Pulmonary pharmacology最新文献

Using radioactive tracers, we measured blood volume, albumin exchanges and blood leukocyte sequestration within lungs, following an intravenous injection of lipopolysaccharide (0.1–1 mglkg). Neutrophil infiltration into the airways was followed in parallel experiments. Dexamethasone pretreatment (20 mg/kg, subcutaneous) failed to prevent early pulmonary changes induced by lipopolysaccharide as decreased blood volume, leukocyte sequestration, leukopenia or the increased trans-endothelial albumin exchanges. However, dexamethasone provided a significant protection against the later albumin leakage through the endothelial/epithelial barrier and the neutrophil accumulation in the airways observed in lipopolysaccharide-treated guinea-pigs. Our results indicate that the protective effect of dexamethasone in lipopolysaccharide-induced lung injury might derive from an initial reduction of leukocyte adhesion and a later decrease in alveolo-capillary permeability.

Previous studies in our laboratory and others suggested that activation of 5-HT₂ receptors mediates 5-hydroxytryptamine (5-HT)-induced contraction of airway smooth muscle and that this response is dependent in part on endogenous acetylcholine (ACh). The purpose of the present study was to confirm a role for 5-HT₂ receptors and endogenous ACh in 5-HT-induced contraction of rat bronchi. In this study, we examined the effects of 5-HT₂ receptor antagonists (ketanserin and LY53857), acetylcholinesterase inhibitors (physostigmine and neostigmine), and a muscarinic receptor alkylating agent [propylbenzilylcholine mustard (PBCM) on contractile responses evoked by 5-HT and the 5-HT₂ receptor agonist, α-methyl-5-hydroxytryptamine (α-Me-5-HT). Concentration-response curves generated in isolated rat intrapulmonary bronchi in response to 5-HT and α-Me-5-HT were superimposable. Inhibition of acetylcholinesterase by physostigmine or neostigmine potentiated contractile responses elicited by 5-HT and α-Me-5-HT. Alkylation of muscarinic receptors with PBCM decreased maximal responses elicited by 5-HT or α-Me-5-HT in a concentration-dependent manner. Maximum contraction attained with exogenous ACh was decreased by PBCM in a concentration-dependent manner and, at the highest concentration evaluated, ACh-induced contractions were abolished. 5-Hydroxytryptamine-induced contraction was inhibited competitively by low concentrations of the 5-HT₂-receptor selective antagonist, ketanserin; higher concentrations abolished contractile responses to the amine. The inhibition of 5-HT-induced contractile responses by another 5-HT₂-receptor selective antagonist, LY53857, was non-competitive in nature. Together, the results suggest that 5-HT contracts rat airways directly by activating 5-HT₂ receptors located on airway smooth muscle and indirectly by activation of 5-HT₂ receptors on parasympathetic nerve endings to cause release of ACh. The potential physiological implication of these findings is that 5-HT released in inflammatory conditions such as asthma may play a role in causing bronchoconstriction by releasing ACh or by augmenting release of ACh from activated cholinergic nerves.

Many experimental protocols and published guidelines for performing bronchoscopy, bronchoalveolar lavage (BAL), bronchial biopsies, and segmental antigen challenge (SAC) of allergic asthmatic subjects recommend treating subjects with a β-agonist prior to the procedure. However, the effect of β-agonist pretreatment has not been reported. In a retrospective analysis of ragweed allergic subjects undergoing bronchoscopy, SAC, and BAL, we examined the effect of albuterol pretreatment on cellular influx and lung injury produced by antigen challenge. Forty-eight subjects, 17 who received no pretreatment and 31 who received four puffs of albuterol prior to bronchoscopy, comprised the study groups. No parameter monitored in BAL fluid 24 h after SAC (total cells, macrophages, neutrophils, eosinophiis, lymphocytes, total protein, albumin, or eosinophil cationic protein) differed in subjects pretreated with albuterol when compared with subjects who were not pretreated. Although additional, prospective studies are warranted, we conclude that β-agonist pretreatment of experimental subjects does not alter many aspects of the inflammatory response produced by SAC.

It has been considered that thromboxane A₂ (TXA₂) is involved in the development of bronchial hyperresponsiveness (BHR), a characteristic feature of asthma. To ensure the involvement of TXA₂ in BHR of asthma, effects of a 1-week treatment with two orally active TXA₂ antagonists, BAY u 3405 and S-1452, on BHR were examined in 10 and 13 patients with stable asthma, respectively, in two consecutive double-blinded, randomized, placebo-controlled, two-phase crossover studies. Provocative concentration of methacholine causing a 20% fall in FEV, (PC₂₀-FEV₁) with BAY u 3405 (0.78 (GSEM, 1.50) mg/ml) was significantly greater than the value with placebo (0.65 (GSEM, 1.46) mg/ml) (ratio 1.23 times, 95% CI 1.01 to 1.46: P=0.0401). PC₂₀-FEV₁ was also significantly increased with S-1452 (0.43 (GSEM, 1.39) mg/ml) compared with placebo (0.29 (GSEM, 1.27) mg/ml) (ratio 1.75 times, 95% CI 1.05 to 2.45: P=0.0189). Baseline pulmonary function was not altered by these treatments. These results may ensure that TXA₂ is significantly involved in the BHR of asthma while the degree of contribution may be small.

Summary: There is much evidence that neural mechanisms are involved in the mechanisms and symptoms of asthma. Afferent nerves may be activated and sensitized by inflammatory mechanisms, resulting in symptoms such us cough and chest tightness, in activation of cholinergic reflexes and in the release of inflammatory neuropeptides. Cholinergic mechanisms are the predominant bronchoconstrictor neural pathway and may be enhanced in asthma, particularly during exacerbations, through several mechanisms, including impaired function of muscarinic autoreceptors on cholinergic nerve terminals. There may also be abnormalities in adrenergic control and in the function of β-adrenoceptors, particularly in severe asthma. The neurotransmitter of bronchodilator nerves is now identified as nitric oxide and this mechanism may be impaired during asthma exacerbations. Finally, neurogenic inflammation, due to release of neuropeptides from sensory nerves, may contribute and amplify the inflammation in asthmatic airways.