The study for the roles of intratracheally administered histamine in the neutrophil-mediated acute lung injury in rats:

Koh, Younsuck; Hybertson, Brooks M; Jepson, Eric K; Kim, Mi Jung; Lee, In Chul; Lim, Chae Man; Lee, Sang Do; Kim, Woo Sung; Kim, Dong Soon; Kim, Won Dong; Repine, John E

Abstract

BACKGROUND
Neutrophils are considered to play critical roles in the development of acute respiratory distress syndrome. Histamine, which is distributed abundantly in lung tissue, increases the rolling of neutrophills via increase of P-selectin expression on the surface of endothelial cells and is known to have some interrelationships with IL-1, IL-8 and TNF-alpha. We studied to investigate the effect of the histamine on the acute lung injury of the rats induced by intratracheal insufflation of TNF-alpha which has less potency to cause lung injury compared to IL-1 in rats.
METHODS
We intratracheally instilled saline or TNF(R&D, 500ng), IL-1(R&D, 50ng)or histamine of varius dose(1.1, 11 and 55 microg/kg) with and without TNF separately in Sprague-Dawley rats weighing 270-370 grams. We also intratracheally treated IL-l(50ng) along with histamine(55 microg/kg). In cases, there were synergistic effects induced by histamine on the parameters of TNF-induced acute lung injury, antihistainmes(Sigma, mepyramine as a H1 receptor blockade and ranitidine as a H2 receptor blockade, 10 mg/kg in each)were co-administered intravenously to the rats treated TNF along with histamine(1.1 microg/kg) intratracheally. Then after 5 h we measured lung lavage neutrophil numbers, lavage cytokine-induced neutrophil chemoatt- ractants(CINC), lung myeloperoxidase activity(MPO) and lung leak. We also intratracheally insufflated TNF with/without histamine(11 microg/kg), then after 24 h measured lung leak in rats. Statistical analyses were done by Kruskal-Wallis nonparametric ANOVA test with Dunn's multiple comparison test or by Mann-Whitney U test.
RESULTS
We found that rats given TNF, histamine alone(11 and 55 microg/kg), and TNF with histamine(1.1, 11, and 55 microg/kg) intratracheally had increased (P<0.05) lung MPO activity compared with saline-treated control rats. TNF with histamine 11 microg/kg had increased MPO activity (P=0.0251) compared with TNF-treated rats. TNF and TNF with histamine(l.l, 11,, and 55 microg/kg) intratracheally had all increased (P<0.05) lung leak, lavage neutophil numbers and lavage CINC activities compared with saline. TNF with histamine 1.1 microg/kg had increased (P=0.0367) lavage neutrophil numbers compared with TNF treated rats. But there were no additive effect of histamine with TNF compared with TNF alone in acute lung leak on 5 h and 24 h in rats. Treatment of rats with the H1 and H2 antagonists resulted in inhibitions of lavage neutrophil accumulations and lavage CINC activity elevations elicited by co-treated histamine in TNF-induced acute lung injury intratracheally in rats. We also found that rats given IL-1 along with histamine intratracheally did not have increase in lung leak compared with IL-1 treated rats.
CONCLUSION
Histamine administered intratracheally did not have synergistic effects on TNF-induced acute lung leak inspite of additive effects on increase in MPO activity and lavage neutrophil numbers in rats. These observations suggest that instilling histamine intratracheally would not play synergistic roles in neutrophil-mediated acute lung injury in rats.