Faculty Collaboration Database

Protection by 20-5,14-HEDGE against surgically induced ischemia reperfusion lung injury in rats. Ann Thorac Surg 2012 Jan;93(1):282-8

Date

11/26/2011

Pubmed ID

22115333

Pubmed Central ID

PMC3268555

DOI

10.1016/j.athoracsur.2011.08.074

Scopus ID

2-s2.0-84055189348 (requires institutional sign-in at Scopus site)   16 Citations

Abstract

BACKGROUND: We previously reported that the cytochrome P450 product 20-hydroxyeicosatetraenoic acid has prosurvival effects in pulmonary artery endothelial cells and ex vivo pulmonary arteries. We tested the potential of a 20-hydroxyeicosatetraenoic acid analog N-[20-hydroxyeicosa-5(Z),14(Z)-dienoyl]glycine (20-5,14-HEDGE) to protect against lung ischemic reperfusion injury in rats. Furthermore, we examined activation of innate immune system components, high mobility group box 1 (HMGB1) and toll-like receptor 4 (TLR4), in this model as well as the effect of 20-5,14-HEDGE on this signaling pathway.

METHODS: Sprague-Dawley rats treated with 20-5,14-HEDGE or vehicle were subjected to surgically induced, unilateral lung ischemia for 60 minutes followed by reperfusion for 2 hours in vivo. Injury was assessed histologically by hematoxylin and eosin, and with identification of myeloperoxidase immunohistochemically. The HMGB1 and TLR4 proteins were identified by Western blot. Caspase 3 activity or 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, a yellow tetrazole, incorporation were used to measure apoptosis and cell survival.

RESULTS: The ischemia reperfusion injury evoked atelectasis and hemorrhage, an influx of polymorphonuclear cells, and increased TLR4 and HMGB1 expression. Caspase 3 activity was increased, and 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide incorporation was decreased. The 20-5,14-HEDGE protected against each of these endpoints, including infiltration of polymorphonuclear cells, with no changes in caspase 3 activity in other organs.

CONCLUSIONS: Lung ischemia reperfusion produces apoptosis and activation of the innate immune system including HMGB1 and TLR4 within 2 hours of reperfusion. Treatment with 20-5,14-HEDGE decreases activation of this response system, and salvages lung tissue.

Author List

Ali I, Gruenloh S, Gao Y, Clough A, Falck JR, Medhora M, Jacobs ER

Author

Anne Clough PhD Professor in the Mathematics, Statistics, and Computer Science department at Marquette University

MESH terms used to index this publication - Major topics in bold

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid
Acute Lung Injury
Animals
Apoptosis
Caspase 3
Disease Models, Animal
HMGB1 Protein
Lipopeptides
Lung
Male
Rats
Rats, Sprague-Dawley
Reperfusion Injury
Signal Transduction
Toll-Like Receptor 4