Novel therapeutic approaches for pulmonary fibrosis.
Pulmonary fibrosis represents the end stage of a number of heterogeneous conditions and is, to a greater or lesser degree, the hallmark of the interstitial lung diseases. It is characterized by the excessive deposition of extracellular matrix proteins within the pulmonary interstitium leading to the obliteration of functional alveolar units and in many cases, respiratory failure. While a small number of interstitial lung diseases have known aetiologies, most are idiopathic in nature, and of these, idiopathic pulmonary fibrosis is the most common and carries with it an appalling prognosis - median survival from the time of diagnosis is less than 3 years. This reflects the lack of any effective therapy to modify the course of the disease, which in turn is indicative of our incomplete understanding of the pathogenesis of this condition. Current prevailing hypotheses focus on dysregulated epithelial-mesenchymal interactions promoting a cycle of continued epithelial cell injury and fibroblast activation leading to progressive fibrosis. However, it is likely that multiple abnormalities in a myriad of biological pathways affecting inflammation and wound repair - including matrix regulation, epithelial reconstitution, the coagulation cascade, neovascularization and antioxidant pathways - modulate this defective crosstalk and promote fibrogenesis. This review aims to offer a pathogenetic rationale behind current therapies, briefly outlining previous and ongoing clinical trials, but will focus on recent and exciting advancements in our understanding of the pathogenesis of idiopathic pulmonary fibrosis, which may ultimately lead to the development of novel and effective therapeutic interventions for this devastating condition.
Centre for Respiratory Research, University College London, Rayne Institute, UK.
Arnab
A
Datta
Chris J
CJ
Scotton
Rachel C
RC
Chambers
D000818:Animals; D002986:Clinical Trials as Topic; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000188:drug therapy* / Q000473:pathology; D058990:Molecular Targeted Therapy
J Cell Biochem. 2003 Mar 1;88(4):660-72
12577300
Am J Respir Crit Care Med. 2000 Dec;162(6):2302-7
11112155
Sarcoidosis Vasc Diffuse Lung Dis. 2002 Mar;19(1):54-8
12002386
Respirology. 2009 Jul;14(5):723-8
19659650
Lab Invest. 1989 Apr;60(4):473-85
2651799
J Cell Mol Med. 2006 Jan-Mar;10(1):76-99
16563223
Expert Opin Investig Drugs. 2008 Jul;17(7):1137-40
18549349
Exp Lung Res. 1998 Nov-Dec;24(6):721-43
9839161
J Aerosol Med Pulm Drug Deliv. 2010 Jun;23(3):161-72
20109123
J Clin Invest. 2006 Jun;116(6):1606-14
16710477
J Immunol. 2003 Sep 1;171(5):2684-93
12928422
Nat Med. 2010 Sep;16(9):1009-17
