Mediator Of Airway Hyperreactivity Research Articles

Contribution of angiotensin II in hepatic ischemia /reperfusion induced lung injury: Acute versus chronic usage of captopril

BackgroundAcute lung injury is one of the most popular consequences of hepatic ischemia/reperfusion (I/R) injury. Recently it was documented that renin-angiotensin system plays a key role in tissue inflammation, generation of reactive oxygen species (ROS) and tumor necrosis factor-alpha (TNF-α) (the principal liver injury mediators) during I/R. Material and methodsWe investigated the effect of acute versus chronic usage of angiotensin converting enzyme inhibitor (captopril) on liver inflammation and lung injury caused by hepatic ischemia for 1h followed by 24h reperfusion. Forty adult Wistar male rats were divided into sham, I/R, I/R-acute captopril (100 mg/kg, 24 and 1.5 h before surgery) and I/R-chronic captopril (10 mg/kg/day for 28 days before surgery) groups. ResultsWe found captopril pretreatment significantly decreased liver damage indices, adhesion molecules, and TNF-α level in hepatic and tracheal tissues. Histologically, acute captopril pretreatment significantly decreased hepatic Kupffer cells number and lung α-smooth muscle actin expression more than chronic pretreatment. Increased tracheal tone, in response to acetylcholine, was suppressed by acute and chronic captopril pretreatment. ConclusionAngiotensin II plays a key role in tissue inflammation and airway hyperresponsiveness (AHR) via enhancing production of TNF-α. With more protection observed in lung, acute captopril could attenuate liver-induced lung injury via lowering TNF-α; a suggested possible mediator of airway hyperreactivity.

Tachykinin‐induced bronchoconstriction in sheep is NK‐1 receptor mediated and exhibits tachyphylaxis

Tachykinins are mediators of airway hyper-reactivity and inflammation. There is in vitro evidence that ovine responses to tachykinins correlate closely to human responses. This study was designed to characterize the effect of intravenously administered tachykinins on sheep lung resistance in vivo to determine the effect of dose timing on reproducibility of responses and the induction of tachyphylaxis. We then used this information to help further characterize the response with several pharmacological agents. Substance P (SP) was administered by infusion to conscious merino ewes and lung resistance (RL) was measured. Infusions were given at 30, 60, 120 min and 24 h intervals. The effect of various agents on the response to SP was then assessed. Substance P led to a transient increase in RL, mean (+/- SEM) 754.8 (+/- 139)% of baseline, with marked tachyphylaxis at 30, 60 and 120 min. Phosphoramidon increased the peak response to 1151.5 +/- 196%. Atropine and CP 96 345 abolished the response to SP, while indomethacin, sodium cromoglycate and pyrilamine had no significant effect. Substance P had a greater effect on RL than did neurokinin A. Substance P increases RL in sheep via a cholinergic mechanism which is mediated by NK-1 receptors, and is subject to tachyphylaxis. These findings have implications for the design of studies using the ovine model in the evaluation of tachykinin antagonists as potential therapeutic agents.

Enhancement of leukotriene D 4-induced contraction of guinea-pig isolated trachea by platelet activating factor

The effect of platelet activating factor (PAF), a potent lipid mediator of inflammation, was examined in the induction of airway hyperreactivity to known mediators of anaphylaxis. Concentration-dependent contractions of the isolated guinea-pig trachea to PAF (10 −7 − 10 −5M) were produced and an EC 50 value was found to be 7.5 × 10 −7M. Pretreatment for 30 min with a known PAF inhibitor, CV-3988 (10 −5 or 10 −4M), produced significant inhibition of PAF contractions; however, at 10 −6M, CV-3988 had no effect. In the presence of meclofenamic acid (10 −6M), the concentration-response curve to PAF was shifted significantly upward and to the left. This potentiation could be reversed by pretreating the tissues with the peptidoleukotriene antagonists, FPL 55712 or SK&F 102922 (10 −5M). Pretreatment with PAF concentrations having essentially no intrinsic activity (10 −8, 10 −7) significantly enhanced the contraction of guinea-pig trachea to various concentrations of LTD 4 and to certain concentrations of a thromboxane mimic (U-46619). Pretreatment with lyso-PAF failed to potentiate the LTD 4 response, while pretreatment with CV-3988 reverse the potentiation by PAF of the lower concentrations of LTD 4. However, PAF failed to enhance contractions (with or without the presence of meclofenamic acid) to acetylcholine, histamine, PGD 2 or LTC 4 (in the presence of serine borate). These results indicate a possible role for PAF as a mediator of airway hyperreactivity.