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Cigarette Smoke Impairs Clearance of Apoptotic Cells through Oxidant-dependent Activation of RhoA

¹ Chronic Obstructive Pulmonary Disease Center, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Denver, Aurora, Colorado; ² Division of Pulmonary Sciences and Critical Care Medicine, Denver Veterans Administration Medical Center, Denver, Colorado; ³ Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan; and ⁴ Department of Medicine and ⁵ Department of Immunology, National Jewish Health, Denver, Colorado

Correspondence and requests for reprints should be addressed to R. William Vandivier, M.D., University of Colorado Denver, COPD Center, Division of Pulmonary Sciences and Critical Care Medicine, Research Building 2, Box C272, 12700 E. 19th Avenue, Aurora, CO 80045. E-mail: Bill.Vandivier{at}uchsc.edu

Rationale: Cigarette smoke (CS) is the primary cause of chronic obstructive pulmonary disease (COPD), an effect that is, in part, due to intense oxidant stress. Clearance of apoptotic cells (efferocytosis) is a critical regulator of lung homeostasis, which is defective in smokers and in patients with COPD, suggesting a role in disease pathogenesis.

Objectives: We hypothesized that CS would impair efferocytosis through oxidant-dependent activation of RhoA, a known inhibitor of this process.

Methods: We investigated the effect of CS on efferocytosis in vivo and ex vivo, using acute, subacute, and long-term mouse exposure models.

Measurements and Main Results: Acute and subacute CS exposure suppressed efferocytosis by alveolar macrophages in a dose-dependent, reversible, and cell type–independent manner, whereas more intense CS exposure had an irreversible effect. In contrast, CS did not alter ingestion through the Fc receptor. The inhibitory effect of CS on apoptotic cell clearance depended on oxidants, because the effect was blunted in oxidant-resistant ICR mice, and was prevented by either genetic or pharmacologic antioxidant strategies in vivo and ex vivo. CS inhibited efferocytosis through oxidant-dependent activation of the RhoA–Rho kinase pathway because (1) CS activated RhoA, (2) antioxidants prevented RhoA activation by CS, and (3) inhibitors of the RhoA–Rho kinase pathway reversed the suppressive effect of CS on apoptotic cell clearance in vivo and ex vivo.

Conclusions: These findings advance the hypothesis that impaired efferocytosis may contribute to the pathogenesis of COPD and suggest the therapeutic potential of drugs targeting the RhoA–Rho kinase pathway.

Key Words: pulmonary disease, chronic obstructive • phagocytosis • macrophages, alveolar • superoxides • Rho-associated kinases

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Clearance of apoptotic cells is impaired in smokers and patients with chronic obstructive pulmonary disease (COPD). However, the mechanism by which cigarette smoke (CS) dysregulates apoptotic cell homeostasis and the implications for disease pathogenesis have not been explored. What This Study Adds to the Field CS inhibits clearance of apoptotic cells through oxidant-mediated activation of the RhoA–Rho kinase pathway, advancing the hypothesis that failed apoptotic cell clearance contributes to the pathogenesis of COPD and suggesting a new therapeutic target.

 

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