20818376
J Clin Invest. 2009 Jan;119(1):213-24
19104148
Int J Immunopharmacol. 1999 Nov;21(11):759-75
10576621
Mol Biol Cell. 2004 Jun;15(6):2707-19
15047866
Am J Physiol. 1996 Oct;271(4 Pt 1):L495-505
8897895
Am J Pathol. 1993 Sep;143(3):651-5
8362967
Am J Respir Crit Care Med. 1997 May;155(5):1763-9
9154889
Thorax. 1995 Sep;50(9):984-9
8539681
Am J Respir Crit Care Med. 1997 Aug;156(2 Pt 1):631-6
9279250
J Investig Med. 1998 Jun;46(5):223-31
9676055
Am J Respir Crit Care Med. 2003 Aug 15;168(4):431-5
12746254
J Clin Invest. 1987 Apr;79(4):1285-8
3470308
Proc Natl Acad Sci U S A. 1989 Feb;86(3):802-6
2915979
Am J Respir Cell Mol Biol. 2004 Dec;31(6):679-86
15333329
Am J Physiol Lung Cell Mol Physiol. 2004 Jan;286(1):L156-64
12754187
Proc Natl Acad Sci U S A. 2002 Apr 30;99(9):6292-7
11983918
Am J Respir Crit Care Med. 2002 Aug 15;166(4):510-3
12186829
Prog Med Chem. 1985;22:165-242
3915365
Front Biosci (Elite Ed). 2009 Jun 01;1(1):115-22
19482630
N Engl J Med. 2005 Nov 24;353(21):2229-42
16306520
J Cell Sci. 1995 Jun;108 ( Pt 6):2241-51
7673344
Chest. 2004 Jun;125(6):2169-74
15189938
Am J Med. 2001 Mar;110(4):278-82
11239846
Cancer Res. 2002 Sep 1;62(17):4854-9
12208730
Arthritis Rheum. 1986 Jul;29(7):851-6
3091039
J Cell Biol. 1996 Jun;133(6):1403-15
8682874
J Environ Pathol Toxicol Oncol. 1999;18(3):169-77
15281229
Cancer Res. 2003 Apr 1;63(7):1657-66
12670920
J Clin Invest. 2004 Aug;114(3):438-46
15286810
Respir Res. 2010 Mar 20;11:34
20302663
FASEB J. 2005 Apr;19(6):580-2
15665032
Am J Respir Crit Care Med. 2002 Jan 15;165(2):229-35
11790660
Lancet. 1995 Oct 21;346(8982):1071-3
7564789
Int J Biochem Cell Biol. 2008;40(3):484-95
17931953
Proc Am Thorac Soc. 2006 Jun;3(4):373-6
16738203
Am J Respir Crit Care Med. 2008 Oct 15;178(8):838-46
18635891
Int Arch Allergy Immunol. 2003 Oct;132(2):168-76
14600429
Eur Respir J. 2010 Apr;35(4):728-9
20356985
PLoS One. 2009 Nov 24;4(11):e8013
19956603
J Pathol. 1985 Oct;147(2):107-19
4067730
Am J Respir Crit Care Med. 2003 Oct 1;168(7):770-8
12816739
Am J Physiol Lung Cell Mol Physiol. 2000 Jul;279(1):L143-51
10893213
J Immunol. 1999 Nov 15;163(10):5686-92
10553099
Am J Respir Crit Care Med. 2001 Oct 1;164(7):1171-81
11673205
J Exp Med. 2010 Aug 2;207(8):1589-97
20643828
Eur Respir J. 2002 Jun;19(6):1124-7
12108867
Nat Med. 2006 Jan;12(1):99-106
16327802
Thorax. 2008 Mar;63(3):251-8
17951277
Am J Respir Crit Care Med. 2005 Apr 15;171(8):889-98
15563636
Am J Respir Cell Mol Biol. 2002 Dec;27(6):752-8
12444036
Am J Respir Crit Care Med. 1996 Jun;153(6 Pt 1):1918-23
8665056
Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):4082-5
7513432
Chest. 2005 Nov;128(5 Suppl 1):526S-532S
16304243
Am J Respir Crit Care Med. 2005 Jun 1;171(11):1279-85
