Bricher Choque Pamela Nithzi, Vieira Rodolfo P, Ulloa Luis, Grabulosa Caren, Irigoyen Maria Claudia, De Angelis Katia, Ligeiro De Oliveira Ana Paula, Tracey Kevin J, Pavlov Valentin A, Consolim-Colombo Fernanda Marciano
Laboratory of Pulmonary Immunology, Postgraduate Program in Medicine, Universidade Nove de Julho (UNINOVE), São Paulo, Brazil.
Post-graduation Program in Bioengineering and in Biomedical Engineering, Universidade Brasil, São Paulo, Brazil.
Front Pharmacol. 2021 May 4;12:624895. doi: 10.3389/fphar.2021.624895. eCollection 2021.
Acute respiratory distress syndrome (ARDS) is a critical illness complication that is associated with high mortality. ARDS is documented in severe cases of COVID-19. No effective pharmacological treatments for ARDS are currently available. Dysfunctional immune responses and pulmonary and systemic inflammation are characteristic features of ARDS pathogenesis. Recent advances in our understanding of the regulation of inflammation point to an important role of the vagus-nerve-mediated inflammatory reflex and neural cholinergic signaling. We examined whether pharmacological cholinergic activation using a clinically approved (for myasthenia gravis) cholinergic drug, the acetylcholinesterase inhibitor pyridostigmine alters pulmonary and systemic inflammation in mice with lipopolysaccharide (LPS)-induced ARDS. Male C57Bl/6 mice received one intratracheal instillation of LPS or were sham manipulated (control). Both groups were treated with either vehicle or pyridostigmine (1.5 mg/kg twice daily, 3 mg/day) administered by oral gavage starting at 1 h post-LPS and euthanized 24 h after LPS administration. Other groups were either sham manipulated or received LPS for 3 days and were treated with vehicle or pyridostigmine and euthanized at 72 h. Pyridostigmine treatment reduced the increased total number of cells and neutrophils in the bronchoalveolar lavage fluid (BALF) in mice with ARDS at 24 and 72 h. Pyridostigmine also reduced the number of macrophages and lymphocytes at 72 h. In addition, pyridostigmine suppressed the levels of TNF, IL-1β, IL-6, and IFN-γ in BALF and plasma at 24 and 72 h. However, this cholinergic agent did not significantly altered BALF and plasma levels of the anti-inflammatory cytokine IL-10. Neither LPS nor pyridostigmine affected BALF IFN-γ and IL-10 levels at 24 h post-LPS. In conclusion, treatments with the cholinergic agent pyridostigmine ameliorate pulmonary and systemic inflammatory responses in mice with endotoxin-induced ARDS. Considering that pyridostigmine is a clinically approved drug, these findings are of substantial interest for implementing pyridostigmine in therapeutic strategies for ARDS.
急性呼吸窘迫综合征（ARDS）是一种与高死亡率相关的危重病并发症。在重症新型冠状病毒肺炎（COVID-19）病例中已证实存在ARDS。目前尚无针对ARDS的有效药物治疗方法。免疫反应失调以及肺部和全身炎症是ARDS发病机制的特征性表现。我们对炎症调节的最新认识进展表明，迷走神经介导的炎症反射和神经胆碱能信号传导起着重要作用。我们研究了使用临床批准用于治疗重症肌无力的胆碱能药物、乙酰胆碱酯酶抑制剂吡啶斯的明进行药理学胆碱能激活，是否会改变脂多糖（LPS）诱导的ARDS小鼠的肺部和全身炎症。雄性C57Bl/6小鼠接受一次气管内注入LPS或进行假手术操作（对照）。两组在LPS注射后1小时开始，均通过口服灌胃给予溶剂或吡啶斯的明（1.5 mg/kg，每日两次，3 mg/天），并在LPS给药后24小时处死。其他组要么进行假手术操作，要么接受LPS处理3天，并给予溶剂或吡啶斯的明治疗，在72小时处死。吡啶斯的明治疗可降低ARDS小鼠在24小时和72小时时支气管肺泡灌洗液（BALF）中细胞总数和中性粒细胞数量的增加。吡啶斯的明在72小时时还可减少巨噬细胞和淋巴细胞数量。此外，吡啶斯的明在24小时和72小时时可抑制BALF和血浆中TNF、IL-1β、IL-6和IFN-γ的水平。然而，这种胆碱能药物并未显著改变抗炎细胞因子IL-10的BALF和血浆水平。在LPS给药后24小时，LPS和吡啶斯的明均未影响BALF中IFN-γ和IL-10的水平。总之，胆碱能药物吡啶斯的明治疗可改善内毒素诱导的ARDS小鼠肺部和全身的炎症反应。鉴于吡啶斯的明是一种临床批准的药物，这些发现对于将吡啶斯的明应用于ARDS治疗策略具有重要意义。
