Lung Vascular Permeability and Inflammatory Lung Injury

A Department of Medicine Research Spotlight

Professor of Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine
Merlin K. DuVal, MD, Endowed Chair for Leadership and Innovation, UA College of Medicine
Senior Vice President for Health Sciences, UA Health Sciences, University of Arizona

I’m a physician-scientist whose work has focused on the mechanistic basis of lung vascular permeability and on the genetic basis of inflammatory lung injury. Our laboratory, The Garcia Lab, is a state-of-the-art pulmonary research lab focusing on the genetics and proteomics of lung biology and disease. The lab encompasses a mosaic of specialized talents to investigate all aspects of research including gene discovery, protein function assessment, single nucleotide polymorphism (SNP) discovery, genetic manipulation, in vivo testing, and candidate gene and biomarker identification. Using this bench-to-bedside approach, we hope to translate our basic research into potential novel clinical therapies.

Medical imaging of lungsVascular leak occurs when blood cells and fluid escape from blood vessels into the surrounding tissues, including the lungs. This follows acute injury or infection and occurs in response to the stresses of mechanical ventilation. Acute lung injury is a complex illness with high mortality rate (> 35%) and often requires the use of mechanical ventilator support due to respiratory failure. Our studies of the basic biology of this process have focused on signal transduction pathways and the cytoskeleton of the endothelium. Our laboratory was the first to clone the non-muscle myosin light chain kinase (nmMLCK) gene and demonstrate the importance nmMLCK in actin-cytoskeleton reorganization of vascular endothelial cells (EC) during inflammatory response. In addition, our lab identified Pre-B cell colony enhancing factor (PBEF, aka NAMPT or visfatin) as a novel biomarker for inflammatory response and developed an anti-PBEF antibody treatment for neutralizing extracellular-secreted PBEF.

Here are a few examples of our translational biomedical research projects for the trainees at the resident/fellow level:

Project 1: To extend the mechanistic understanding of the role of post-translational modification (PTM) of nmMLCK in cytoskeleton rearrangement and acute respiratory distress syndrome (ARDS), we will identify the location of ARDS-related stimuli (such as LPS challenge)-induced tyrosine nitration on this key endothelial barrier regulatory protein, and confirm the functional outcome of the PTM on nmMLCK. In addition, we will confirm these PTMs on human ARDS patient tissues.

Project 2: To define the epigenetic regulation of NAMPT expression upon VILI, we will characterize the DNA methylation profile on the promoter of NAMPT gene upon VILI (ventilator-induced lung injury)-related stimuli, and elucidate the functional outcome of the DNA methylation dysregulation. In addition, we will further confirm these epigenetic regulations with human patient tissues.

Project 3: We will perform in-depth analysis of our human genetic data from our newly established patient cohorts (including ARDS, pulmonary hypertension, and idiopathic pulmonary fibrosis), such as GWAS (genome-wide association study) datasets, to identify the novel genetic variations and related genes which are significantly associated with these diseases.

 

Release Date: 
03/14/2016 - 5:15pm