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Molecular understanding of IPF

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Molecular understanding of IPF

What is the pathogenesis of IPF?

  • The molecular cause(s) of IPF are not yet fully understood
  • However, there are a number of known risk factors (see About IPF: Risk Factors)

Current model of IPF pathogenesis

The current model of IPF pathogenesis suggests multiple factors and pathways interact through various stages of disease development to produce the histopathologic and clinical features of IPF1 
 
1. Wolters PJ et al. Annu Rev Pathol. 2014;9:157-179.

Current hypothesis for IPF

Predisposition
Initiation
Progression

Current hypothesis for IPF

Predisposition
Predisposing triggers result in epithelial cell dysfunction, creating a susceptible lung epithelium1
 
1. Wolters PJ et al. Annu Rev Pathol. 2014;9:157-179.

Current hypothesis for IPF

Initiation
Aberrant wound healing in responseto lung injury initiates pathogenic changes2
 
2. Knipe RS et al. Pharmacol Rev. 2015;67(1):103-117.

Current hypothesis for IPF

Progression
Disease progression occurs due to ongoing extracellular matrix deposition, accumulation of myofibroblasts, and aberrant tissue remodeling1

1. Wolters PJ et al. Annu Rev Pathol. 2014;9:157-179.

Predisposition

Patients with IPF likely have underlying predisposing factors

Various genetic variants, environmental exposures, and aging have all been linked to increased IPF susceptibility3-10
 
3. Thomas AQ et al. Am J Respir Crit Care Med. 2002;165(9):1322-1328.
4. van Moorsel CH et al. Am J Respir Crit Care Med. 2010;182(11):1419-1425.
5. Wang Y et al. Am J Hum Genet. 2009;84(1):52-59.
6. Armanios MY et al. N Engl J Med. 2007;356(13):1317-1326.
7. Tsakiri KD et al. Proc Natl Acad Sci U S A. 2007;104(18):7552-7557.
8. Fingerlin TE et al. Nat Genet. 2013;45(6):613-620.
9. Noth I et al. Lancet Respir Med. 2013;1(4):309-317.
10. Seibold MA et al. N Engl J Med. 2011;364(16):1503-1512.

A number of genetic polymorphisms are commonly associated with IPF

Mucin-related8-10
MUC5B
MUC2

Telomere-related8
TERT
TERC
OBFC1

Lung epithelium integrity8
DPP9
DSP

Other8,9
TOLLIP
MAPT  
FAM13A 
7q22 
ATP11A 
15q14-15 
MDGA2 
SPPL2C

These mutations cumulatively may be responsible for as much as 31% of the genetic risk for IPF8

8. Fingerlin TE et al. Nat Genet. 2013;45(6):613-620.
9. Noth I et al. Lancet Respir Med. 2013;1(4):309-317.
10. Seibold MA et al. N Engl J Med. 2011;364(16):1503-1512.

A common mutation associated with IPF is found in the promoter for the MUC5B gene

In 2011, a genome-wide linkage study identified a polymorphism in the promoter of the gene encoding MUC5B that was associated with a 9-fold increased risk of IPF10
 
Among patients with IPF, the minor allele frequency of MUC5B was 34% compared with 9% in control subjects10

MUC5B, mucin 5B.

10. Seibold MA et al. N Engl J Med 2011;364(16):1503-1512.

The MUC5B promoter polymorphism is associated with increased risk of asymptomatic lung abnormalities

  • This polymorphism has also been associated with increased MUC5B mRNA expression10 
  • MUC5B has a role in host defense responses in the airways, although its role in IPF pathogenesis is not yet clear12
10. Seibold MA et al. N Engl J Med 2011;364(16):1503-1512.
11. Hunninghake GM et al. N Engl J Med. 2013;368(23):2192-2200.
12. Roy MG et al. Nature. 2014;505(7483):412-416. 

Rare variants tend to be linked to familial cases of IPF

Rare Variants
 
Surfactant Genes3-5
SFTPC 
SFTPA2

Telomere-RelatedGenes6,7,13
TERT 
TERC 
DKC1

In familial cases of pulmonary fibrosis, the most likely mode of genetic transmission is autosomal dominant with variable penetrance14 

3. Thomas AQ et al. Am J Respir Crit Care Med. 2002;165(9):1322-1328.
4. van Moorsel CH et al. Am J Respir Crit Care Med. 2010;182(11):1419-1425.
5. Wang Y et al.Am J Hum Genet. 2009;84(1):52-59.
6. Armanios MY et al. N Engl J Med. 2007;356(13):1317-1326.
7. Tsakiri KD et al. Proc Natl Acad Sci U S A. 2007;104(18):7552-7557.
13. Kropski JA et al. Chest. 2014;146(1):e1-e7.
14. Steele MP et al. Am J Respir Crit Care Med. 2005;172(9):1146-1152.

