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.

Grant Number: 5R01HL167192-03
NIH Institute/Center: NIH
Principal Investigator: Anna Birukova