Monday, April 29, 2024
4/29/2024
PROJECT SUMMARY/ABSTRACT Overwhelming bacterial pneumonia injures and stiffens the lung leading to acute respiratory distress syndrome (ARDS) that carries a mortality of up to 50%. Given many failed pharmacologic treatments, ARDS management is supportive. ARDS is a consequence of endothelial and alveolar epithelial injury followed by recruitment and accumulation of inflammatory cells in the injured alveolus. Macrophages are the key effector cells in the lung injury process by phagocytizing invading pathogens and secreting cytokines. We have identified that the mechanosensitive ion channel, transient receptor potential vanilloid 4 (TRPV4), protects the lung from injury in an in vivo model of chronic Pseudomonas aeruginosa pneumonia through a novel mechanism of MAPK molecular switching, from JNK to p38. However, the key intracellular signaling molecules that link TRPV4 to the MAPK molecular switch and the precise cell phenotype/function that increases phagocytosis/bacterial clearance and decreases lung injury are unknown. Uncovering novel mechanosensitive signaling mechanisms that control macrophage function when the lung is injured/stiff will fulfill the unmet medical need to design therapies to treat this devastating disease. This research proposal investigates the mechanism whereby TRPV4 adapts the host defense to enhance the lung injury response to P. aeruginosa pneumonia. The long-term goal of our studies is to deduce TRPV4-dependent intracellular signals in macrophages that protect and resolve pneumonia- associated lung injury. Our preliminary data show that macrophage TRPV4 signals through specific intracellular signaling molecules to alter the macrophage activation response in vitro. Therefore, we propose the novel hypothesis: TRPV4 tailors the host response to protect the lung from injury after P. aeruginosa pneumonia through macrophage intracellular signals. This hypothesis will be tested through three interrelated, but independent specific aims: (1) to determine the mechanism whereby TRPV4 enhances macrophage phagocytosis, (2) to determine the mechanism whereby TRPV4 limits pro-inflammatory cytokine production, and (3) to compare the role of TRPV4 in alveolar vs interstitial macrophages in bacterial clearance and infection-induced lung injury after P. aeruginosa pneumonia in mice. Our proposal is innovative in concept as it is the first to implicate a matrix stiffness-sensing cation channel (TRPV4) and its intracellular signaling molecules in bacterial pneumonia and associated lung tissue injury. The proposed research is significant and relevant to the NIH’s mission as we aim to explore how TRPV4 in macrophages integrates the infection and matrix mechanical signaling to protect the lung from injury. The pathways discovered will identify novel therapeutic targets to treat infection-associated ARDS.
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