A subset of families with IPF have dominant mutations in 1 of 2 surfactant proteins

Surfactant protein C (SFTPC) and Surfactant protein A (SFTPA2) are produced by AECs3-5
 
In patients with mutations in surfactant proteins, defects in protein folding induce ER stress, which leads to epithelial cell death3,15

AEC, alveolar epithelial cell; ER, endoplasmic reticulum.

3. Thomas AQ et al. Am J Respir Crit Care Med. 2002;165(9):1322-1328.
4. van Moorsel CH et al. Am J Respir Crit Care Med. 2010;182(11):1419-1425.
5. Wang Y et al.Am J Hum Genet. 2009;84(1):52-59.
15. Mulugeta S et al. Am J Respir Cell Mol Biol. 2005;32(6):521-530.

Cases of familial pulmonary fibrosis have led to identification of rare variants in telomere-related proteins

Telomere-Related Genes
 
Rare Variants6,7,13
TERT 
TERC 
DKC1

In patients with telomerase mutations, the proliferative capacity of alveolar progenitor cells may be limited6,7

6. Armanios MY et al. N Engl J Med. 2007;356(13):1317-1326.
7. Tsakiri KD et al. Proc Natl Acad Sci U S A. 2007;104(18):7552-7557.
13. Kropski JA et al. Chest. 2014;146(1):e1-e7.

Additional evidence indicates telomeres are involved in sporadic forms of IPF as well

Up to one-third of patients with short telomeres in peripheral blood mononuclear cells were diagnosed with IPF, suggesting that defects in telomere maintenance may underlie one path to lung fibrosis13,16,17
 
13. Kropski JA et al. Chest. 2014;146(1):e1-e7.
16. Alder JK et al. Proc Natl Acad Sci U S A. 2008;105(35):13051-13056.
17. Cronkhite JT et al. Am J Respir Crit Care Med. 2008;178(7):729-737.

Certain polymorphisms are associated with outcomes in IPF

  • Select variations in TOLLIP are associated with reduced susceptibility to IPF9
  • One mutation in MUC5B may result in decreased mortality from IPF9
  • A specific mutation in TLR3 results in greater risk of mortality and accelerated FVC decline18
However, it is not clear whether these gene variants can be incorporated into prognostic models to affect the clinical care of patients9

TOLLIP, Toll interacting protein; TLR3, toll-like receptor 3; FVC, forced vital capacity.
9. Noth I et al. Lancet Respir Med. 2013;1:309-317. 18. O'Dwyer DN et al. Am J Respir Crit Care Med. 2013;188(12):1442-1450.

Predisposition to developing IPF is also associated with particular polymorphisms

  • Oxidative stress contributes to epithelial injury and fibroblast differentiation19-23 
  • Aging leads to alterations in epithelial repair through autophagy pathways and worsens several animal models of lung fibrosis24-26 
  • Mechanical factors including stretch/stress injury alter epithelial cell phenotype and cytokine production27-29 
19. Rahman I et al. Free Radic Biol Med. 1999;27(1-2):60-68.
20. Waghray M et al. FASEB J. 2005;19(7):854-856.
21. Kliment CR et al. J Biol Chem. 2009;284(6):3537-3545.
22. Bocchino M et al. PLoS One. 2010;5(11):e14003.
23. Hecker L et al. Nat Med. 2009;15(9):1077-1081.
24. Sueblinvong V et al. Am J Med. Sci 2012;344(1):41-51.
25. Araya J et al. Am J Physiol Lung Cell Mol Physiol. 2013;304(1):L56-L69.
26. Torres-Gonzalez E et al. Am J Respir Cell Mol Biol. 2012;46(6):748-756.
27. Heise RL et al. J Biol Chem. 2011;286(20):17435-17444.
28. Yamamoto H et al. Respir Physiol. 2001;127(2-3):105-111.
29. Cabrera-Benitez NE et al. Crit Care Med 2012;40(2):510-517.

