Protection from pulmonary fibrosis in the absence of CCR2 signaling

Pulmonary fibrosis can be modeled in animals by intratracheal instillation of FITC, which results in acute lung injury, inflammation, and extracellula r matrix deposition. We have previously shown that despite chronic inflamma tion, this model of pulmonary fibrosis is lymphocyte independent. The CC ch emokine monocyte-chemoattractant protein-1 is induced following FITC deposi tion. Therefore, we have investigated the contribution of the main monocyte -chemoattractant protein-1 chemokine receptor, CCR2, to the fibrotic diseas e process. We demonstrate that CCR2(-/-) mice are protected from fibrosis i n both the FITC and bleomycin pulmonary fibrosis models. The protection is specific for the absence of CCR2, as CCR5(-/-) mice are not protected. The protection is not explained by differences in acute lung injury, or the mag nitude or composition of inflammatory cells. FITC-treated CCR2(-/-) mice di splay differential patterns of cellular activation as evidenced by the alte red production of cytokines and growth factors following FITC inoculation c ompared with wild-type controls. CCR2(-/-) mice have increased levels of GM -CSF and reduced levels of TNF-alpha compared with FITC-treated CCR2(+/+) m ice. Thus, CCR2 signaling promotes a profibrotic cytokine cascade following FITC administration.