A role for C‐C chemokines in fibrotic lung disease

Pulmonary fibrosis is the end point of a chronic inflammatory process characterized by leukocyte recruitment and activation, fibroblast proliferation, and increased extracellular matrix production. Previous studies of models of pulmonary fibrosis have investigated the role of cytokines in the evolution of the fibrotic response. The involvement of tumor necrosis factor and interleukin‐1 in bleomycin‐induced lung injury, a model of idiopathic pulmonary fibrosis, has been well established, suggesting that cytokines mediate the initiation and maintenance of chronic inflammatory lesions. However, the aforementioned cytokines alone cannot account for the recruitment and activation of specific leukocyte populations found in the bleomycin model. Recently, a family of novel proinflammatory cytokines (chemokines) was cloned and characterized, yielding many putative mediators of leukocyte functions. Macrophage inflammatory protein‐1α (MIP‐1α) and monocyte chemoattractant protein‐1 (MCP‐1) belong to the C‐C chemotactic cytokine family, a group of low‐molecular‐weight peptides. These molecules modulate chemotaxis, proliferation, and cytokine expression in leukocyte subsets. Our group has investigated the roles of MCP‐1 and MIP‐1α in the bleomycin model. Both MCP‐1 and MIP‐1α are expressed in a time‐dependent manner after bleomycin challenge, and passive immunization of these animals with either anti‐MIP‐1α or anti‐MCP‐1 antibodies attenuated leukocyte accumulation. In addition, we have identified specific cell types expressing MCP‐1 or MIP‐1α by in situ hybridization and immunohistochemical localization, respectively. Furthermore, our results indicate that MIP‐1α expression is mediated by alveolar macrophage‐derived tumor necrosis factor, identifying an important cytokine pathway in the initiation of pulmonary fibrosis. Finally, anti‐MIP‐1α therapy attenuated fibrosis, providing direct evidence for its involvement in fibrotic pathology. Our work has clearly established that the C‐C chemokines MCP‐1 and MIP‐1α are expressed and contribute to the initiation and maintenance of the bleomycin‐induced pulmonary lesion. J. Leukoc. Biol. 57: 782–787; 1995.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141648/1/jlb0782.pd

C‐C chemokine‐induced eosinophil chemotaxis during allergic airway inflammation

The production of eosinophil‐specific chemotactic factors during allergic airway responses may be a pivotal event resulting in eosinophil accumulation, activation, and airway damage. Recent studies have identified specific chemokines that may play crucial roles in recruitment of eosinophils to the site of allergic reactions. In this study we have utilized an established model of schistosome egg antigen (SEA)‐mediated allergic responses to examine the role of specific C‐C chemokines [macrophage inflammatory protein‐1α (MIP‐1α), RANTES, and monocyte chemoattractant protein‐1 (MCP‐1)] in eosinophil recruitment. We have previously identified a role for MIP‐1α in eosinophil accumulation in the lung and airway during allergic airway inflammation. We extend those studies using in vitro eosinophil chemotaxis to establish that both MIP‐1α and RANTES are potent eosinophil chemotactic factors in lungs during allergic airway responses. Morphometric analysis demonstrated a peribronchial accumulation of eosinophils within the lungs beginning at 8 h, peaking at 24 h, and plateauing at 48–96 h after allergen (SEA) challenge. Utilizing whole‐lung homogenates from allergen‐challenged mice, in vitro eosinophil chemotactic assays demonstrated significant increases in eosinophil chemotactic activity with 8‐h lung homogenates and peak activity with samples from 24‐h lung homogenates. These data correlated with the morphometric analysis of peribronchial eosinophil accumulation in situ. When lung homogenates from allergen‐challenged mice were preincubated in vitro with antibodies specific for MIP‐1α, RANTES, or MCP‐1, a significant reduction in eosinophil chemotaxis was observed with only MIP‐1α and RANTES neutralization. Altogether, these studies indicate that RANTES and MIP‐1α are major eosinophil chemotactic factors produced during allergic airway responses. J. Leukoc. Biol. 60:573–578; 1996.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141543/1/jlb0573.pd