Mechanical ventilation is a life-saving intervention in critically ill patients with respiratory failure due to acute respiratory distress syndrome (ARDS). Paradoxically, mechanical ventilation also creates excessive mechanical stress that directly augments lung injury, a syndrome known as ventilator-induced lung injury (VILI).
The pathobiology of VILI and ARDS shares many inflammatory features including increases in lung vascular permeability due to loss of endothelial cell barrier integrity resulting in alveolar flooding. Unfortunately, insights into VILI pathobiology have been incremental with no viable therapies realized. One of the major research interests in the Division of Translational and Regenerative Medicine is to focus on increasing understanding of: i) the transcription factors that relay the effects of excessive mechanical stress; ii) post-translational modifications (PTMs) that influence key signaling pathways involved in responses to VILI; iii) racially- and ethnic-specific genetic and epigenetic influences in novel gene/protein targets involved in VILI responses; and iv) novel therapeutic strategies for VILI.
The key novel genes that comprise the focus of the studies on VILI and ARDS were identified by our genomic-intensive approaches and selected for their capacity to contribute to a spectrum of VILI responses ranging from VILI-induced lung inflammation, increased vascular permeability and injury; to VILI resolution with restoration of lung vascular barrier integrity. These strategies are integrated across various research projects by the investigators in the division and represent thematic underpinnings of the study focus in this field. These studies are conducted by an outstanding group of gifted and interactive translational scientists utilizing clinically-relevant pre-clinical models to mimic VILI in the setting of ARDS.
There are four projects currently ongoing on this topic:
- Project 1 is to extend novel insights regarding the critical role of nicotinamide phosphoribosyltransferase (NAMPT), encoding NAMPT, and TLR4 (Toll-like receptor 4) in excessive mechanical stress-induced NFκB signaling and lung injury. This project will detail contributions of NAMPT/TLR4 single nucleotide polymorphisms (SNPs) and PTMs and address NAMPT and TLR4 as therapeutic targets.
- Project 2 examines the NFκB-dependent mechanisms (including protein nitration) by which VILI downregulates expression of SOX18, a critical lung vascular barrier-protective transcription factor.
- Project 3 interrogates genetic and epigenetic regulation of mechanical stress-mediated sphingosine 1-phosphate receptor expression (S1PR1, S1PR3) and the role of VILI-induced nitration of Rac1 and RhoA GTPases in lung vascular barrier regulation.
- Project 4 studies the role of the signaling axis comprised of GADD45α (growth arrest and DNA damage-inducible gene), UCHL1 (ubiquitin carboxy-terminal hydrolase L1, a deubiquitinating enzyme), and Akt1 (a UCHL1 target and major barrier-regulatory kinase) in barrier-restoration following VILI.
The synergy derived from each project’s interactions with our four research cores—each with enviable expertise in molecular biology, genetic epidemiology, pre-clinical models of disease, and protein chemistry—will advance our programmatic approaches to promote the development of novel, individualized therapies to attenuate VILI especially in populations at risk for ARDS.
Related lines of research include: