I. Differential gene expression in human peripheral blood monocytes and alveolar macrophages. II. Macrophage colony-stimulating factor is important in the development of pulmonary fibrosis.

摘要

Monocytes are precursors to tissue macrophages, and while numerous studies have examined monocyte differentiation in vitro, none have yet analyzed the gene expression profiles of native tissue macrophages compared to circulating monocytes. We aimed to generate a library of expression information detailing the distinction of these cell types. To this end, we performed a pilot study utilizing cDNA microarray technology. Our data indicates that several hundred genes are differentially regulated in peripheral blood monocytes and alveolar macrophages. These include genes involved in, or postulated to be involved in, cellular scavenging, intracellular signaling pathways, cellular survival and/or differentiation. Based on our observation that the chemokine receptor expression profiles of monocytes and alveolar macrophages differed in the gene array analysis, we confirmed these results by reverse transcriptase polymerase chain reaction, flow cytometry and functional analyses. Our data indicates that circulating monocytes express the chemokine receptors CCR1 and CCR2, and that monocytes functionally respond by migrating toward both MCP-1 and the macrophage inflammatory protein MIP-1α. In contrast, alveolar macrophages do not express CCR1 or CCR2, but do express the MIP-1α chemokine receptor CCR5. Alveolar macrophages did not respond to MCP-1 but did respond to MIP-1α in a migration assay. The addition of an anti-CCR5 blocking antibody completely abrogated MIP-1α-induced migration in alveolar macrophages, but did not affect monocytes. These data may be helpful in understanding the regulated recruitment of inflammatory cells, and in distinguishing the regulatory pathways controlling the recruitment of circulating monocytes and native alveolar macrophages in areas of lung inflammation.; This data is relevant to human disease, as in pulmonary fibrosis high concentrations of MCP-1 are found in the lung lavage fluid from affected patients but not in normal volunteers. Pulmonary fibrosis is a serious lung disease characterized by progressive scarring of the lung tissue, eventually leading to hypoxemia and death of the affected patient. In human idiopathic pulmonary fibrosis, prognosis is worsened in patients with more monocytes and macrophages in their lungs. We used an animal model of bleomycin-induced pulmonary fibrosis to examine the role of Macrophage Colony-Stimulating Factor (M-CSF) in the development of this disease. We chose this model because mice that are genetically deficient in M-CSF have decreased numbers of circulating monocytes and tissue macrophages, and provide a useful model for studying the role of these cells and this growth factor. We found that mice lacking M-CSF survived better, lost less weight and developed less fibrosis than their M-CSF normal littermates when treated systemically with weight-dependent doses of bleomycin. These data clearly implicate M-CSF-responsive monocytes and tissue macrophages in the development of pulmonary fibrosis.