[EngO4-4] Crucial role of IL-1R signaling in neutrophils to increase lung permeability in LPS/mechanical ventilation acute lung injury
Background: Acute respiratory distress syndrome (ARDS) is very serious disease which leads to high mortality rate up to 25%. Due to its direct clinical impact, ARDS is an area of intense research. Neutrophilic lung inflammation is a key pathology of acute lung injury (ALI). Recently, we reported a critical role of NLRP3 inflammasome and interleukin (IL)-1 signaling for the development of hypoxemia in ALI model due to LPS plus high-volume mechanical ventilation (HVV). We hypothesized that IL-1 signaling contributes to the activation of neutrophils which results in the uptick of lung permeability leading to hypoxemia.
Methods: We created a two-hit mouse model of ALI by 2.5-hour long HVV (30 ml/kg) and intratracheal LPS (0.2 mg/kg) which was administered 2 hours before starting HVV. Measures of injury included arterial partial pressure of oxygen and bronchoalveolar lavage (BAL) parameters such as neutrophils counts, albumin and cytokine levels. We assessed the effect of neutrophils or IL-1R signaling against development of ALI using intraperitoneal anti-neutrophil (Ly6G[1A8]) monoclonal antibody (mAb) treatment and Il-1r1-deficient mice, respectively.
Results: Our two-hit model achieved significant hypoxemia, alveolar neutrophil infiltration and alveolar leakage. While LPS plus low-volume ventilation (LVV; 7 ml/kg) and LPS+HVV exhibited similar alveolar neutrophil infiltration, only LPS+HVV model had increased lung permeability resulting in hypoxemia although LPS+LVV did not develop hypoxemia. Anti-neutrophil mAb treatment significantly improved the development of hypoxemia and alveolar leakage with inhibition of alveolar neutrophil infiltration. In addition, Il1r1-deficient mice had significantly protected from hypoxemia and alveolar leakage despite similar alveolar neutrophil infiltration, suggested that two kinds of neutrophil activation are involved in hypoxemia induced by LPS+HVV. These findings were corroborated by increased myeloperoxidase and neutrophil elastase in BAL as markers of neutrophil activation, which was significantly inhibited in Il1r1-deficient mice.
Conclusion: Our data indicates that neutrophil activation via IL-1R signal is required for inducing lung vascular permeability in ALI model induced by LPS+HVV.
Methods: We created a two-hit mouse model of ALI by 2.5-hour long HVV (30 ml/kg) and intratracheal LPS (0.2 mg/kg) which was administered 2 hours before starting HVV. Measures of injury included arterial partial pressure of oxygen and bronchoalveolar lavage (BAL) parameters such as neutrophils counts, albumin and cytokine levels. We assessed the effect of neutrophils or IL-1R signaling against development of ALI using intraperitoneal anti-neutrophil (Ly6G[1A8]) monoclonal antibody (mAb) treatment and Il-1r1-deficient mice, respectively.
Results: Our two-hit model achieved significant hypoxemia, alveolar neutrophil infiltration and alveolar leakage. While LPS plus low-volume ventilation (LVV; 7 ml/kg) and LPS+HVV exhibited similar alveolar neutrophil infiltration, only LPS+HVV model had increased lung permeability resulting in hypoxemia although LPS+LVV did not develop hypoxemia. Anti-neutrophil mAb treatment significantly improved the development of hypoxemia and alveolar leakage with inhibition of alveolar neutrophil infiltration. In addition, Il1r1-deficient mice had significantly protected from hypoxemia and alveolar leakage despite similar alveolar neutrophil infiltration, suggested that two kinds of neutrophil activation are involved in hypoxemia induced by LPS+HVV. These findings were corroborated by increased myeloperoxidase and neutrophil elastase in BAL as markers of neutrophil activation, which was significantly inhibited in Il1r1-deficient mice.
Conclusion: Our data indicates that neutrophil activation via IL-1R signal is required for inducing lung vascular permeability in ALI model induced by LPS+HVV.