GPR68 as a novel modulator of septic lung injury

Severe sepsis is a common, expensive, and frequently fatal condition which is the leading cause of death in the ICU in the United States. Typically, 50% of all sepsis cases start as a pulmonary infection and vast majority of cases develop as mono-microbial sepsis. Alarming reports indicate that the frequency of gram-positive sepsis has been increasing, likely due to the ability of S. aureus to colonize intravascular catheters or surgically implanted materials, as well as the spread of antibiotic-resistant S. aureus, such as methicillin-resistant S. aureus (MRSA). Sepsis is typically accompanied by multiple organ dysfunction, cytokine storm, disseminated coagulation syndrome that often provoke indirect lung injury culminating in Acute Respiratory Distress Syndrome (ARDS). ARDS is also the primary means of respiratory failure and deaths from the ongoing COVID-19 pandemic. There are no effective pharmacological interventions for ARDS; rather, current treatment is primarily limited to respiratory support through mechanical ventilation; however, suboptimal ventilation volumes can worsen or even cause de novo lung injury. The hallmarks of ARDS are increased cytokine and chemokine levels, inflammatory cell infiltrates, fibrosis, and loss of vascular integrity. This project will test a novel hypothesis that mechano-sensitive proton sensing receptor GPR68 is a key mediator of ARDS pathophysiology that might control the magnitude of lung inflammation initiated by primary infection insult and mitigate ARDS severity associated with suboptimal mechanical ventilation. We will test this hypothesis using our novel first-in-class small molecule GPR68 inhibitor developed by our group through four specific aims: 1) To examine molecular mechanisms of GPR68 activation by pro-inflammatory factors in the in vitro and ex vivo models of inflammatory lung injury; 2) To study the functional role of GPR68 in modulation of pulmonary endothelial response to ARDS-related insults; 3) To examine mechano-sensitive regulation of GPR68 activity; 4) To evaluate a therapeutic potential of pharmacological GPR68 inhibition for mitigation of lung dysfunction in one-hit and two-hit mouse models of bacterial ALI. By better understanding how GPR68 contributes to lung barrier dysfunction and determining whether its inhibition can ameliorate the ARDS phenotype, we will be able to develop and test novel therapeutic agents for treatment of ARDS associated with sepsis, bacterial, viral infection, chemical injury, transfusion related lung injury and other.