Fisher Aron B, Dodia Chandra, Tao Jian-Qin, Feinstein Sheldon I, Chatterjee Shampa
Department of Physiology and Institute for Environmental Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
Peroxitech, Inc., Philadelphia, PA 19104, USA.
Antioxidants (Basel). 2021 Oct 24;10(11):1676. doi: 10.3390/antiox10111676.
The use of agents to inhibit the production of reactive oxygen species (ROS) has been proposed for the treatment of Acute Lung Injury (ALI). However, this approach also inhibits the bactericidal activity of polymorphonuclear leucocytes (PMN) and other cells, raising the possibility of aggravating lung injury in ALI associated with bacterial infection. We used the cecal ligation and puncture (CLP) model of ALI associated with sepsis to investigate the effect of inhibiting NADPH oxidase 2 (NOX2)-derived ROS production, the main source of ROS in lungs. A phospholipase A inhibitor called peroxiredoxin 6 inhibitory peptide-2 (PIP-2) was used to inhibit NOX2 activation; the peptide prevents liberation of Rac, a necessary NOX2 co-factor. At 18 h after intravenous treatment with 2 µg PIP-2 /gram body weight (wt), the number of colony-forming bacteria in lungs and peritoneal fluid of mice with CLP was approximately doubled as compared to untreated mice. Treatment with 10 µg PIP-2/g body wt resulted in 100% mortality within 18 h. Antibiotic treatment abolished both the increase in lung bacteria with low dose PIP-2 and the increased mortality with high dose PIP-2. Treatment with PIP-2 plus antibiotics resulted in significantly improved lung histology, decreased PMN infiltration, decreased lung fluid accumulation, and decreased oxidative lung injury compared to antibiotics alone. We conclude that the administration of PIP-2 provides partial protection against lung injury in a model of ALI due to bacterial infection, while concurrent antibiotic treatment abolishes the deleterious effects of PIP-2 on lung bacterial clearance. These results suggest that addition of PIP-2 to the antibiotic regimen is beneficial for treatment of ALI associated with bacterial infection.
有人提出使用药物抑制活性氧（ROS）的产生来治疗急性肺损伤（ALI）。然而，这种方法也会抑制多形核白细胞（PMN）和其他细胞的杀菌活性，增加了在与细菌感染相关的ALI中加重肺损伤的可能性。我们使用与脓毒症相关的ALI盲肠结扎穿刺（CLP）模型，来研究抑制肺中ROS的主要来源——NADPH氧化酶2（NOX2）产生的ROS的效果。一种名为过氧化物酶6抑制肽-2（PIP-2）的磷脂酶A抑制剂被用于抑制NOX2的激活；该肽可阻止Rac（一种必要的NOX2辅助因子）的释放。在用2μg PIP-2/克体重（wt）进行静脉治疗18小时后，与未治疗的小鼠相比，CLP小鼠肺和腹腔液中的菌落形成细菌数量大约增加了一倍。用10μg PIP-2/克体重进行治疗导致18小时内死亡率达到100%。抗生素治疗消除了低剂量PIP-2导致的肺细菌增加以及高剂量PIP-2导致的死亡率增加。与单独使用抗生素相比，PIP-2加抗生素治疗可使肺组织学显著改善、PMN浸润减少、肺液积聚减少以及氧化性肺损伤减轻。我们得出结论，在因细菌感染导致的ALI模型中，给予PIP-2可提供部分肺损伤保护，而同时使用抗生素可消除PIP-2对肺细菌清除的有害影响。这些结果表明，在抗生素治疗方案中添加PIP-2对治疗与细菌感染相关的ALI有益。
