Protection by 20-5,14-HEDGE Against Surgically-Induced Ischemia Reperfusion Lung Injury in Rats

Authors

Irshad Ali, Medical College of Wisconsin
Stephanie Gruenloh, Medical College of Wisconsin
Ying Gao, Medical College of Wisconsin
Anne V. Clough, Marquette UniversityFollow
John R. Falck, University of Texas Southwestern Medical Center
Meetha Medhora, Medical College of Wisconsin
Elizabeth R. Jacobs, Medical College of Wisconsin

Document Type

Article

Language

eng

Publication Date

1-2012

Publisher

Elsevier

Source Publication

The Annals of Thoracic Surgery

Source ISSN

0003-4975

Original Item ID

DOI: 10.1016/j.athoracsur.2011.08.074

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.

Comments

Accepted version. The Annals of Thoracic Surgery, Vol. 93, No. 1 (January 2012): 282-288. DOI. © 2012 Elsevier. Used with permission.

Recommended Citation

Ali, Irshad; Gruenloh, Stephanie; Gao, Ying; Clough, Anne V.; Falck, John R.; Medhora, Meetha; and Jacobs, Elizabeth R., "Protection by 20-5,14-HEDGE Against Surgically-Induced Ischemia Reperfusion Lung Injury in Rats" (2012). Mathematics, Statistics and Computer Science Faculty Research and Publications. 266.
https://epublications.marquette.edu/mscs_fac/266