Soluble adenylyl cyclase isoform 10 (AC10 aka sAC) is an edema factor that increases mortality in an acute mouse model of P. aeruginosa-induced lung injury

Rationale: Bacterial pneumonia is a common cause of acute respiratory distress syndrome (ARDS). During ARDS, the pulmonary endothelial barrier, which is critical in maintaining efficient gas exchange, is disrupted, leading to increased permeability, fluid-filled airspaces and respiratory failure. Another key feature of ARDS is infiltration of immune cells which act to neutralize the pathogen, but an exacerbated immune response can induce collateral tissue damage and increase the severity of ARDS. Pulmonary microvascular endothelial soluble adenylyl cyclase isoform 10 (AC10 or sAC) is activated by bicarbonate to disrupt the endothelial barrier and is required for LPS-induced permeability in the isolated lung, yet its role in a mouse model of lung injury is not fully resolved. Thus, these studies tested the hypothesis that loss of AC10 attenuates lung edema and increased survival in a well-established model of P. aeruginosa -induced pneumonia. Methods: Wild type and AC10 knockout mice were intratracheally inoculated with P. aeruginosa (1E6 to 2.5E6 colony forming units, CFUs) or vehicle control (PBS). Following infection, bronchoalveolar lavage fluid (BALF) was collected and analyzed for protein content. Further, BALF and lung tissue was analyzed by FACS and flow cytometry for the number of CD45 + leukocytes and Ly6G + neutrophils. Mice were monitored over 96-hours to assess survival. Lungs were formalin-fixed for histological analysis of tissue damage. In order to determine bacterial clearance following infection, organs (lungs, kidney, liver, spleen and brain) were harvested 6- and 24-hours after inoculation, homogenized and the homogenates cultured overnight at 37°C on Pseudomonas isolation agar and the number of CFUs quantified. Results: Following infection, AC10 knockout mice had decreased protein content in BALF compared to wild type mice; however, there was no difference in number of CD45 + and Ly6G + cells detected in the BALF and lung tissue between wild type and AC10 knockout animals. Ninety-six hours post infection, AC10 knockout mice exhibit increased survival compared to wild type controls and histological analysis suggested attenuated lung injury in the AC10 knockout animals compared to wild type. Further, there was no difference in the ability of AC10 knockout versus wild type mice to clear bacteria from the lung or any of the organs tested. Conclusion: These findings suggest that in an acute mouse model of P. aeruginosa -induced lung injury, AC10 attenuates survival and increases alveolar-capillary permeability, yet following infection, AC10 does not regulate the number of leukocytes or neutrophils in the airspaces and tissue of the lung. Thus, AC10 is an edema factor that increases mortality in an acute mouse model of P. aeruginosa -induced lung injury. HL121513 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.