Fibrocytes Contribute to Inflammation and Fibrosis in Chronic Hypersensitivity Pneumonitis through Paracrine Effects

Rationale: Hypersensitivity pneumonitis (HP) represents a lung inflammation provoked by exposure to a variety of antigens. Chronic HP may evolve to lung fibrosis. Bone marrow derived fibrocytes migrate to injured tissues and contribute to fibrogenesis, but their role in HP is unknown. Objectives: To assess the possible participation of fibrocytes in chronic HP. Methods: CD45(+)/CXCR4(+)/Col-I+ circulating fibrocytes were evaluated by flow cytometry, and the presence of fibrocytes in HP and normal lungs by confocal microscopy. The concentration of CXCL12 in plasma and bronchoalveolar lavage fluids was quantified by ELISA. The effect of fibrocytes on lung fibroblasts and T lymphocytes was examined in co-cultures. Measurements and Main Results: The percentage of circulating fibrocytes was significantly increased in patients with HP compared with healthy individuals (5.3 +/- 3.4% vs. 0.8 +/- 0.7%; P = 0.00004). Numerous fibrocytes were found infiltrating the HP lungs near fibroblasts and lymphocytes. Plasma CXCL12 concentration was significantly increased in patients with HP (2,303.3 +/- 813.7 vs. 1,385.6 +/- 318.5 pg/ml; P=0.00003), and similar results were found in bronchoalveolar lavage fluids. The chemokine was primarily expressed by epithelial cells. In co-cultures, fibrocytes induced on lung fibroblasts a significant increase in the expression of alpha(1) type I collagen, matrix metalloprotease-1, and platelet-derived growth factor-beta. Likewise, fibrocytes induced the up-regulation of CCL2 in HP lymphocytes and fibroblasts. Conclusions: These findings demonstrate that high levels of fibrocytes are present in the peripheral blood of patients with chronic HP and that these cells infiltrate the HP lungs. Fibrocytes may participate in the pathogenesis of HP, amplifying the inflammatory and fibrotic response by paracrine signaling inducing the secretion of a variety of proinflammatory and profibrotic molecules.