15735062
J Immunol. 1997 May 1;158(9):4129-36
9126972
Am J Respir Cell Mol Biol. 2002 Oct;27(4):419-27
12356575
Thorax. 1963 Sep;18:225-37
14064617
Am J Respir Cell Mol Biol. 1996 Feb;14(2):131-8
8630262
Am J Physiol Lung Cell Mol Physiol. 2003 Mar;284(3):L501-7
12573988
Am J Respir Crit Care Med. 2000 Apr;161(4 Pt 1):1172-8
10764308
Sarcoidosis Vasc Diffuse Lung Dis. 2004 Mar;21(1):35-42
15127973
Am J Respir Crit Care Med. 2000 Feb;161(2 Pt 1):646-64
10673212
EMBO J. 2004 Mar 10;23(5):1155-65
14976548
Wound Repair Regen. 2007 Sep-Oct;15(5):607-16
17971005
Am J Pathol. 1994 Jul;145(1):114-25
7518191
Eur J Pharmacol. 2008 Dec 3;599(1-3):44-53
18938156
Am J Respir Cell Mol Biol. 2010 Aug;43(2):161-72
19767450
Mol Med. 1994 Nov;1(1):71-81
8790603
Am J Pathol. 2005 May;166(5):1353-65
15855637
Eur Respir J. 2001 Feb;17(2):180-9
11334117
Science. 1989 Aug 18;245(4919):752-5
2475908
Biochem Cell Biol. 2003 Dec;81(6):355-63
14663501
FASEB J. 2004 Aug;18(11):1258-60
15208274
Pulm Pharmacol Ther. 1998 Apr-Jun;11(2-3):221-5
9918760
Recent Results Cancer Res. 2008;177:137-50
18084956
J Exp Med. 1998 Jun 1;187(11):1885-92
9607928
Nat Rev Mol Cell Biol. 2008 Mar;9(3):219-30
18270516
Proc Assoc Am Physicians. 1997 May;109(3):254-68
9154642
Am J Respir Cell Mol Biol. 1992 Nov;7(5):492-9
1419025
Cancer Res. 1991 Jan 15;51(2):672-5
1702361
Biochim Biophys Acta. 2010 Dec;1803(12):1386-95
20833210
Am J Pathol. 1998 Sep;153(3):825-32
9736031
J Immunol. 2007 Jul 1;179(1):708-14
17579094
J Nephrol. 2001 Nov-Dec;14(6):453-60
11783601
Am J Physiol Lung Cell Mol Physiol. 2010 Oct;299(4):L439-41
20675435
Am J Respir Crit Care Med. 2003 Sep 1;168(5):543-8
12773329
J Pathol. 2004 Apr;202(4):486-95
15095276
Cell Signal. 2007 Apr;19(4):659-71
17188462
Cytokine Growth Factor Rev. 2000 Mar-Jun;11(1-2):59-69
10708953
Am J Respir Cell Mol Biol. 1999 Dec;21(6):693-700
10572066
Am Rev Respir Dis. 1987 Jan;135(1):62-5
3099617
Thorax. 1995 Sep;50 Suppl 1:S53-8
7570466
Am Rev Respir Dis. 1989 Feb;139(2):370-2
2913886
Oncogene. 2000 Jul 20;19(31):3521-8
10918610
J Immunol. 1997 Jan 15;158(2):954-9
8993016
Thorax. 2006 Nov;61(11):980-5
16844727
Eur Respir J. 2002 May;19(5):906-11
12030732
Am J Respir Crit Care Med. 2002 Sep 1;166(5):646-50
12204859
Chest. 2007 Oct;132(4):1311-21
17934117
J Biol Chem. 1997 Jul 4;272(27):17097-103
9202027
Am J Respir Crit Care Med. 2010 Jul 1;182(1):73-82
20203246
J Lab Clin Med. 1995 Jun;125(6):779-85
7539478
Clin Exp Allergy. 2008 Apr;38(4):619-28
18266877
Thorax. 2004 Jan;59(1):31-8
14694243
Am J Respir Cell Mol Biol. 2004 Nov;31(5):510-6
15256388
Immunol Rev. 1999 Jun;169:175-94
10450517
Int J Biochem Cell Biol. 2008;40(10):2129-40
18374622
Am J Pathol. 2001 Oct;159(4):1383-95
