Abstract
Acute lung injury (ALI) is characterized by alveolar damage, lung edema, and exacerbated inflammatory response. Growth arrest-specific protein 6 (Gas6) mediates many different functions, including cell survival, proliferation, inflammatory signaling, and apoptotic cell clearance (efferocytosis). The role of Gas6 in bleomycin (BLM)-induced ALI is unknown. We investigated whether exogenous administration of mouse recombinant Gas6 (rGas6) has anti-inflammatory and anti-apoptotic effects on BLM-induced ALI. Compared to mice treated with only BLM, the administration of rGas6 reduced the secretion of proinflammatory cytokines, including tumor necrosis factor-α, interleukin-1β, and macrophage inflammatory protein-2, and increased the secretion of hepatocyte growth factor in bronchoalveolar lavage (BAL) fluid. rGas6 administration also reduced BLM-induced inflammation and apoptosis as evidenced by reduced neutrophil recruitment into the lungs, total protein levels in BAL fluid, caspase-3 activity, and TUNEL-positive lung cells in lung tissue. Apoptotic cell clearance by alveolar macrophages was also enhanced in mice treated with both BLM and rGas6 compared with mice treated with only BLM. rGas6 also had pro-resolving and anti-apoptotic effects in mouse bone marrow-derived macrophages and alveolar epithelial cell lines stimulated with BLM in vitro. These findings indicate that rGas6 may play a protective role in BLM-induced ALI.
Highlights
Acute lung injury (ALI), a critical illness with high morbidity and mortality, is an intense pulmonary inflammatory response characterized by neutrophil recruitment, interstitial edema, disruption of epithelial integrity, and parenchymal injury [1]
Our data indicate that the administration of recombinant Gas6 (rGas6) reduced the levels of proinflammatory cytokines, such as TNF-α, IL-1β, and MIP-2, in bronchoalveolar lavage (BAL) fluid and enhanced the levels of the anti-inflammatory cytokine HGF post-BLM treatment. rGas6 suppressed neutrophil recruitment and protein levels in BAL fluid
The administration of rGas6 resulted in a significant reduction in caspase-3 activity and apoptosis of lung cells. rGas6 treatment enhanced the phosphorylation of the anti-apoptotic kinase Akt in lungs post-BLM treatment
Summary
Acute lung injury (ALI), a critical illness with high morbidity and mortality, is an intense pulmonary inflammatory response characterized by neutrophil recruitment, interstitial edema, disruption of epithelial integrity, and parenchymal injury [1]. The injurious event concomitantly activates a fibroproliferative response, which leads to increased fibroblast proliferation and extracellular matrix synthesis [2]. BLM causes an interstitial pneumonitis that can lead to fibrosis [6]. Because the development of fibrosis is directly influenced by the extent of the initial lung injury, it is critical to understand the early changes caused by BLM [7]. Despite improvements in supportive care, the overall mortality rate of ALI patients is still nearly 40% [2,8,9]
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