Initiation

IPF may be initiated by an injury to the alveolar epithelium

IPF may be caused by an inappropriate or overexuberant wound-healing response in response to AEC injury,30 although the source of injury is generally unknown1
 
1. Wolters PJ et al. Annu Rev Pathol. 2014;9:157-179.
30. Selman M et al. Ann Intern Med 2001;134(2):136-151.

Injury to the alveolar epithelium causes death of AECs

Alveolar injury results in the death of some AECs through apoptosis and other pathways, as well as a loss of epithelial integrity31,32 
 
31. Uhal BD et al. Am J Physiol. 1995;269(6 Pt 1):L819-L828.
32. Tsujino K et al. Am J Respir Crit Care Med. 2012;186(2):170-180.

AECs play an essential role in pulmonary function

Type I AECs
  • Comprise >90% of alveolar surface of lung33-35
  • Interface with pulmonary capillaries to provide a surface for gas exchange33,34
  • Are sensitive to damage33-35
Type II AECs
  • Are responsible for secreting surfactant34-36
  • Act as progenitor cells for both Type Iand II AECs33-36
  • Play a role in innate immunity34,36

33. Williams MC. Annu Rev Physiol. 2003;65:669-695.
34. Castranova V et al. Toxicol Appl Pharmacol. 1988;93(3):472-483.
35. Féréol S et al. Respir Physiol Neurobiol. 2008;163(1-3):3-16.
36. Fehrenbach H. Respir Res. 2001;2(1):33-46.

AECs appear to turn over most frequently in the peripheral lung during maintenance

The association between this turnover concentration and the earliest radiographic changes in IPF suggests that IPF may be related to these epithelial repair mechanisms38,39

37. Desai TJ et al. Nature. 2014;507(7491):190-194.
38. Rosas IO et al. Am J Respir Crit Care Med. 2007;176(7):698-705.
39. King TE Jr et al. Lancet. 2011;378(9807):1949-1961. 

In response to AEC death, multiple cell types release cytokines and chemokines

AEC death initiates a profibrotic response that results in extracellular matrix deposition, increased cell migration, and the formation of a fibroblastic focus39 
 
39. King TE Jr et al. Lancet. 2011;378(9807):1949-1961.

In response to AEC death, multiple cell types release cytokines and chemokines(cont.)

Surviving AECs, as well as activated platelets and inflammatory cells, release of a variety of cytokines and chemokines, including TGF-β and PDGF30,40-43
 
TGF-β, transforming growth factor-beta; PDGF, platelet-derived growth factor.

30. Selman M et al. Ann Intern Med 2001;134(2):136-151.
39. King TE Jr et al. Lancet. 2011;378(9807):1949-1961.
40. Gunther A et al. Thromb Haemost 2000;83(6):853-860.
41. Antoniades HN et al. J Clin Invest. 1990;86(4):1055-1064.
42. Scotton CJ et al. J Clin Invest. 2009;119(9):2550-2563.
43. Mercer PF et al. Am J Respir Crit Care Med. 2009;179(5):414-425.

TGF-β likely plays a role in lung fibrosis

Both in vitro and in vivo studies have suggested that overexpression of TGF-β can lead to lung fibrosis44-46

Clinical investigations have found increased levels of active TGF-β in the lungs of IPF patients47

44. Sime PJ et al. J Clin Invest. 1997;100(4):768-776.
45. Xu YD et al. Am J Physiol Lung Cell Mol Physiol. 2003;285(3):L527-L539.
46. Lee CG et al. J Exp Med. 2004;200(3):377-389.
47. Khalil N et al. Thorax. 2001;56(12):907-915.

These factors activate wound healing and epithelial repair pathways

  • In response to these molecular signals – particularly TGF-β – epithelial cells initiate repair programs30,45
  • Surviving epithelial cells also alter their phenotypes in response to injury-induced procoagulant signals39
30. Selman M et al. Ann Intern Med 2001;134(2):136-151.
39. King TE Jr et al. Lancet. 2011;378(9807):1949-1961.
45. Xu YD et al. Am J Physiol Lung Cell Mol Physiol. 2003;285(3):L527-L539.

These factors activate wound healing and epithelial repair pathways (cont.)

Localized production of TGF-β and PDGF also activate fibroblasts, which differentiate into myofibroblasts44,48

30. Selman M et al. Ann Intern Med 2001;134(2):136-151.
44. Sime PJ et al. J Clin Invest. 1997;100(4):768-776.
48. Bostrom H et al. Cell. 1996;85(6):863-873.