11583966
Eur Respir J. 1998 Dec;12(6):1409-14
9877500
Am J Respir Crit Care Med. 2006 Aug 15;174(4):420-7
16690978
Oncogene. 1998 Oct 1;17(13):1743-7
9796704
J Immunol. 1998 May 1;160(9):4606-14
9574568
Histopathology. 1993 Apr;22(4):343-7
8514277
J Lab Clin Med. 2003 Mar;141(3):210-6
12624602
J Immunol. 2005 Jul 15;175(2):1224-31
16002726
Thorax. 2004 Nov;59(11):977-80
15516475
Mayo Clin Proc. 1997 Mar;72(3):201-9
9070193
J Clin Invest. 2009 Sep;119(9):2550-63
19652365
J Pharmacol Exp Ther. 2000 Mar;292(3):988-94
10688614
Exp Cell Res. 2005 Mar 10;304(1):16-27
15707570
Proc Am Thorac Soc. 2006 Jun;3(4):339-44
16738198
Am J Physiol Lung Cell Mol Physiol. 2006 Aug;291(2):L144-56
16473862
J Clin Invest. 2010 Jun;120(6):1950-60
20501949
Am J Pathol. 2003 Feb;162(2):533-46
12547711
Thromb Haemost. 1995 Aug;74(2):704-10
8585010
Am J Respir Crit Care Med. 2003 Sep 1;168(5):531-7
12791580
Histochem Cell Biol. 2008 Apr;129(4):453-62
18236067
Am J Respir Cell Mol Biol. 1992 Sep;7(3):293-9
1520492
Eur Respir J. 1999 Aug;14(2):376-82
10515417
Am J Pathol. 2005 Mar;166(3):675-84
15743780
J Clin Invest. 1996 Apr 15;97(8):1827-36
8621765
Drugs Today (Barc). 2010 Jul;46(7):473-82
20683502
J Cell Biol. 2007 Dec 17;179(6):1311-23
18086923
Am J Respir Crit Care Med. 2001 Dec 15;164(12):2239-42
11751193
Am J Respir Crit Care Med. 1994 Oct;150(4):967-72
7921471
Int J Biochem Cell Biol. 2008;40(3):362-82
17936056
Nat Rev Mol Cell Biol. 2003 Aug;4(8):657-65
12923528
J Cell Commun Signal. 2010 Mar;4(1):25-30
19916059
J Immunol. 2004 Sep 1;173(5):3425-31
15322207
Am J Respir Cell Mol Biol. 2003 Nov;29(5):537-44
12738687
Exp Lung Res. 1993 May-Jun;19(3):327-44
8319603
Am J Physiol Lung Cell Mol Physiol. 2003 Sep;285(3):L527-39
12598227
Am J Respir Crit Care Med. 2003 Dec 1;168(11):1358-65
14644925
J Inorg Biochem. 2004 Dec;98(12):2160-7
15541506
Am J Pathol. 2003 May;162(5):1495-502
12707032
J Clin Invest. 1990 Oct;86(4):1055-64
2170444
J Exp Med. 1989 Sep 1;170(3):655-63
2475571
Am J Pathol. 1991 May;138(5):1257-65
2024710
Lancet. 1991 Jul 27;338(8761):215-6
1676780
Br J Pharmacol. 2008 Mar;153 Suppl 1:S367-78
18223674
Respir Res. 2002;3:3
11806838
Mol Biol Cell. 2004 Oct;15(10):4532-43
15282343
Connect Tissue Res. 1989;20(1-4):289-94
2558843
Exp Mol Pathol. 2007 Aug;83(1):39-46
17274978
Am J Pathol. 2005 May;166(5):1321-32
15855634
Am J Pathol. 2010 Dec;177(6):2753-64
20971733
Am J Pathol. 2009 Apr;174(4):1264-79
19147812
Chest. 2005 Sep;128(3):1475-82
16162746
Am J Respir Crit Care Med. 2010 Jul 15;182(2):220-9
20395557
J Clin Invest. 1997 Aug 15;100(4):768-76
9259574
Am J Respir Crit Care Med. 2005 Feb 1;171(3):261-8
15502109
Cell. 1999 Feb 5;96(3):319-28
10025398
Curr Pharm Des. 2007;13(12):1247-56
