Cigarette smoke impairs clearance of apoptotic cells through oxidant-dependent activation of RhoA.

Abstract

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 gamma 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.

• Authors: Tiffany R Richens, Derek J Linderman, Sarah A Horstmann, Cherie Lambert, Yi-Qun Xiao, Robert L Keith, Darren M Boé, Konosuke Morimoto, Russell P Bowler, Brian J Day, William J Janssen, Peter M Henson, R William Vandivier
• Journal: American journal of respiratory and critical care medicine (Am J Respir Crit Care Med) Vol. 179 Issue 11 Pg. 1011-21 (Jun 01 2009) ISSN: 1535-4970 [Electronic] United States
• PMID: 19264974 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Tumor Necrosis Factor-alpha
• rho-Associated Kinases
• RhoA protein, mouse
• rho GTP-Binding Proteins
• rhoA GTP-Binding Protein

Topics

• Animals
• Apoptosis
• Cell Line, Tumor
• Humans
• Macrophages, Alveolar (drug effects, immunology)
• Male
• Mice
• Mice, Inbred ICR
• Mice, Knockout
• Neutrophils
• Oxidative Stress (drug effects, immunology)
• Phagocytosis (drug effects)
• Pulmonary Disease, Chronic Obstructive (physiopathology)
• Signal Transduction (drug effects)
• Smoking (immunology, physiopathology)
• Tumor Necrosis Factor-alpha
• rho GTP-Binding Proteins (drug effects, metabolism)
• rho-Associated Kinases (drug effects)
• rhoA GTP-Binding Protein