Gefitinib decreased lung fibrosis, but worsened inflammation, in rats

The early study suggested that TGF-α overexpression caused pulmonary fibrosis in transgenic mice [ref1], whereas TGF-α deficiency reduced pulmonary fibrosis in TGF-α knockout mice [ref2]. Therefore, it is plausible to treat patients with IPF by inhibition of TGF-α/EGF signaling. In a bleomycin-induced lung fibrosis model in mice,  it was shown that EGFR tyrosine kinase inhibitors, gefitinib and AG1478. Both inhibitors attenuated lung fibrosis [ref3].

Recently, Dr. Sone group examined the effect of gefitinib in a radiation induced injury model in rats. The new study found that gefitinib attenuated fibrotic lung remodeling, but exaggerated lung inflammation [ref4].



References

Hardie WD, Le Cras TD, Jiang K, Tichelaar JW, Azhar M, Korfhagen TR. Conditional expression of transforming growth factor-alpha in adult mouse lung causes pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 2004;286:L741–L749.


Madtes DK, Elston AL, Hackman RC, Dunn AR, Clark JG. Transforming growth factor-alpha deficiency reduces pulmonary fibrosis in transgenic mice. Am J Respir Cell Mol Biol 1999;20:924–934.

Ishii Y, Fujimoto S, Fukuda T. Gefitinib prevents bleomycin-induced lung
fibrosis in mice. Am J Respir Crit Care Med. 2006 Sep 1;174(5):550-6. Epub 2006
Jun 1. PubMed PMID: 16741154.

Miyake K, Tani K, Kakiuchi S, Suzuka C, Toyoda Y, Kishi J, Tezuka T, Yuasa S,
Hanibuchi M, Aono Y, Nishioka Y, Sone S. Epidermal growth factor
receptor-tyrosine kinase inhibitor (gefitinib) augments pneumonitis, but
attenuates lung fibrosis in response to radiation injury in rats. J Med Invest.
2012;59(1-2):174-85. PubMed PMID: 22450006.

PPARδ agonist for liver fibrosis in mice

Two peroxisome proliferator-activated receptor delta (PPARδ) agonists KD3010 and GW501516 were evaluated in their role in liver injury and fibrosis. Dr. Schnabla and colleagues in UCSD found that PPARδ agonist KD3010, but not GW501516, dramatically ameliorates liver injury and fibrosis in a carbon tetrachloride (CCl(4)) injection in mice.

Reference:
1: Iwaisako K, Haimerl M, Paik YH, Taura K, Kodama Y, Sirlin C, Yu E, Yu RT, Downes M, Evans RM, Brenner DA, Schnabl B. Protection from liver fibrosis by a peroxisome proliferator-activated receptor δ agonist. Proc Natl Acad Sci U S A. 2012 Apr 25. [Epub ahead of print] PubMed PMID: 22538808.

MMP3 and lung fibrosis

An increase in MMP3 was found in IPF lung tissue. Mmmp3–/– mice were protected from bleomycin induced lung fibrosis, through beta-catenin mediated EMT.


References:
Am J Pathol. 2011 Oct;179(4):1733-45. Epub 2011 Aug 24.
Matrix metalloproteinase 3 is a mediator of pulmonary fibrosis.
Yamashita CM, Dolgonos L, Zemans RL, Young SK, Robertson J, Briones N, Suzuki T, Campbell MN, Gauldie J, Radisky DC, Riches DW, Yu G, Kaminski N, McCulloch CA, Downey GP.
Source
Department of Medicine, University of Western Ontario, London, Ontario, Canada; Division of Pulmonary and Critical Care Medicine, Departments of Medicine and Pediatrics, National Jewish Health, Denver, Colorado.
Abstract
Idiopathic pulmonary fibrosis (IPF) may be triggered by epithelial injury that results in aberrant production of growth factors, cytokines, and proteinases, leading to proliferation of myofibroblasts, excess deposition of collagen, and destruction of the lung architecture. The precise mechanisms and key signaling mediators responsible for this aberrant repair process remain unclear. We assessed the importance of matrix metalloproteinase-3 (MMP-3) in the pathogenesis of IPF through i) determination of MMP-3 expression in patients with IPF, ii) in vivo experiments examining the relevance of MMP-3 in experimental models of fibrosis, and iii) in vitro experiments to elucidate possible mechanisms of action. Gene expression analysis, quantitative RT-PCR, and Western blot analysis of explanted human lungs revealed enhanced expression of MMP-3 in IPF, compared with control. Transient adenoviral vector-mediated expression of recombinant MMP-3 in rat lung resulted in accumulation of myofibroblasts and pulmonary fibrosis. Conversely, MMP-3-null mice were protected against bleomycin-induced pulmonary fibrosis. In vitro treatment of cultured lung epithelial cells with purified MMP-3 resulted in activation of the β-catenin signaling pathway, via cleavage of E-cadherin, and induction of epithelial-mesenchymal transition. These processes were inhibited in bleomycin-treated MMP-3-null mice, as assessed by cytosolic translocation of β-catenin and cyclin D1 expression. These observations support a novel role for MMP-3 in the pathogenesis of IPF, through activation of β-catenin signaling and induction of epithelial-mesenchymal transition.
Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
PMID: 21871427 [PubMed - in process] PMCID: PMC3181358 [Available on 2012/10/1]