17504233
J Pharmacol Exp Ther. 1999 Oct;291(1):367-73
10490926
Nature. 2006 Apr 27;440(7088):1222-6
16642001
J Exp Med. 2004 Aug 2;200(3):377-89
15289506
J Cardiovasc Pharmacol. 1998;31 Suppl 1:S360-3
9595482
Am J Respir Cell Mol Biol. 2011 Jul;45(1):136-44
21749980
Am J Pathol. 2003 Jul;163(1):345-54
12819039
Histol Histopathol. 1996 Apr;11(2):463-83
8861769
Nitric Oxide. 2002 Sep;7(2):109-18
12223180
Chest. 2000 Jun;117(6):1619-26
10858393
Am J Respir Crit Care Med. 2007 Jul 1;176(1):78-89
17431224
Am J Respir Crit Care Med. 2004 Jun 1;169(11):1179-80
15161610
N Engl J Med. 2004 Jan 8;350(2):125-33
14711911
Annu Rev Immunol. 2000;18:451-94
10837066
Am J Respir Crit Care Med. 2003 Feb 1;167(3):438-43
12406847
Free Radic Biol Med. 1999 Jul;27(1-2):60-8
10443920
Am J Respir Cell Mol Biol. 2001 May;24(5):591-8
11350829
Am J Respir Crit Care Med. 2009 Apr 1;179(7):588-94
19151190
Am Rev Respir Dis. 1991 Nov;144(5):1080-4
1952435
Am J Pathol. 2010 Jan;176(1):85-97
20008127
Am J Pathol. 2003 Dec;163(6):2523-30
14633624
Dig Dis Sci. 2010 Oct;55(10):2821-30
20108118
Antioxid Redox Signal. 2008 Feb;10(2):321-32
17999635
J Biol Chem. 2000 Nov 10;275(45):35584-91
10952976
J Clin Invest. 2009 Dec;119(12):3713-22
19884654
Am J Respir Crit Care Med. 1998 Nov;158(5 Pt 1):1524-7
9817703
Am J Respir Cell Mol Biol. 2007 Jul;37(1):3-8
17413030
Eur Respir J. 2005 Mar;25(3):528-33
15738299
Nature. 1999 Feb 25;397(6721):710-3
10067896
J Immunol. 2004 Apr 1;172(7):4068-76
15034018
Eur J Pharmacol. 2002 Jun 20;446(1-3):167-76
12098599
Cytokine. 2003 Apr;22(1-2):12-20
12946101
Am J Respir Crit Care Med. 1996 Aug;154(2 Pt 1):477-83
8756825
Eur Respir J. 2004 Jul;24(1):57-65
15293605
Antioxid Redox Signal. 2009 Feb;11(2):227-40
18783310
J Biol Chem. 1996 Jul 26;271(30):17779-84
8663511
Eur J Cell Biol. 2008 Sep;87(8-9):601-15
18342983
Am J Respir Crit Care Med. 2008 Jan 1;177(1):75-81
17901413
Ann N Y Acad Sci. 1990;580:233-44
2110794
Chest. 2002 Dec;122(6 Suppl):286S-289S
12475801
Int J Biochem Cell Biol. 2009 Aug-Sep;41(8-9):1708-18
19433312
Am J Respir Crit Care Med. 2007 Nov 15;176(10):1007-14
17717200
Eur Respir J. 2010 Apr;35(4):830-6
19840957
Am J Respir Crit Care Med. 2008 Jan 1;177(1):56-65
17916809
Chest. 2005 Jan;127(1):266-74
15653994
Eur Respir J. 2010 Apr;35(4):821-9
19996196
J Clin Microbiol. 2003 Jun;41(6):2633-40
12791891
Am J Physiol Lung Cell Mol Physiol. 2006 Nov;291(5):L887-95
16844946
Am J Respir Cell Mol Biol. 1997 Feb;16(2):187-93
9032126
Am J Respir Cell Mol Biol. 2006 Aug;35(2):175-81
16543609
Am Rev Respir Dis. 1991 Aug;144(2):291-6
1859050
Am J Respir Crit Care Med. 1997 Aug;156(2 Pt 1):600-8
9279246
Lab Invest. 2002 Oct;82(10):1335-45
12379768
