD for helpful comments and
expertise.
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the author(s).
AUTHOR CONTRIBUTIONS
Author contributions: J.P.K. and R.M.S. drafted manuscript; J.P.K. and
R.M.S. edited and revised manuscript; J.P.K. and R.M.S. approved final
version of manuscript; R.M.S. drafted manuscript while on an Intergovernmental Personnel Agreement (IPA) with DLD, NHLBI, NIH.
REFERENCES
1. Aberle DR, Adams AM, Berg CD, Black WC, Clapp JD, Fagerstrom
RM, Gareen IF, Gatsonis C, Marcus PM, Sicks JD. Reduced lungcancer mortality with low-dose computed tomographic screening. N Engl
J Med 365: 395–409, 2011.
2. Al-Garawi A, Husain M, Ilieva D, Humbles AA, Kolbeck R, Stampfli
MR, O’Byrne PM, Coyle AJ, Jordana M. Shifting of immune responsiveness to house dust mite by influenza A infection: genomic insights. J
Immunol 188: 832–843, 2012.
3. Almodovar S, Knight R, Allshouse AA, Roemer S, Lozupone C,
McDonald D, Widmann J, Voelkel NF, Shelton RJ, Suarez EB,
Hammer KW, Goujard C, Petrosillo N, Simonneau G, Hsue PY,
Humbert M, Flores SC. Human immunodeficiency virus nef signature
sequences are associated with pulmonary hypertension. AIDS Res Hum
Retroviruses 28: 607–618, 2012.
4. Bochkov YA, Palmenberg AC, Lee WM, Rathe JA, Amineva SP, Sun
X, Pasic TR, Jarjour NN, Liggett SB, Gern JE. Molecular modeling,
organ culture and reverse genetics for a newly identified human rhinovirus
C. Nat Med 17: 627–632, 2011.
5. Carsillo T, Astrinidis A, Henske EP. Mutations in the tuberous sclerosis
complex gene TSC2 are a cause of sporadic pulmonary lymphangioleiomyomatosis. Proc Natl Acad Sci USA 97: 6085–6090, 2000.
6. Celli BR, Locantore N, Yates J, Tal-Singer R, Miller BE, Bakke P,
Calverley P, Coxson H, Crim C, Edwards LD, Lomas DA, Duvoix A,
MacNee W, Rennard S, Silverman E, Vestbo J, Wouters E, Agusti A.
Inflammatory biomarkers improve clinical prediction of mortality in
chronic obstructive pulmonary disease. Am J Respir Crit Care Med 185:
1065–1072, 2012.
7. Diette GB, Accinelli RA, Balmes JR, Buist AS, Checkley W, Garbe P,
Hansel NN, Kapil V, Gordon S, Lagat DK, Yip F, Mortimer K,
Perez-Padilla R, Roth C, Schwaninger JM, Punturieri A, Kiley JP.
Obstructive lung disease and exposure to burning biomass fuel in the
indoor environment. Global Heart. In Press.
8. Doyle TJ, Hunninghake GM, Rosas IO. Subclinical interstitial lung
disease: why you should care. Am J Respir Crit Care Med 185: 1147–
1153, 2012.
9. Goncharova EA, Goncharov DA, Eszterhas A, Hunter DS, Glassberg
MK, Yeung RS, Walker CL, Noonan D, Kwiatkowski DJ, Chou MM,
Panettieri RA Jr, Krymskaya VP. Tuberin regulates p70 S6 kinase
activation and ribosomal protein S6 phosphorylation. A role for the TSC2
tumor suppressor gene in pulmonary lymphangioleiomyomatosis (LAM).
J Biol Chem 277: 30958 –30967, 2002.
10. Gordon C, Gudi K, Krause A, Sackrowitz R, Harvey BG, StruloviciBarel Y, Mezey JG, Crystal RG. Circulating endothelial microparticles
as a measure of early lung destruction in cigarette smokers. Am J Respir
Crit Care Med 184: 224 –232, 2011.
11. Grayson MH, Cheung D, Rohlfing MM, Kitchens R, Spiegel DE,
Tucker J, Battaile JT, Alevy Y, Yan L, Agapov E, Kim EY, Holtzman
MJ. Induction of high-affinity IgE receptor on lung dendritic cells during
viral infection leads to mucous cell metaplasia. J Exp Med 204: 2759 –
2769, 2007.
12. Islam MN, Das SR, Emin MT, Wei M, Sun L, Westphalen K,
Rowlands DJ, Quadri SK, Bhattacharya S, Bhattacharya J. Mitochondrial transfer from bone-marrow-derived stromal cells to pulmonary alveoli protects against acute lung injury. Nat Med 18: 759 –765, 2012.
