Lowe Alexander P P, Thomas Rhian S, Nials Anthony T, Kidd Emma J, Broadley Kenneth J, Ford William R
Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Redwood Building, Cardiff (A.P.P.L., R.S.T., E.J.K., K.J.B., W.R.F.), and Discovery Biology, Respiratory Centre of Excellence for Drug Discovery, GlaxoSmithKline Medicines Research Centre, Stevenage (A.T.N.), United Kingdom.
Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Redwood Building, Cardiff (A.P.P.L., R.S.T., E.J.K., K.J.B., W.R.F.), and Discovery Biology, Respiratory Centre of Excellence for Drug Discovery, GlaxoSmithKline Medicines Research Centre, Stevenage (A.T.N.), United Kingdom
J Pharmacol Exp Ther. 2017 Aug;362(2):327-337. doi: 10.1124/jpet.117.241927. Epub 2017 Jun 2.
Lipopolysaccharide (LPS) contributes to asthma exacerbations and development of inhaled corticosteroid insensitivity. Complete resistance to systemic corticosteroids is rare, and most patients lie on a continuum of steroid responsiveness. This study aimed to examine the sensitivity of combined ovalbumin- (Ova) and LPS-induced functional and inflammatory responses to inhaled and systemic corticosteroid in conscious guinea pigs to test the hypothesis that the route of administration affects sensitivity. Guinea pigs were sensitized to Ova and challenged with inhaled Ova alone or combined with LPS. Airway function was determined by measuring specific airway conductance via whole-body plethysmography. Airway hyper-responsiveness to histamine was determined before and 24 hours post-Ova challenge. Airway inflammation and underlying mechanisms were determined from bronchoalveolar lavage cell counts and lung tissue cytokines. Vehicle or dexamethasone was administered by once-daily i.p. injection (5, 10, or 20 mg/kg) or twice-daily inhalation (4 or 20 mg/ml) for 6 days before Ova challenge or Ova with LPS. LPS exacerbated Ova-induced responses, elongating early asthmatic responses (EAR), prolonging histamine bronchoconstriction, and further elevating airway inflammation. Intraperitoneal dexamethasone (20 mg/kg) significantly reduced the elongated EAR and airway inflammation but not the increased bronchoconstriction to histamine. In contrast, inhaled dexamethasone (20 mg/ml), which inhibited responses to Ova alone, did not significantly reduce functional and inflammatory responses to combined Ova and LPS. Combined Ova and LPS-induced functional and inflammatory responses are insensitive to inhaled, but they are only partially sensitive to systemic, dexamethasone. This finding suggests that the route of corticosteroid administration may be important in determining corticosteroid sensitivity of asthmatic responses.
脂多糖（LPS）会导致哮喘加重以及吸入性糖皮质激素不敏感的发生。对全身性糖皮质激素完全耐药的情况较为罕见，大多数患者处于糖皮质激素反应性的连续区间内。本研究旨在检测卵清蛋白（Ova）和LPS联合诱导的功能性及炎症反应对清醒豚鼠吸入性和全身性糖皮质激素的敏感性，以验证给药途径会影响敏感性这一假说。豚鼠对Ova致敏，然后单独吸入Ova或联合LPS进行激发。通过全身体积描记法测量比气道传导率来确定气道功能。在Ova激发前及激发后24小时测定气道对组胺的高反应性。从支气管肺泡灌洗细胞计数和肺组织细胞因子来确定气道炎症及潜在机制。在Ova激发或Ova与LPS激发前6天，每天一次腹腔注射（5、10或20mg/kg）或每天两次吸入（4或20mg/ml）溶媒或地塞米松。LPS加剧了Ova诱导的反应，延长了早期哮喘反应（EAR），延长了组胺诱导的支气管收缩，并进一步加剧了气道炎症。腹腔注射地塞米松（20mg/kg）显著缩短了延长的EAR并减轻了气道炎症，但并未减轻对组胺增加的支气管收缩。相比之下，吸入地塞米松（20mg/ml）虽能抑制单独对Ova的反应，但并未显著减轻对Ova和LPS联合刺激的功能性及炎症反应。Ova和LPS联合诱导的功能性及炎症反应对吸入性糖皮质激素不敏感，但对全身性地塞米松仅部分敏感。这一发现表明，糖皮质激素的给药途径在决定哮喘反应的糖皮质激素敏感性方面可能很重要。
