CC-chemokine receptor 2 required for bleomycin-induced pulmonary fibrosis

• Published in: Cytokine (Philadelphia, Pa.) Pa.), 2003-12, Vol.24 (6), p.266-276
• Main Authors: Gharaee-Kermani, Mehrnaz, McCullumsmith, Robert E, Charo, Israel F, Kunkel, Steven L, Phan, Sem H
• Format: Article
• Language: English
• Subjects: Animals; Antibiotics, Antineoplastic - pharmacology; Bleomycin - pharmacology; Cell Differentiation - drug effects; Chemokine; Chemokine CCL2 - metabolism; Chemokine receptor; Fibroblasts - drug effects; Inflammation; Mice; Mice, Knockout; Pulmonary fibrosis; Pulmonary Fibrosis - metabolism; Receptors, CCR2; Receptors, Chemokine - genetics; Receptors, Chemokine - metabolism; TGF-β
• ISSN: 1043-4666; 1096-0023
• DOI: 10.1016/j.cyto.2003.08.003

MCP-1, which signals via the CC chemokine receptor 2 (CCR2), is induced in lung fibrosis that is accompanied by mononuclear cell recruitment and activation of lung fibroblasts. To evaluate the role of CCR2 in lung fibrosis, CCR2 knockout (ko) mice were used in a model of bleomycin-induced lung fibrosis. Wild type (wt) and ko mice were injected endotracheally with bleomycin to induce lung injury and fibrosis, and then analyzed for degree of lung fibrosis and cytokine expression. The results showed significantly reduced fibrosis in ko mice as evidenced by decreased lung type I collagen gene expression and hydroxyproline content relative to those in wt mice. Lung TNF-α and TGF-β1 expression was significantly lower in ko vs. wt mice, while MCP-1 expression was unaffected. Interestingly, lung α-smooth muscle actin (α-SMA) expression, a marker for myofibroblast differentiation, was also decreased in ko mice, which was confirmed by analysis of isolated lung fibroblasts. Fibroblasts from ko mice exhibited decreased responsiveness to TGF-β1 induced α-SMA expression, which was associated with reduced expression of TGF-β receptor II (TβRII) and Smad3. These findings suggest that CCR2 signaling plays a key role in bleomycin-induced pulmonary fibrosis by regulating fibrogenic cytokine expression and fibroblast responsiveness to TGF-β.