Connective Tissue Growth Factor Is Crucial to Inducing a Profibrotic Environment in “Fibrosis-Resistant” Balb/c Mouse Lungs

Abstract

The individual susceptibility to pulmonary fibrosis (PF) remains a mystery, suggesting a role for genetic predisposition. The pathogenesis of PF involves a multitude of factors mediating crosstalk between various tissue components. Some factors, such as transforming growth factor beta, are recognized as key elements in the process, whereas the role of others, such as connective tissue growth factor (CTGF), is unclear. We investigated if Balb/c mice, known to be fibrosis resistant partly due to lack of CTGF induction upon stimulation with bleomycin, can be transformed into fibrosis-sensitive individuals by generation of a CTGF-rich environment using transient overexpression of CTGF by adenoviral gene transfer (AdCTGF). We show that AdCTGF is not sufficient to cause fibrosis, and that bleomycin challenge results in inflammation, but not fibrosis, in Balb/c mouse lungs. This inflammation is accompanied by lower levels of CTGF and tissue inhibitor of metalloproteinase-1 gene expression compared with fibrosis-prone C57BL/6 mice. However, concomitant administration of AdCTGF and bleomycin leads to a persistent upregulation of tissue inhibitor of metalloproteinase-1 gene and a significant fibrotic response in Balb/c similar to that in C57BL/6 mice. We propose that CTGF is an important mediator in the pathogenesis of PF in that it provides a local microenvironment in the lung that causes individual susceptibility. CTGF should be considered as a novel drug target and as a potential marker for identifying individuals at risk.

Pivotal role of connective tissue growth factor in lung fibrosis: MAPK‐dependent transcriptional activation of type I collagen

“…Moreover, mice treated with the anti-CTGF antibody after bleomycin challenge displayed improved lung tissue architecture and reduced expression of type I collagen and ␣-SMA. Thus, these data are consistent with recent findings showing that, whereas CTGF overexpression is, on its own, insufficient for causing lung fibrosis in vivo, CTGF expression produces a susceptibility to lung fibrosis and enhances the fibrotic response (32,33). The findings from a very recent report, in which application of the anti-CTGF antibody reduced TGF␤-induced skin fibrosis in mice (34), also support our findings and strengthen the notion of a direct role for CTGF in fibrosis enhancement and progression.…”

“…First, in a bleomycin-resistant mouse model (BALB/c), CTGF was not up-regulated in response to challenge with bleomycin (6). Moreover, Bonniaud and colleagues further demonstrated that adenovirus-based delivery of CTGF to a bleomycin-sensitive mouse strain (C57BL/6) caused a transient fibrotic response (32), but in the resistant BALB/c strain, the lung was rendered susceptible to bleomycin-induced fibrosis (33).…”

α2-Antiplasmin Is Associated with the Progression of Fibrosis

“…26 An increase in CTGF expression is believed to induce a profibrotic environment. 27 We confirmed the expression of CTGF to be induced in bleomycin-injected mice. CTGF promotes fibroblast proliferation and myofibroblast differentiation, thereby inducing ECM production and fibrosis.…”

Complex Regulation of Pulmonary Inflammation and Fibrosis by CCL18

“…22,34,35 We first instilled mice with AdV-CCL18 as described 11 and then, at the peak of CCL18 production (day 7), performed a second intratracheal instillation with either PBS (as a control) or bleomycin in a lower (0.01 U/mouse) or higher (0.03 U/mouse) dose to induce lung inflammation and fibrosis. Of note, the selected doses of bleomycin alone were found to be insufficient to achieve a plateauing effect on lung inflammation and fibrosis in preliminary experiments (data not shown).…”