Kasetty Gopinath, Papareddy Praveen, Bhongir Ravi K V, Egesten Arne
Respiratory Medicine & Allergology (G.K., R.K.V.B., A.E.) and Infection Medicine (P.P.), Department of Clinical Sciences Lund, Lund University, Skåne University Hospital, Lund, Sweden
Respiratory Medicine & Allergology (G.K., R.K.V.B., A.E.) and Infection Medicine (P.P.), Department of Clinical Sciences Lund, Lund University, Skåne University Hospital, Lund, Sweden.
J Pharmacol Exp Ther. 2016 Apr;357(1):66-72. doi: 10.1124/jpet.115.229641. Epub 2016 Feb 10.
Exacerbations present a major clinical problem in many patients suffering from chronic obstructive pulmonary disease (COPD). Roflumilast, an inhibitor of phosphodiesterase 4, has shown beneficial effects in several clinical trials and is currently widely used to prevent exacerbations in severe COPD. Roflumilast has anti-inflammatory properties that may interfere with potentially important host defense functions, including cytotoxic properties of neutrophils at sites of inflammation. Since chronic bacterial infection is prevalent in severe COPD, Pseudomonas aeruginosa being a major pathogen, we hypothesized that this drug could impair host defense against P. aeruginosa. In this study, mice were pretreated with vehicle alone or roflumilast at doses of 5 mg/kg or 10 mg/kg, followed by instillation of P. aeruginosa in the airways. Bacterial load and dissemination, as well as inflammatory markers and immune cells, present in the airways were monitored. Roflumilast increased mortality, bacterial load, and dissemination in mice infected with P. aeruginosa. In addition, roflumilast-treated mice had significantly lower numbers of neutrophils in the bronchi, but not in the lung tissue airways, compared with untreated mice. Several proinflammatory cytokines decreased in roflumilast-treated mice but in neither the neutrophil-recruiting chemokine KC nor IL-6. These findings show that roflumilast treatment impairs host defense against P. aeruginosa in the airways, which may indicate that patients suffering from chronic bacterial infection of the airways could benefit from withholding of treatment with roflumilast.
急性加重是许多慢性阻塞性肺疾病（COPD）患者面临的主要临床问题。罗氟司特是一种磷酸二酯酶4抑制剂，在多项临床试验中显示出有益效果，目前广泛用于预防重度COPD的急性加重。罗氟司特具有抗炎特性，可能会干扰潜在的重要宿主防御功能，包括炎症部位中性粒细胞的细胞毒性特性。由于慢性细菌感染在重度COPD中普遍存在，铜绿假单胞菌是主要病原体，我们推测这种药物可能会损害宿主对铜绿假单胞菌的防御能力。在本研究中，小鼠分别用单独的赋形剂或5mg/kg或10mg/kg剂量的罗氟司特进行预处理，然后将铜绿假单胞菌滴注到气道中。监测气道中存在的细菌载量和扩散情况，以及炎症标志物和免疫细胞。罗氟司特增加了感染铜绿假单胞菌小鼠的死亡率、细菌载量和扩散。此外，与未治疗的小鼠相比，用罗氟司特治疗的小鼠支气管中的中性粒细胞数量显著减少，但肺组织气道中的中性粒细胞数量没有减少。在罗氟司特治疗的小鼠中，几种促炎细胞因子减少，但趋化因子KC和白细胞介素-6均未减少。这些发现表明，罗氟司特治疗会损害气道中宿主对铜绿假单胞菌的防御能力，这可能表明患有气道慢性细菌感染的患者可能会因停用罗氟司特治疗而受益。