13. Joss-Moore LA, Metcalfe DB, Albertine KH, McKnight RA, Lane
RH. Epigenetics and fetal adaptation to perinatal events: diversity through
fidelity. J Anim Sci 88: E216 –222, 2010.
14. Kaddurah-Daouk R, Baillie RA, Zhu H, Zeng ZB, Wiest MM, Nguyen
UT, Wojnoonski K, Watkins SM, Trupp M, Krauss RM. Enteric
microbiome metabolites correlate with response to simvastatin treatment.
PLoS One 6: e25482, 2011.
15. Kang MJ, Lee CG, Lee JY, Dela Cruz CS, Chen ZJ, Enelow R, Elias
JA. Cigarette smoke selectively enhances viral PAMP- and virus-induced
pulmonary innate immune and remodeling responses in mice. J Clin Invest
118: 2771–2784, 2008.
AJP-Lung Cell Mol Physiol • doi:10.1152/ajplung.00305.2012 • www.ajplung.org
Downloaded from http://ajplung.physiology.org/ by 10.220.33.6 on May 2, 2017
ety of epithelial, vascular, and mesenchymal cell types in the
normal lung including vascular and epithelial, for these cells to
establish the lung architecture for gas exchange and for ways to
deliver these cells to the lungs (17). Developing strategies for
lung regeneration and repair will undoubtedly be an important
direction for future lung research.
Acute lung injury affecting alveolar epithelial cells may be
susceptible to reparative effects from bone marrow-derived
mesenchymal cells. The mechanism appears to involve direct
mitochondrial transfer from mesenchymal cells via channels
connecting these cells to alveolar type 1 cells (12). Studies
such as these and others with fat stem cells that reduce the
effects of smoke on alveolar remodeling suggest the possibility
that nonpulmonary cells and factors from extrapulmonary cells
may be a source of therapeutics for lung injury (24).
Research to identify therapeutic targets in critical gene
pathways is another strategy that can be used to develop new
treatments for lung diseases. Translation of the results from the
laboratory to clinical practice can be done rapidly if the targets
are amenable to therapeutic agents that are already FDA
approved for other purposes. For example, the chain of events
that led from the discovery that mutations causing dysfunction
of the TSC2 gene underlie the molecular defect in LAM, to the
identification of mTOR as a key factor in regulating LAM cell
growth, to proof-of-concept testing in an animal model, to
clinical trials, to demonstrating that sirolimus (rapamycin)
could slow progression of loss of pulmonary function in LAM
patients took about 13 years (5, 9, 20). Efforts to identify both
novel and repurposed agents show promise for the future but
need to move at a more rapid pace.
L731
Editorial
L732
PULMONARY RESEARCH IN 2013 AND BEYOND: AN NHLBI PERSPECTIVE
26.
27.
28.
29.
30.
31.
32.
33.
34.
DA. A common MUC5B promoter polymorphism and pulmonary fibrosis.
N Engl J Med 364: 1503–1512, 2011.
Sonnenschein-van der Voort AM, Jaddoe VW, Raat H, Moll HA,
Hofman A, de Jongste JC, Duijts L. Fetal and infant growth and asthma
symptoms in preschool children: the Generation R Study. Am J Respir Crit
Care Med 185: 731–737, 2012.
Stein RT, Martinez FD. Respiratory syncytial virus and asthma: still no
final answer. Thorax 65: 1033–1034, 2010.
Tang YW, Johnson JE, Browning PJ, Cruz-Gervis RA, Davis A,
Graham BS, Brigham KL, Oates JA Jr, Loyd JE, Stecenko AA.
Herpesvirus DNA is consistently detected in lungs of patients with
idiopathic pulmonary fibrosis. J Clin Microbiol 41: 2633–2640, 2003.
Thomas AQ, Lane K, Phillips J 3rd, Prince M, Markin C, Speer M,
Schwartz DA, Gaddipati R, Marney A, Johnson J, Roberts R, Haines
J, Stahlman M, Loyd JE. Heterozygosity for a surfactant protein C gene
mutation associated with usual interstitial pneumonitis and cellular nonspecific interstitial pneumonitis in one kindred. Am J Respir Crit Care
Med 165: 1322–1328, 2002.
Wang S, Zhang C, Zhang M, Liang B, Zhu H, Lee J, Viollet B, Xia L,
Zhang Y, Zou MH. Activation of AMP-activated protein kinase alpha2
by nicotine instigates formation of abdominal aortic aneurysms in mice in
vivo. Nat Med 18: 902–910, 2012.
Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, Dugar B,
Feldstein AE, Britt EB, Fu X, Chung YM, Wu Y, Schauer P, Smith
JD, Allayee H, Tang WH, DiDonato JA, Lusis AJ, Hazen SL. Gut flora
metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 472: 57–63, 2011.
