The Role of PPARs in Lung Fibrosis.
Pulmonary fibrosis is a group of disorders characterized by accumulation of scar tissue in the lung interstitium, resulting in loss of alveolar function, destruction of normal lung architecture, and respiratory distress. Some types of fibrosis respond to corticosteroids, but for many there are no effective treatments. Prognosis varies but can be poor. For example, patients with idiopathic pulmonary fibrosis (IPF) have a median survival of only 2.9 years. Prognosis may be better in patients with some other types of pulmonary fibrosis, and there is variability in survival even among individuals with biopsy-proven IPF. Evidence is accumulating that the peroxisome proliferator-activated receptors (PPARs) play important roles in regulating processes related to fibrogenesis, including cellular differentiation, inflammation, and wound healing. PPARalpha agonists, including the hypolidipemic fibrate drugs, inhibit the production of collagen by hepatic stellate cells and inhibit liver, kidney, and cardiac fibrosis in animal models. In the mouse model of lung fibrosis induced by bleomycin, a PPARalpha agonist significantly inhibited the fibrotic response, while PPARalpha knockout mice developed more serious fibrosis. PPARbeta/delta appears to play a critical role in regulating the transition from inflammation to wound healing. PPARbeta/delta agonists inhibit lung fibroblast proliferation and enhance the antifibrotic properties of PPARgamma agonists. PPARgamma ligands oppose the profibrotic effect of TGF-beta, which induces differentiation of fibroblasts to myofibroblasts, a critical effector cell in fibrosis. PPARgamma ligands, including the thiazolidinedione class of antidiabetic drugs, effectively inhibit lung fibrosis in vitro and in animal models. The clinical availability of potent and selective PPARalpha and PPARgamma agonists should facilitate rapid development of successful treatment strategies based on current and ongoing research.
Lakatos
Heather F
HF
Department of Environmental Medicine, University of Rochester, Rochester, NY 14642, USA.
Thatcher
Thomas H
TH
Kottmann
R Matthew
RM
Garcia
Tatiana M
TM
Phipps
Richard P
RP
Sime
Patricia J
PJ
Hepatology. 2004 Jan;39(1):97-108
14752828
Respir Res. 2005;6:102
16153299
Lab Invest. 1984 May;50(5):487-8
6201673
Am J Pathol. 1997 Aug;151(2):317-22
9250144
Mol Pharmacol. 2006 Jul;70(1):415-25
16611854
Curr Top Pathol. 1999;93:173-82
10339910
Gut. 2006 Jul;55(7):1020-9
16484506
Biochem Biophys Res Commun. 2006 Sep 15;348(1):253-8
16876120
J Cell Biol. 2001 Aug 20;154(4):799-814
11514592
Respir Res. 2002;3:1
11806836
Am J Pathol. 2006 Oct;169(4):1183-93
17003477
Chest. 2002 Dec;122(6 Suppl):286S-289S
12475801
Cancer Res. 2007 Mar 15;67(6):2595-602
17363578
Am J Respir Crit Care Med. 2003 Aug 15;168(4):436-42
12791582
Eur J Pharmacol. 2006 Mar 8;533(1-3):101-9
16458290
Exp Cell Res. 2000 May 25;257(1):180-9
10854066
Am J Respir Cell Mol Biol. 1999 Dec;21(6):658-65
10572062
Int J Obes Relat Metab Disord. 2003 Dec;27 Suppl 3:S41-5
14704743
Respir Res. 2006;7:104
16875506
J Clin Invest. 1997 Aug 15;100(4):768-76
9259574
Annu Rev Med. 2004;55:395-417
14746528
J Biol Chem. 2006 Mar 24;281(12):7960-7
16431920
Methods Mol Med. 2005;117:3-44
16130230
Curr Opin Pharmacol. 2006 Jun;6(3):263-70
16580256
Nature. 1990 Oct 18;347(6294):645-50
2129546
Mol Cell. 1999 Oct;4(4):585-95
10549290
Biochem Biophys Res Commun. 2004 Nov 12;324(2):697-704
15474484
Ann Intern Med. 2001 Jan 16;134(2):136-51
11177318
Am J Pathol. 2006 Sep;169(3):846-60
16936261
Curr Pharm Des. 2003;9(1):39-49
12570673
Semin Liver Dis. 1990 Feb;10(1):iii-iv
2186484
Pancreas. 2004 Jul;29(1):67-74
