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Innate Immune Processes Are Sufficient for Driving Cigarette Smoke–Induced Inflammation in Mice

¹ Department of Pathology and Molecular Medicine, Centre for Gene Therapeutics, ² Medical Sciences Program, and ³ Department of Medicine, McMaster University, Hamilton, Ontario, Canada

Correspondence and requests for reprints should be addressed to Martin R. Stämpfli, Ph.D., McMaster University Department of Pathology and Molecular Medicine 1200 Main Street West Hamilton, ON, L8N 3Z5 Canada. E-mail: stampfli{at}mcmaster.ca

The objective of this study was to characterize the impact of cigarette smoke exposure on lung immune and inflammatory processes. BALB/c and C57BL/6 mice were exposed to cigarette smoke for 4 days (acute) or at least 5 weeks (prolonged). Both mouse strains manifested an inflammatory response after acute smoke exposure, characterized by an influx of neutrophils and mononuclear cells. Multiplex analysis revealed a greater than twofold increase of the cytokines IL-1, -5, -6, and -18, as well as the chemokines monocyte chemotactic protein-1 and -3, macrophage inflammatory protein-1, -β, and -, -2, -3β, macrophage defined chemokine, granulocyte chemotactic protein-2, and interferon-–inducible protein-10. In BALB/c mice, neutrophilia persisted after prolonged exposure, whereas C57BL/6 showed evidence of attenuated neutrophilia both in the bronchoalveolar lavage and the lungs. In both mouse strains, cigarette smoke exposure was associated with an expansion of mature (CD11c^hi/major histocompatibility complex class II^hi) myeloid dendritic cells; we observed no changes in plasmacytoid dendritic cells. Lymphocytes in the lungs displayed an activated phenotype that persisted for CD4 T cells only after prolonged exposure. In BALB/c mice, T cells acquired T helper (Th) 1 and Th2 effector function after 5 weeks of smoke exposure, whereas, in C57BL/6 mice, neither Th1 nor Th2 cells were detected. In both mouse strains, cigarette smoke exposure led to an accumulation of FoxP3⁺ T regulatory cells in the lungs. Studies in RAG1 knockout mice suggest that these regulatory cells may participate in controlling smoke-induced inflammation. Acute and prolonged cigarette smoke exposure was associated with inflammation, activation of the adaptive immune system, and expansion of T regulatory cells in the lungs.

Key Words: cigarette smoke • flow cytometry • macrophages • dendritic cells • lymphocytes

CLINICAL RELEVANCE Cigarette smoke exposure in mice leads to activation of effector T cells, as well as accumulation of T regulatory cells in the lungs. Although lymphocytes are redundant to the inflammatory process, T regulatory cells appear to control the inflammatory response.