The protective role of endogenous estrogens in carrageenan-induced lung injury in the rat.
BACKGROUND
We have recently demonstrated that 17beta-estradiol (E2) inhibits the increase of inducible nitric oxide synthetase (iNOS) activity in selected model systems such as macrophages, microglia, smooth muscle cells, and proposed that this effect might be associated with an anti-inflammatory activity of this hormone. Here we investigate the effects of endogenous estrogens in rats subjected to carrageenan-induced pleurisy.


METHODS
Adult female rats were ovariectomized 3 weeks before the experiments to deplete circulating estrogens. Selected inflammatory markers, landmarks of the delayed phase of carrageenan-induced pleurisy, were measured in intact (N-OVX), and ovariectomized (OVX) female rats. In addition, the effect of hormone replacement was evaluated in ovariectomized rats with intraperitoneal injection of 17beta-estradiol (E2; 50 microg/kg) 1 hr before carrageenan treatment (OVX + E2).


RESULTS
Ovariectomy enhanced the carrageenan-induced degree of pleural exudation and polymorphonuclear leukocyte migration in rats subjected to carrageenan-induced pleurisy. Lung myeloperoxidase (MPO) activity and lipid peroxidation were significantly increased in estrogens-deprived rats. The iNOS in lung samples was significantly increased by the surgery. The increase of iNOS activity was correlated with a marked enhancement in the production of TNF-alpha and IL-1beta. Immunohistochemical analysis for P-selectin and ICAM-I, as well as nitrotyrosine and poly (ADP-ribose) synthetase (PARS) revealed a positive staining in lungs from carrageenan-treated rats, which was markedly enhanced in ovariectomized rats when compared to cycling rats, particularly in the estrous phase of the cycle. Estrogen replacement counteracted the effect of surgery on all of the above indicators of lung inflammation, suggesting that in the cycling rat this hormone plays a key role in the increased sensitivity to inflammatory injury observed in the OVX rat.


CONCLUSIONS
This study demonstrates that endogenous estrogens production plays an important protective role against carrageenan-induced acute inflammation by decreasing the expression of specific markers of the delayed phase of this well-known model of acute inflammation.
Cuzzocrea
S
S
Institute of Pharmacology, University of Messina, Italy. salvator@www.unime.it
Mazzon
E
E
Sautebin
L
L
Serraino
I
I
Dugo
L
L
Calabró
G
G
Caputi
A P
AP
Maggi
A
A
D000818:Animals; D002351:Carrageenan / Q000633:toxicity; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D016207:Cytokines / Q000096:biosynthesis; D004958:Estradiol / Q000008:administration & dosage; D004967:Estrogens / Q000502:physiology*; D005260:Female; D015227:Lipid Peroxidation / Q000187:drug effects; D008168:Lung / Q000187:drug effects* / Q000503:physiopathology; D055370:Lung Injury; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D010052:Ovariectomy; D009195:Peroxidase / Q000378:metabolism; D010998:Pleurisy / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control; D051381:Rats; D017207:Rats, Sprague-Dawley
D016207:Cytokines; D004967:Estrogens; D004958:Estradiol; D002351:Carrageenan; D009195:Peroxidase