Acute Respiratory Distress Syndrome (ARDS) is characterized by damage to alveolar epithelial barrier with subsequent pulmonary edema formation and profound hypoxia. Although there are many potential causes of ARDS, it is usually seen as a complication of mechanical ventilation in sepsis contributing to Multiple Organ Failure Syndrome. It is now recognized that injurious high tidal volume mechanical ventilation results in a condition called Ventilator-Induced Lung Injury (VILI) with pathological features identical to the early inflammatory phase of ARDS. VILI is thought to be a significant contributor to alveolar epithelial damage in ARDS. Human studies suggest that low-tidal volume ventilation reduces the chance of VILI. This observation led to the currently recommended ?lung protective ventilation strategies? but they offer only limited benefit because they cannot prevent alveolar over-distension and injury in the lung adjacent to the inflamed tissue. It will be critical to develop new therapies to retain epithelial integrity in patients at risk of lung injury. We have identified and recently published that the Protein kinase RNA-like Endoplasmic Reticulum Kinase (PERK)- activated Integrated Stress Response (ISR) intracellular signaling pathway has an important role in transmitting mechanical injury signals in the alveolar epithelium (Dolinay et al. AJRCMB 2017). We believe that further understanding of how this mechanical stress response pathway mediates barrier properties in the lung will provide us with new insights to the mechanism of injury and powerful levers to manipulate permeability. Based on our findings, we hypothesize that 1) injurious mechanical ventilation activates the ISR in the epithelium, and that chemical or genetic inhibition of ISR mitigates lung injury during stretch (Aim 1); and 2) the inhibition of ISR activation preserves the epithelial barrier by preventing the stretch-induced barrier dysfunction (Aim 2). To explore the validity of our hypothesis, the candidate will first develop an epithelial cell specific PERK gene deleted mice and expose them to VILI. Tissue and cellular injury responses in PERK-deleted and control mice will be used to identify downstream target molecules that modulate epithelial permeability. Second, using our in vitro primary isolated epithelial cell model, the candidate will delineate the mechano-sensor function of PERK in response to stretch injury. Findings will expand our understanding of the cellular pathology of VILI and provide potential new targets to inhibit injury signaling. The coordinated research and training plan will develop the candidate?s experience in epithelial cell imaging, advanced gene expression analysis, development of a novel epithelial specific PERK knock out mouse, and will provide the candidate with key preliminary data for an independent R01 grant application focused on conducting preclinical trials to translate ISR inhibition from the bench to bedside.
Acute respiratory distress syndrome (ARDS) is a common complication of injurious mechanical ventilation, called ventilator-induced lung injury (VILI), which carries significant disease burden and often leads to death. Our research identified that the Integrated Stress Response (ISR) intracellular pathway in alveolar epithelial cells is activated by mechanical stretch and contributes VILI. In this application the candidate outlined a detailed scientific plan to identify the role of the ISR in VILI, which will potentially lead to the development of new drugs that inhibit ISR activation and improve the outcome of this life-threatening disease.
