Gas6 Ameliorates Inflammatory Response and Apoptosis in Bleomycin-Induced Acute Lung Injury

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.

Potential protective effect of 3,3′-methylenebis(1-ethyl-4-hydroxyquinolin-2(1H)-one) against bleomycin-induced lung injury in male albino rat via modulation of Nrf2 pathway: biochemical, histological, and immunohistochemical study

“…In this research paper, the caspase-3 immuno-expression was significantly increased in the BLM group compared with control subgroups. This result agrees with a previous histopathological study (Elgendy et al 2021 ; Kim et al 2021 ). Some proinflammatory cytokines such as IL-1β, TNF-α, and IFN-γ induce cell death (apoptosis) in various cell types.…”

Administration of Gas6 Attenuates Lung Fibrosis via Inhibition of the Epithelial-Mesenchymal Transition and Fibroblast Activation

“…rGas6 (50 µg/kg) or saline treatment was given intraperitoneally (i.p.) 1 day before BLM treatment and then once every 2 days thereafter [20,21]. Mice were euthanized on day 14 or 21 following BLM treatment.…”

“…TAM signaling plays an important role in modulating the innate immune response. Previous research suggests that Gas6/Mer or Axl signaling plays a protective role in mouse models of multi-organ dysfunction syndrome, acute lung injury [17][18][19][20][21], and acute liver injury [22]. Furthermore, data from our previous in vitro study suggest that Gas6 signaling events may reprogram lung epithelial cells to resist EMT via the production of cyclooxygenase-2 (COX-2)-derived prostaglandin E2 (PGE2), PGD2, and their receptors [23].…”

Mechanisms of efferocytosis in determining inflammation resolution: Therapeutic potential and the association with cardiovascular disease

“…Thirdly, interventions targeting the critical molecules or pathways by which efferocytosis determines inflammation resolution may also provide therapeutic targets for inflammatory diseases. For example, the activation of TAM receptors through providing exogenous GAS6 and protein S may exert a protective effect in acute lung injury (Kim et al, 2021) and allergic bronchial asthma, respectively (Asayama et al, 2020). The agonist targeting LXR could increase SPMs synthesis in macrophages (Snodgrass et al, 2021) and promote inflammation resolution in acute lung injury (Madenspacher et al, 2020).…”