Other factors also contribute to fibroblast differentiation

This process appears to be mediated at least in part through activation of developmental pathways(eg, Wnt/β-catenin axis49-51, Sonic hedgehog pathway52) and altered microRNA expression53,54
 
49. Chilosi M et al. Am J Pathol. 2003;162(5):1495-1502.
50. Konigshoff M et al. PLoS One. 2008;3(5):e2142.
51. Tanjore H et al. Am J Respir Crit Care Med. 2013;187(6):630-639.
52. Bolanos AL et al. Am J Physiol Lung Cell Mol Physiol. 2012;303(11):L978-L990.
53. Pandit KV et al. Am J Respir Crit Care Med. 2010;182(2):220-229.
54. Milosevic J et al. Am J Respir Cell Mol Biol. 2012;47(6):879-887.

Myofibroblasts accumulate in fibroblast foci

These differentiated fibroblasts then secrete additional extracellular matrix as a part of the normal wound healing process23,30,44
 
23. Hecker L et al. Nat Med. 2009;15(9):1077-1081.
30. Selman M et al. Ann Intern Med 2001;134(2):136-151.
44. Sime PJ et al. J Clin Invest. 1997;100(4):768-776.

Additional signals promote fibroblast migration

Factors that signal fibroblasts to migrate to the injured region of the lung and deposit extracellular matrix include:
–Cytokines55-57
–Chemokines58 
–Lipid-mediated chemotaxis and proliferation59
–Possible recruitment of circulating fibrocytes60 
 
55. Xu SW et al. J Biol Chem. 2004;279(22):23098-23103.
56. Bogatkevich GS et al. Am J Physiol Lung Cell Mol Physiol. 2008;295(4):L603-L611.
57. Martinet Y et al. Nature 1986;319(6049):158-160.
58. Phillips RJ et al. J Clin Invest. 2004;114(3):438-446.
59. Tager AM et al. Nat Med. 2008;14(1):45-54.
60. Andersson-Sjoland A et al. Int J Biochem Cell Biol. 2008;40(10):2129-2140.

Recurrent or ongoing injury may lead to fibrosis instead of normal repair

Repeated cycles of injury and/or incomplete repair may lead to progressive scar formation, which results in clinically evident lung fibrosis over time39
 
39. King TE Jr et al. Lancet. 2011;378(9807):1949-1961.

Progression

Progression is characterized by fibroblast differentiation and ECM deposition and remodeling

  • Disease progression in IPF is mediated by repeated cycles of injury, ECM deposition, and abnormal tissue remodeling1,30
  • Repeated microinjury and aberrant wound healing response lead to clinically evident fibrosis over time39
ECM, extracellular matrix.

1. Wolters PJ et al. Annu Rev Pathol. 2014;9:157-179.
30. Selman M et al. Ann Intern Med 2001;134(2):136-151.
39. King TE Jr et al. Lancet. 2011;378(9807):1949-1961.

After injury, the ECM gets remodeled by a variety of cells

Differentiated fibroblasts (ie, myofibroblasts), epithelial cells, and macrophages produce a variety of MMPs and TIMPs that work to remodel the ECM61-65 
 
MMP, matrix metalloproteinase; TIMP, tissue inhibitors of matrix metalloproteinases.

61. Zuo F et al. Proc Natl Acad Sci U S A. 2002;99(9):6292-6297.
62. Pardo A et al. Fibrogenesis & Tissue Repair. 2012;5(Suppl 1):59.
63. Hayashi T et al. Am J Pathol. 1996;149(4):1241-1256.
64. Swiderski RE et al. Am J Pathol. 1998;152(3):821-828.
65. Ramos C et al. Am J Respir Cell Mol Biol. 2001;24(5):591-598.

Myofibroblasts produce increased amounts of collagen and other extracellular matrix proteins

  • Enhanced collagen production and matrix remodeling create a positive feedback cycle that alters gene expression patterns, leading to further myofibroblast differentiation and activation of TGF-β through stretch-mediated integrin signaling66-68 
  • These actions then further increase matrix remodeling1
1. Wolters PJ et al. Annu Rev Pathol. 2014;9:157-179.
39. King TE Jr et al. Lancet. 2011;378(9807):1949-1961.
66. Horowitz JC et al. J Biol Chem. 2004;279(2):1359-1367.
67. Booth AJ et al. Am J Respir Crit Care Med. 2012;186(9):866-876.
68. Henderson NC et al. Nat Med. 2013;19(12):1617-1624.

