Protective Role of Rho Guanosine Diphosphate (GDP)‐Dissociation Inhibitor Ly‐GDI in Acute Pulmonary Alveolitis

Abstract

Ly‐GDI is an inhibitory protein of Rho GTPases. Growing evidences indicate that Ly‐GDI plays an essential role in regulating actin cytoskeletal alteration which is indispensible for the process such as phagocytosis. However, the role of Ly‐GDI in inflammation remains largely unknown. In the current study, we found that Ly‐GDI expression was significantly decreased in the IgG immune complex‐injured lungs. To determine if Ly‐GDI might regulate the lung inflammatory response, we constructed adenovirus vectors that could mediate ectopic expression of Ly‐GDI (Adeno‐Ly‐GDI). In vivo mouse lung expression of Ly‐GDI resulted in a significant attenuation of IgG immune complex‐induced lung injury, which was due to the decreased pulmonary permeability and lung inflammatory cells, especially neutrophil accumulation. Upon IgG immune complex deposition, mice with Ly‐GDI over‐expression in the lungs produced significant less inflammatory mediators (TNF‐α, IL‐6, MCP‐1, and MIP‐1α) in bronchoalveolar lavage fluid when compared control mice receiving airway injection of Adeno‐GFP. Mechanically, IgG immune complex‐induced NF‐κB activity was markedly suppressed by Ly‐GDI in both alveolar macrophages and lungs as measured by luciferase assay and electrophoretic mobility shift assay. These findings suggest that Ly‐GDI is a critical regulator of inflammatory injury after deposition of IgG immune complexes and that it negatively regulates the lung NF‐kB activity.