Wilson AA, Murphy GJ, Hamakawa H, Kwok LW, Srinivasan S,
Hovav AH, Mulligan RC, Amar S, Suki B, Kotton DN. Amelioration of
emphysema in mice through lentiviral transduction of long-lived pulmonary alveolar macrophages. J Clin Invest 120: 379 –389, 2010.
Yang Q, Cogswell ME, Flanders WD, Hong Y, Zhang Z, Loustalot F,
Gillespie C, Merritt R, Hu FB. Trends in cardiovascular health metrics
and associations with all-cause and CVD mortality among US adults.
JAMA 307: 1273–1283, 2012.
Young LR, Vandyke R, Gulleman PM, Inoue Y, Brown KK, Schmidt
LS, Linehan WM, Hajjar F, Kinder BW, Trapnell BC, Bissler JJ,
Franz DN, McCormack FX. Serum vascular endothelial growth factor-D
prospectively distinguishes lymphangioleiomyomatosis from other diseases. Chest 138: 674 –681, 2010.
AJP-Lung Cell Mol Physiol • doi:10.1152/ajplung.00305.2012 • www.ajplung.org
Downloaded from http://ajplung.physiology.org/ by 10.220.33.6 on May 2, 2017
16. Kim EY, Battaile JT, Patel AC, You Y, Agapov E, Grayson MH,
Benoit LA, Byers DE, Alevy Y, Tucker J, Swanson S, Tidwell R,
Tyner JW, Morton JD, Castro M, Polineni D, Patterson GA, Schwendener RA, Allard JD, Peltz G, Holtzman MJ. Persistent activation of an
innate immune response translates respiratory viral infection into chronic
lung disease. Nat Med 14: 633–640, 2008.
17. Kotton DN. Next-generation regeneration: the hope and hype of lung stem
cell research. Am J Respir Crit Care Med 185: 1255–1260, 2012.
18. Lloyd-Jones DM. Improving the cardiovascular health of the US population. JAMA 307: 1314 –1316, 2012.
19. Martin WJ 2nd, Glass RI, Balbus JM, Collins FS. Public health. A
major environmental cause of death. Science 334: 180 –181, 2011.
20. McCormack FX, Inoue Y, Moss J, Singer LG, Strange C, Nakata K,
Barker AF, Chapman JT, Brantly ML, Stocks JM, Brown KK, Lynch
JP 3rd, Goldberg HJ, Young LR, Kinder BW, Downey GP, Sullivan
EJ, Colby TV, McKay RT, Cohen MM, Korbee L, Taveira-DaSilva
AM, Lee HS, Krischer JP, Trapnell BC. Efficacy and safety of sirolimus
in lymphangioleiomyomatosis. N Engl J Med 364: 1595–1606, 2011.
21. Munzer A, Mannino DM, Zheng Zhi-Jie, Schraufnagel DE. To
breathe . . . In: Breathing in America: Diseases, Progress, and Hope,
edited by Schraufnagel DE. New York: Am. Thor. Soc., 2010, p. 1–14.
22. Navarro S, Cossalter G, Chiavaroli C, Kanda A, Fleury S, Lazzari A,
Cazareth J, Sparwasser T, Dombrowicz D, Glaichenhaus N, Julia V.
The oral administration of bacterial extracts prevents asthma via the
recruitment of regulatory T cells to the airways. Mucosal Immunol 4:
53–65, 2011.
23. Richards TJ, Kaminski N, Baribaud F, Flavin S, Brodmerkel C,
Horowitz D, Li K, Choi J, Vuga LJ, Lindell KO, Klesen M, Zhang Y,
Gibson KF. Peripheral blood proteins predict mortality in idiopathic
pulmonary fibrosis. Am J Respir Crit Care Med 185: 67–76, 2012.
24. Schweitzer KS, Johnstone BH, Garrison J, Rush NI, Cooper S,
Traktuev DO, Feng D, Adamowicz JJ, Van Demark M, Fisher AJ,
Kamocki K, Brown MB, Presson RG Jr, Broxmeyer HE, March KL,
Petrache I. Adipose stem cell treatment in mice attenuates lung and
systemic injury induced by cigarette smoking. Am J Respir Crit Care Med
183: 215–225, 2011.
25. Seibold MA, Wise AL, Speer MC, Steele MP, Brown KK, Loyd JE,
Fingerlin TE, Zhang W, Gudmundsson G, Groshong SD, Evans CM,
Garantziotis S, Adler KB, Dickey BF, du Bois RM, Yang IV, Herron
A, Kervitsky D, Talbert JL, Markin C, Park J, Crews AL, Slifer SH,
Auerbach S, Roy MG, Lin J, Hennessy CE, Schwarz MI, Schwartz