Inflammation. 2000 Oct;24(5):477-91
10921510
PLoS One. 2006 Dec 27;1:e108
17205112
Hum Pathol. 1985 Oct;16(10):1015-24
4043950
Eur Respir J. 2002 Jun;19(6):1119-23
12108866
N Engl J Med. 2010 Aug 12;363(7):620-8
20484178
Am J Pathol. 1997 Mar;150(3):981-91
9060836
J Clin Invest. 2009 Apr;119(4):772-87
19287097
Am J Pathol. 2001 Apr;158(4):1411-22
11290559
Am J Respir Crit Care Med. 2001 Nov 15;164(10 Pt 1):1939-47
11734450
FEBS Lett. 1988 Oct 10;238(2):249-52
3139457
FASEB J. 2005 May;19(7):854-6
15857893
Am J Physiol. 1999 Feb;276(2):L311-8
9950894
Proc Natl Acad Sci U S A. 2006 Aug 29;103(35):13180-5
16924102
Am J Respir Cell Mol Biol. 1998 Jan;18(1):60-5
9448046
Biochem Biophys Res Commun. 1995 Apr 17;209(2):393-9
7733905
Thorax. 1980 Aug;35(8):593-9
7444826
Infect Immun. 2002 Jun;70(6):2989-94
12010989
Nat Med. 2008 Jan;14(1):45-54
18066075
Nat Rev Immunol. 2004 Aug;4(8):583-94
15286725
Eur Respir J. 1991 Jul;4(7):845-52
1720100
J Immunol. 2007 Aug 15;179(4):2592-9
17675522
Am J Respir Crit Care Med. 2009 May 15;179(10):903-13
19218193
Am J Physiol Lung Cell Mol Physiol. 2008 Jun;294(6):L1119-26
18390830
J Clin Invest. 2004 Nov;114(9):1308-16
15520863
Lancet. 2009 Jul 18;374(9685):222-8
19570573
Nat Med. 2009 Sep;15(9):1077-81
19701206
J Hepatol. 2002 Nov;37(5):584-91
12399223
J Biol Chem. 1982 Aug 10;257(15):8630-3
6954152
J Clin Pathol. 2001 Feb;54(2):132-8
11215282
Lancet. 1993 Jun 19;341(8860):1550-4
8099638
Cochrane Database Syst Rev. 2003;(3):CD003134
12917947
Biochim Biophys Acta. 1991 Jan 31;1091(2):231-5
1995081
Am J Physiol. 1999 May;276(5):L885-9
10330045
J Clin Invest. 1986 Mar;77(3):700-8
3081573
Chest. 1998 Aug;114(2):507-12
9726738
Arthritis Rheum. 2010 May;62(5):1523-32
20213804
Anat Rec. 1994 Jan;238(1):57-67
7509580
Am J Physiol. 1998 Dec;275(6):L1192-9
9843857
Proc Natl Acad Sci U S A. 2010 Aug 10;107(32):14309-14
20660310
Lab Invest. 1994 Feb;70(2):192-202
7511187
Eur Respir J. 1995 Aug;8(8):1286-92
7489792
Am J Respir Crit Care Med. 2010 Mar 15;181(6):604-10
20007927
N Engl J Med. 1999 Oct 21;341(17):1264-9
10528036
Eur J Pharmacol. 2002 Jun 20;446(1-3):177-85
12098600
Microcirculation. 2003 Jun;10(3-4):273-88
12851645
Lab Invest. 1982 Jan;46(1):39-53
7054589
Exp Lung Res. 1995 Sep-Oct;21(5):791-808
8556994
J Immunol. 1997 Aug 1;159(3):1437-43
9233641
Nature. 2000 Mar 23;404(6776):407-11
10746730
J Cell Sci. 1995 Mar;108 ( Pt 3):985-1002
7542672
Eur J Respir Dis. 1980 Dec;61(6):325-36
7202604
J Clin Invest. 1995 Apr;95(4):1861-8
7706493
Am J Respir Crit Care Med. 2000 Aug;162(2 Pt 1):755-8
10934117
Am J Respir Crit Care Med. 1998 Apr;157(4 Pt 1):1301-15
9563754
J Clin Invest. 1995 Jul;96(1):250-9
7542280
Am J Respir Crit Care Med. 2008 Nov 1;178(9):948-55
18669816