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 dosedependent, reversible, and cell type-independent manner, whereas more intense CS exposure had an irreversible effect. In contrast, CS did not alter ingestion through the Fcg 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.

Vandivier RW, Richens TR, Horstmann SA, deCathelineau AM, Ghosh M, Reynolds SD, Xiao YQ, Riches DW, Plumb J, Vachon E, Downey GP, Henson PM. Dysfunctional cystic fibrosis transmembrane conductance regulator inhibits phagocytosis of apoptotic cells with proinflammatory consequences.

Background-Alcohol abuse increases the risk for acute respiratory distress syndrome (ARDS). Efferocytosis, the clearance of apoptotic cells, is important in the resolution of inflammation and is regulated by RhoA and rho kinase (ROCK) activation. The effects of alcohol on pulmonary Rho pathway activation and efferocytosis have not been determined. We hypothesize that acute and chronic alcohol exposure impair pulmonary efferocytosis, leading to heightened inflammation during ARDS.

Background: Serotonin (5-HT) contributes to the pathogenesis of chronic inflammatory diseases known to have defects in apoptotic cell removal (i.e. efferocytosis). Results: 5-HT impairs macrophage efferocytosis via 5-HT transporter-dependent activation of the RhoA/Rho kinase pathway. Conclusion: Results show a novel mechanism by which 5-HT might disrupt resolution of inflammation. Significance: Targeting the 5-HT transporter may have a therapeutic role in chronic inflammatory disorders.