Epigenetic and transcription changes result in a profibrotic phenotype

Further epigenetic and transcriptional regulatory changes, along with alterations in microRNA expression, lead to large-scale alterations in cellular gene expression patterns, culminating in a profibrotic phenotype54,69-73
 
54. Milosevic J et al. Am J Respir Cell Mol Biol. 2012;47(6):879-887.
69. Sanders YY et al. Am J Respir Crit Care Med. 2012;186(6):525-535.
70. Rabinovich EI et al. PLoS One. 2012;7(4):e33770.
71. Nance T et al. PLoS One. 2014;9(3):e92111.
72. Liu G et al. J Exp Med. 2010;207(8):1589-1597.
73. Lino Cardenas CL et al. PLoS Genet. 2013;9(2):e1003291.

Over time, microscopic changes result in macroscopic disease

These processes result in macroscopic disease, including the gross architectural destruction and honeycomb-like cystic changes that characterize advanced IPF74

74. Kropski JA et al. Dis Model Mech. 2013;6(1):9-17.

Summary

  • The current hypothesis for IPF pathogenesis involves a predisposition, an initiation event, and progression1
  • Genetic factors are implicated in a patient’s predisposition to IPF8-10,75-76
  • Injury to the alveolar tissue is thought to initiate an aberrant wound healing response1
  • Failure to turn off wound healing pathways may lead to disease progression39
1. Wolters PJ et al. Annu Rev Pathol. 2014;9:157-179.
8. Fingerlin TE et al. Nat Genet. 2013;45(6):613-620.
9. Noth I et al. Lancet Respir Med. 2013;1(4):309-317.
10. Seibold MA et al. N Engl J Med. 2011;364(16):1503-1512.
39. King TE Jr et al. Lancet. 2011;378(9807):1949-1961.
75. Borie R et al. PLoS One 2013;8(8):e70621.
76. Stock CJ et al. Thorax. 2013;68(5):436-441.

References

1.Wolters PJ et al. Annu Rev Pathol. 2014;9:157-179.
2.Knipe RS et al. Pharmacol Rev. 2015;67(1):103-117.
3.Thomas AQ et al. Am J Respir Crit Care Med. 2002;165(9):1322-1328.
4.van Moorsel CH et al. Am J Respir Crit Care Med. 2010;182(11):1419-1425.
5.Wang Y et al. Am J Hum Genet. 2009;84(1):52-59.
6.Armanios MY et al. N Engl J Med. 2007;356(13):1317-1326.
7.Tsakiri KD et al. Proc Natl Acad Sci U S A. 2007;104(18):7552-7557.
8.Fingerlin TE et al. Nat Genet. 2013;45(6):613-620.
9.Noth I et al. Lancet Respir Med. 2013;1(4):309-317.
10.Seibold MA et al. N Engl J Med. 2011;364(16):1503-1512.
11.Hunninghake GM et al. N Engl J Med. 2013;368(23):2192-2200.
12.Roy MG et al. Nature. 2014;505(7483):412-416.
13.Kropski JA et al. Chest. 2014;146(1):e1-e7.
14.Steele MP et al. Am J Respir Crit Care Med. 2005;172(9):1146-1152.
15.Mulugeta S et al. Am J Respir Cell Mol Biol. 2005;32(6):521-530.
16.Alder JK et al. Proc Natl Acad Sci U S A. 2008;105(35):13051-13056.
17.Cronkhite JT et al. Am J Respir Crit Care Med. 2008;178(7):729-737.
18.O'Dwyer DN et al. Am J Respir Crit Care Med. 2013;188(12):1442-1450.
19.Rahman I et al. Free Radic Biol Med. 1999;27(1-2):60-68.
20.Waghray M et al. FASEB J. 2005;19(7):854-856.

References (cont.)