15211114
Cell. 1995 Dec 1;83(5):803-12
8521497
Am J Pathol. 2005 Oct;167(4):947-57
16192631
J Renin Angiotensin Aldosterone Syst. 2006 Sep;7(3):175-80
17094055
Curr Opin Pulm Med. 2000 Mar;6(2):151-6
10741776
Pulm Pharmacol Ther. 2006;19(1):39-46
16286236
J Am Soc Nephrol. 2005 Mar;16(3):638-45
15689403
Am J Epidemiol. 2000 Aug 15;152(4):307-15
10968375
J Pathol. 2003 Jul;200(4):500-3
12845617
Eur J Pharmacol. 2003 Nov 28;481(2-3):261-9
14642794
Am J Respir Cell Mol Biol. 2004 Jan;30(1):1-5
14512375
Arterioscler Thromb Vasc Biol. 2005 Jul;25(7):1364-9
15920037
Chest. 2005 Jan;127(1):275-83
15653995
Biochem Biophys Res Commun. 2006 Nov 17;350(2):385-91
17010940
Am J Physiol. 1997 Mar;272(3 Pt 1):G589-96
9124579
Clin Cancer Res. 2003 Jul;9(7):2798-806
12855660
Cell. 1995 Dec 1;83(5):813-9
8521498
Biochemistry. 1993 Jun 1;32(21):5598-604
7684926
J Biol Chem. 1997 Feb 7;272(6):3406-10
9013583
Am J Respir Cell Mol Biol. 2001 Jun;24(6):688-93
11415933
Pharmacol Rev. 2006 Dec;58(4):760-72
17132853
J Allergy Clin Immunol. 2004 May;113(5):882-8
15131570
Shock. 2005 Dec;24(6):547-55
16317386
Proc Am Thorac Soc. 2006 Aug;3(6):510-1
16921131
J Biol Chem. 2003 Jul 11;278(28):26046-54
12709421
Eur Respir J. 2005 Feb;25(2):225-34
15684285
Pancreas. 2002 Mar;24(2):130-8
11854617
Curr Opin Pulm Med. 2000 Mar;6(2):140-4
10741774
Am J Physiol Lung Cell Mol Physiol. 2005 Jun;288(6):L1146-53
15734787
Chest. 2004 Jun;125(6):2169-74
15189938
Gastroenterology. 2000 Aug;119(2):466-78
10930382
Chest. 2004 Feb;125(2):754-65
14769761
Am J Respir Cell Mol Biol. 2006 Feb;34(2):242-6
16239641
Am J Respir Crit Care Med. 2006 Jan 1;173(1):112-21
16179636
Am J Respir Crit Care Med. 1997 Jan;155(1):242-8
9001319
Nature. 1998 Jan 1;391(6662):82-6
9422509
Virchows Arch. 1997 Mar;430(3):195-207
9099976
J Biol Regul Homeost Agents. 2003 Jan-Mar;17(1):29-45
12757020
J Pathol. 2003 Nov;201(3):343-54
14595745
Trends Immunol. 2002 Mar;23(3):144-50
11864843
Hepatol Res. 2005 Aug;32(4):235-42
16085455
Proc Natl Acad Sci U S A. 2005 Feb 15;102(7):2340-5
15701701
Hypertension. 2003 Oct;42(4):737-43
12860836
Blood. 2004 Sep 1;104(5):1361-8
15130939
FASEB J. 2004 Sep;18(12):1477-9
15247146
Am J Respir Cell Mol Biol. 2003 Dec;29(6):677-82
12805087
Am J Physiol Renal Physiol. 2005 Nov;289(5):F1153-8
15886275
J Am Soc Nephrol. 2006 Jan;17(1):54-65
16291834
Curr Opin Pharmacol. 2006 Aug;6(4):421-7
16777482
Chest. 2006 Jun;129(6):1523-30
16778270
Expert Opin Ther Targets. 2004 Feb;8(1):39-48
14996617
Proc Am Thorac Soc. 2006 Jun;3(4):285-92
16738191
J Leukoc Biol. 2006 May;79(5):999-1010
16501055
Endocrinology. 1996 Jan;137(1):354-66
8536636
Clin Sci (Lond). 2002 Aug;103 Suppl 48:284S-288S
12193105
Inflamm Res. 2005 Nov;54(11):464-70
16307220
J Biol Chem. 1995 Jun 2;270(22):12953-6
7768881
Nephrol Dial Transplant. 2006 Sep;21(9):2399-405
16720596
Swiss Med Wkly. 2003 Jul 26;133(29-30):405-11
14562190
Clin Immunol. 2002 Apr;103(1):22-33
11987982
Clin Immunol. 2001 Jun;99(3):308-19
11358425
Biochem Biophys Res Commun. 2004 Feb 27;315(1):187-95
15013444
Hepatology. 2004 May;39(5):1286-96
15122757
FASEB J. 2006 Jul;20(9):1507-9
16720732
J Biol Chem. 2000 Nov 17;275(46):35715-22
10969082
Am J Respir Crit Care Med. 1998 May;157(5 Pt 1):1666-80
9603153
Proc Natl Acad Sci U S A. 2003 Jan 7;100(1):131-6
12502787
Biochemistry. 1990 Apr 17;29(15):3760-5
2340271
Proc Natl Acad Sci U S A. 1998 Jun 23;95(13):7614-9
9636198
J Steroid Biochem Mol Biol. 2003 Jun;85(2-5):267-73
12943712
Exp Lung Res. 2005 Sep;31(7):685-700
16203623
J Mol Endocrinol. 1993 Aug;11(1):37-47
8240670
Int J Cancer. 2006 May 15;118(10 ):2390-8
16425225
Hepatol Res. 2005 Oct;33(2):167-70
16198619