Tuesday, April 23, 2024
4/23/2024
¿ DESCRIPTION (provided by applicant): Acute Respiratory Distress Syndrome (ARDS) is a clinical syndrome of acute lung injury characterized by a sudden onset and a profound inability of the lungs to oxygenate the blood (hypoxemia). ARDS has a mortality rate of 30% and is responsible for 75,000 deaths annually in the United States despite extensive research efforts. The combination of sepsis plus mechanical ventilation significantly increases the risk for developing ARDS. Therefore, a two-hit model of acute lung injury is of great interest and has been studied extensively in animal models. However, the specific mechanisms underlying the development of acute lung injury through synergy of sepsis and mechanical ventilation (MV) remain unknown. Interleukin 1ß (IL-1ß) is implicated in the pathogenesis of ARDS, and its secretion is regulated by an intracellular complex termed the NLRP3 inflammasome, which we recently demonstrated is activated in macrophages by mitochondrial dysfunction and is associated with cell death. We developed a mouse model in which MV triggers macrophage mitochondrial dysfunction and cell death, and inhaled lipopolysaccharide (LPS) and MV together lead to IL-1ß secretion and the development of acute lung injury, as demonstrated by neutrophil infiltration, alveolar edema, chemokine secretion, and hypoxemia. Interestingly, when IL-1ß signaling was disrupted by the absence of caspase-1 or NLRP3, or by the administration of IL-1R antagonist Anakinra, we observed significant improvement in the development of hypoxemia without significant effects on neutrophil infiltration or alveolar leakage, indicating that the mechanism causing hypoxemia in lung injury is independent of lung inflammation but dependent on IL- 1ß signaling. These data suggest a novel role for IL-1ß and the NLRP3 inflammasome, specifically in the hypoxemia associated with acute lung injury and ARDS. We hypothesize that hypoxic pulmonary vasoconstriction, in which blood is diverted away from areas of poor gas exchange, can help to explain how the development of hypoxemia can be mechanistically distinct from inflammation. Literature suggests that IL- 1ß may modulate hypoxic pulmonary vasoconstriction by affecting nitric oxide production in the lung. Indeed, we found that MV increases expression of nitric oxide synthase 2 (NOS2) and nitric oxide production in the lung, and that Nos2-deficient mice were protected from the development of acute lung injury-related hypoxemia. Based on these data, the central hypothesis for this mentored K08 grant application is that the development of hypoxemia in acute lung injury requires NLRP3 inflammasome activation and IL-1ß secretion, and that the mechanism of hypoxemia is primarily through IL-1ß effects on hypoxic pulmonary vasoconstriction. We now propose to test our hypothesis through the following aims: Aim 1 is to determine the role of alveolar macrophages in the development of hypoxemia in acute lung injury; Aim 2 is to determine the role of nitric oxide in IL-1ß-dependent hypoxemia in acute lung injury; and Aim 3 is to determine if NLRP3 and IL-1ß signaling in acute lung injury disrupts hypoxic pulmonary vasoconstriction.
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