The July 2013 Rsearch Spotlight highlights recent work from the laboratory of Dr. Himanshu Gupta. Dr. Gupta earned the medical degree from the University of Delhi and subsequently completed an internal medicine residency at Wayne State University in 2000. From 2000 to 2004, he performed a clinical and research fellowship in the Division of Cardiovascular Disease at UAB, with specialty training in cardiovascular MRI. Dr. Gupta joined the faculty in the DOM in 2004 and holds the rank of Associate Professor. Dr. Gupta also serves as the Associate Director of the Cardiovascular Magnetic Resonance Center.
Dr. Gupta’s research program focuses on questions in the areas of both clinical and experimental pathophysiology. He is using advanced imaging modalities including cardiac magnetic resonance imaging (cMRI) to non-invasively characterize cardiovascular mechanics for the early detection and diagnosis of cardiovascular pathology. Dr. Gupta’s group is also studying anti-inflammatory mechanisms associated with administration of apolipoprotein mimetic peptides developed in the laboratory of G.M. Anantharamaiah. The current study describes protective effects of an apoA-I mimetic peptide in the context of acute respiratory distress syndrome secondary to sepsis.
Acute respiratory distress syndrome (ARDS) due to sepsis has a high mortality rate with limited treatment options. High density lipoprotein (HDL) exerts innate protective effects in systemic inflammation. However, its role in ARDS has not been well studied. Peptides such as L-4F mimic the secondary structural features and functions of apolipoprotein (apo)A-I, the major protein component of HDL. We set out to measure changes in HDL in sepsis-mediated ARDS patients, and to study the potential of L-4F to prevent sepsis-mediated ARDS in a rodent model of lipopolysaccharide (LPS)-mediated acute lung injury, and a combination of primary human leukocytes and human ARDS serum. We also analyzed serum from non-lung disease intubated patients (controls) and sepsis-mediated ARDS patients. Compared to controls, ARDS demonstrates increased serum endotoxin and IL-6 levels, and decreased HDL, apoA-I and activity of anti-oxidant HDL-associated paraoxanase-1. L-4F inhibits the activation of isolated human leukocytes and neutrophils by ARDS serum and LPS in vitro. Further, L-4F decreased endotoxin activity and preserved anti-oxidant properties of HDL both in vitro and in vivo. In a rat model of severe endotoxemia, L-4F significantly decreased mortality and reduces lung and liver injury, even when administered 1 hour post LPS. Our study suggests the protective role of the apoA-I mimetic peptide L-4F in ARDS and gram-negative endotoxemia and warrant further clinical evaluation. The main protective mechanisms of L-4F are due to direct inhibition of endotoxin activity and preservation of HDL anti-oxidant activity.