21.Kliment CR et al. J Biol Chem. 2009;284(6):3537-3545.
22.Bocchino M et al. PLoS One. 2010;5(11):e14003.
23.Hecker L et al. Nat Med. 2009;15(9):1077-1081.
24.Sueblinvong V et al. Am J Med. Sci 2012;344(1):41-51.
25.Araya J et al. Am J Physiol Lung Cell Mol Physiol. 2013;304(1):L56-L69.
26.Torres-Gonzalez E et al. Am J Respir Cell Mol Biol. 2012;46(6):748-756.
27.Heise RL et al. J Biol Chem. 2011;286(20):17435-17444.
28.Yamamoto H et al. Respir Physiol. 2001;127(2-3):105-111.
29.Cabrera-Benitez NE et al. Crit Care Med. 2012;40(2):510-517.
30.Selman M et al. Ann Intern Med. 2001;134(2):136-151.
31.Uhal BD et al. Am J Physiol. 1995;269(6 Pt 1):L819-L828.
32.Tsujino K et al. Am J Respir Crit Care Med. 2012;186(2):170-180.
33.Williams MC. Annu Rev Physiol. 2003;65:669-695.
34.Castranova V et al. Toxicol Appl Pharmacol. 1988;93(3):472-483.
35.Féréol S et al. Respir Physiol Neurobiol. 2008;163(1-3):3-16.
36.Fehrenbach H. Respir Res. 2001;2(1):33-46.
37.Desai TJ et al. Nature. 2014;507(7491):190-194.
38.Rosas IO et al. Am J Respir Crit Care Med. 2007;176(7):698-705.
39.King TE Jr et al. Lancet. 2011;378(9807):1949-1961.

References (cont.)

40.  Gunther A et al. Thromb Haemost. 2000;83(6):853-860.
41.  Antoniades HN et al. J Clin Invest. 1990;86(4):1055-1064.
42.  Scotton CJ et al. J Clin Invest. 2009;119(9):2550-2563.
43.  Mercer PF et al. Am J Respir Crit Care Med. 2009;179(5):414-425.
44.  Sime PJ et al. J Clin Invest. 1997;100(4):768-776.
45.  Xu YD et al. Am J Physiol Lung Cell Mol Physiol. 2003;285(3):L527-L539.
46.  Lee CG et al. J Exp Med. 2004;200(3):377-389.
47.  Khalil N et al. Thorax. 2001;56(12):907-915.
48.  Bostrom H et al. Cell. 1996;85(6):863-873.
49.  Chilosi M et al. Am J Pathol. 2003;162(5):1495-1502.
50.  Konigshoff M et al. PLoS One. 2008;3(5):e2142.
51.  Tanjore H et al. Am J Respir Crit Care Med. 2013;187(6):630-639.
52.  Bolanos AL et al. Am J Physiol Lung Cell Mol Physiol. 2012;303(11):L978-L990.
53.  Pandit KV et al. Am J Respir Crit Care Med. 2010;182(2):220-229.
54.  Milosevic J et al. Am J Respir Cell Mol Biol. 2012;47(6):879-887.
55.  Xu SW et al. J Biol Chem. 2004;279(22):23098-23103.
56.  Bogatkevich GS et al. Am J Physiol Lung Cell Mol Physiol. 2008;295(4):L603-L611.
57.  Martinet Y et al. Nature. 1986;319(6049):158-160.
58.  Phillips RJ et al. J Clin Invest. 2004;114(3):438-446.

References (cont.)

59.  Tager AM et al. Nat Med. 2008;14(1):45-54.
60.  Andersson-Sjoland A et al. Int J Biochem Cell Biol. 2008;40(10):2129-2140.
61.  Zuo F et al. Proc Natl Acad Sci U S A. 2002;99(9):6292-6297.
62.  Pardo A et al. Fibrogenesis Tissue Repair. 2012;5(Suppl 1):59.
63.  Hayashi T et al. Am J Pathol. 1996;149(4):1241-1256.
64.  Swiderski RE et al. Am J Pathol. 1998;152(3):821-828.
65.  Ramos C et al. Am J Respir Cell Mol Biol. 2001;24(5):591-598.
66.  Horowitz JC et al. J Biol Chem. 2004;279(2):1359-1367.
67.  Booth AJ et al. Am J Respir Crit Care Med. 2012;186(9):866-876.
68.  Henderson NC et al. Nat Med. 2013;19(12):1617-1624.
69.  Sanders YY et al. Am J Respir Crit Care Med. 2012;186(6):525-535.
70.  Rabinovich EI et al. PLoS One. 2012;7(4):e33770.
71.  Nance T et al. PLoS One. 2014;9(3):e92111.
72.  Liu G et al. J Exp Med. 2010;207(8):1589-1597.
73.  Lino Cardenas CL et al. PLoS Genet. 2013;9(2):e1003291.
74.  Kropski JA et al. Dis Model Mech. 2013;6(1):9-17.
75.  Borie R et al. PLoS One. 2013;8(8):e70621.
76.  Stock CJ et al. Thorax. 2013;68(5):436-441.