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Acute Effects of Estradiol on Lung Inflammation Due to Intestinal Ischemic Insult in Male Rats

Breithaupt-Faloppa, Ana Cristina*; Thais Fantozzi, Evelyn; Romero, Daniel Cancelli; Rodrigues, Adriana da Silva; de Sousa, Paulo Thales Rocha*; Lino dos Santos Franco, Adriana; Oliveira-Filho, Ricardo Martins; Boris Vargaftig, Bernardo; Tavares de Lima, Wothan

doi: 10.1097/SHK.0000000000000092
Basic Science Aspects

ABSTRACT Intestinal ischemia and reperfusion (intestinal I/R) causes acute lung inflammation that is characterized by leukocyte migration, increased lung microvascular permeability, and, in severe forms, noncardiogenic pulmonary edema and acute respiratory distress syndrome. Female sex hormones interfere with immune response, and experimental and clinical evidence shows that females are more resistant than males to organ injury caused by gut trauma. To reduce the lung inflammation caused by intestinal I/R, we have acutely treated male rats with estradiol. Intestinal I/R was performed by the clamping (45 min) of the superior mesenteric artery (SMA), followed by 2 h of intestinal reperfusion (unclamping SMA). Groups of rats received 17β estradiol (E2, 280 µg/kg, i.v., single dose) 30 min after the SMA occlusion (ischemia period) or 1 h after the unclamping of SMA (reperfusion period). Leukocytes influx into the lung and microvascular leakage were assessed by lung myeloperoxidase activity and Evans blue dye extravasation, respectively. The lung expression of adhesion molecules (intercellular adhesion molecule 1, platelet endothelial cell adhesion molecule 1, and vascular cell adhesion molecule [VCAM]) was evaluated by immunohistochemistry. Interleukin 1β (IL-1β), IL-10, and NOx concentrations were quantified in supernatants of cultured lung tissue. We have found that intestinal I/R increased the lung myeloperoxidase activity and Evans blue dye extravasation, which were reduced by treatment of rats with E2. Intestinal I/R increased ICAM-1 expression only, and it was decreased by E2 treatment. However, E2 treatment reduced the basal expression of platelet endothelial cell adhesion molecule 1. E2 treatment during intestinal ischemia was effective to reduce the levels of IL-10 and IL-1β in explant supernatant, but only IL-10 levels were reduced by E2 at reperfusion phase. The treatment with E2 did not affect NOx concentration. Taken together, our data suggest that estradiol modulates the lung inflammatory response induced by lung injury, likely by acute effects. Thus, acute estradiol treatment could be considered as a potential therapeutic agent in ischemic events.

*Laboratory of Cardiovascular Surgery and Physiopathology of Circulation (LIM-11), Heart Institute (InCor), Medicine School, Department of Pharmacology, Institute of Biomedical Sciences, and Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil

Received 12 Aug 2013; first review completed 3 Sep 2013; accepted in final form 7 Nov 2013

Address reprint requests to Wothan Tavares de Lima, PhD, Laboratório de Fisiopatologia da Inflamação Experimental, Instituto de Ciências Biomédicas, University of São Paulo, Av Prof Lineu Prestes, 1524, 05508-900 São Paulo, Brazil. E-mail:

This study was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP: 09/54823-2) and Conselho Nacional de Pesquisa (CNPq). W.T.L. is fellow researcher of CNPq.

© 2014 by the Shock Society