Chest Department, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan; Department of Respiratory Therapy, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
PLoS One. 2014 Oct 13;9(10):e109953. doi: 10.1371/journal.pone.0109953. eCollection 2014.
High tidal volume (VT) mechanical ventilation (MV) can induce the recruitment of neutrophils, release of inflammatory cytokines and free radicals, and disruption of alveolar epithelial and endothelial barriers. It is proposed to be the triggering factor that initiates ventilator-induced lung injury (VILI) and concomitant hyperoxia further aggravates the progression of VILI. The Src protein tyrosine kinase (PTK) family is one of the most critical families to intracellular signal transduction related to acute inflammatory responses. The anti-inflammatory abilities of induced pluripotent stem cells (iPSCs) have been shown to improve acute lung injuries (ALIs); however, the mechanisms regulating the interactions between MV, hyperoxia, and iPSCs have not been fully elucidated. In this study, we hypothesize that Src PTK plays a critical role in the regulation of oxidants and inflammation-induced VILI during hyperoxia. iPSC therapy can ameliorate acute hyperoxic VILI by suppressing the Src pathway.
Male C57BL/6 mice, either wild-type or Src-deficient, aged between 2 and 3 months were exposed to high VT (30 mL/kg) ventilation with or without hyperoxia for 1 to 4 h after the administration of Oct4/Sox2/Parp1 iPSCs at a dose of 5×10(7) cells/kg of mouse. Nonventilated mice were used for the control groups.
High VT ventilation during hyperoxia further aggravated VILI, as demonstrated by the increases in microvascular permeability, neutrophil infiltration, macrophage inflammatory protein-2 (MIP-2) and plasminogen activator inhibitor-1 (PAI-1) production, Src activation, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, and malaldehyde (MDA) level. Administering iPSCs attenuated ALI induced by MV during hyperoxia, which benefited from the suppression of Src activation, oxidative stress, acute inflammation, and apoptosis, as indicated by the Src-deficient mice.
The data suggest that iPSC-based therapy is capable of partially suppressing acute inflammatory and oxidant responses that occur during hyperoxia-augmented VILI through the inhibition of Src-dependent signaling pathway.
大潮气量（VT）机械通气（MV）可诱导中性粒细胞募集、炎症细胞因子和自由基释放以及肺泡上皮和内皮屏障破坏。它被认为是引发呼吸机诱导性肺损伤（VILI）的触发因素，同时伴有的高氧进一步加重了 VILI 的进展。Src 蛋白酪氨酸激酶（PTK）家族是与急性炎症反应相关的细胞内信号转导中最重要的家族之一。诱导多能干细胞（iPSCs）的抗炎能力已被证明可改善急性肺损伤（ALI）；然而，调节 MV、高氧和 iPSCs 之间相互作用的机制尚未完全阐明。在这项研究中，我们假设 Src PTK 在高氧时调节氧化应激和炎症诱导的 VILI 中发挥关键作用。iPSC 治疗可通过抑制 Src 通路来改善急性高氧性 VILI。
雄性 C57BL/6 小鼠，野生型或 Src 缺陷型，年龄在 2 至 3 个月之间，在接受 Oct4/Sox2/Parp1 iPSCs 治疗后 1 至 4 小时内接受大潮气量（30 mL/kg）通气，同时给予或不给予高氧。未通气的小鼠作为对照组。
高氧时大潮气量通气进一步加重了 VILI，表现为微血管通透性增加、中性粒细胞浸润、巨噬细胞炎症蛋白-2（MIP-2）和纤溶酶原激活物抑制剂-1（PAI-1）产生增加、Src 激活、烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶活性和丙二醛（MDA）水平升高。给予 iPSCs 可减轻高氧增强的 MV 引起的 ALI，这得益于 Src 缺陷型小鼠中 Src 激活、氧化应激、急性炎症和细胞凋亡的抑制。
数据表明，iPSC 为基础的治疗方法能够通过抑制 Src 依赖性信号通路，部分抑制高氧增强的 VILI 期间发生的急性炎症和氧化应激反应。
