增加SOCS-1使毒烟/雾霾吸入性肺损伤减少的机理

Smoke inhalation or haze leads to acute lung injury (ALI). Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is a devastating clinical problem associated with high mortality。We have found that 1) Suppressor of cytokine signaling-1 (SOCS-1) adeno virus- treated mice (Ad-SOCS-1) live significantly longer with smoke inhalation when compared to green fluorescent protein (GFP) adeno virus-treated (Ad-GFP) mice and SOCS-1 significantly ameliorates smoke-induced acute lung injury, 2) Ad-SOCS-1 cells protected from smoke-induced cell death are associated with reduce in apoptosis and inflammation, and 3) SOCS-1-induced protection against smoke-induced cell death is associated with low apoptosis signal regulating kinase 1 (ASK-1) expression. Our hypothesis is that SOCS-1 inhibits apoptosis and inflammation by inhibiting ASK-1 and inflammasome formation in smoke inhalation induced acute lung injury. We propose the following specific aims to test our hypothesis. Aim 1: To identify the role of ASK-1 in SOCS-1 inhibited death inducing signaling complex (DISC) induced apoptosis. Aim 2: To identify the role of ASK-1 in SOCS-1 inhibited NALP3 inflammasome formation. Aim 3: To determine whether activation of ASK-1 has a role in smoke induced purinergic P2X7 receptors (P2X7R) mediated inflammasome formation. The proposed studies will determine the effects and mechanisms that are mediated by SOCS-1, which confer cytoprotection and help in identifying the cellular processes and genes critical for protection from lung injury. An understanding of the mechanisms of SOCS-1 induced protection against lung injury will provide valuable insights towards therapeutic intervention in smoke inhalation or haze mediated diseases and the resolution of acute lung injury.

吸入火灾产生的毒烟/日常生活中的雾霾能引起急性肺损伤(ALI)。ALI和急性呼吸窘迫综合征(ARDS) 是临床常见的呼吸系统急危重症。我们发现：1）肺部转染细胞因子信号传导抑制因子重组腺病毒（Ad-SOCS-1）的小鼠对毒烟吸入性肺损伤有明显高的抵抗力，小鼠存活率显著增加；2）在转染SOCS-1表达质粒的细胞，毒烟诱导的细胞凋亡和炎症反应减少；3）在转染SOCS-1表达质粒的细胞，毒烟诱导的细胞凋亡信号调节激酶1（ASK-1）表达减少。我们推测：SOCS-1通过诱导ASK-1泛素化而抑制细胞凋亡和炎症反应，从而减少毒烟吸入性肺损伤。我们提出三个目标去检验我们的推测: 1）确定ASK-1在SOCS-1抑制死亡诱导信号复合物盘诱导的细胞凋亡中的作用；2）确定ASK-1在SOCS-1抑制NALP3炎性体形成中的作用；3）确定ASK-1在毒烟诱导嘌呤P2X7受体介导的炎性体形成中的作用。

吸入火灾产生的毒烟/日常生活中的雾霾能引起急性肺损伤(ALI)。ALI和急性呼吸窘迫综合征(ARDS) 是临床常见的呼吸系统急危重症。我们发现：1）肺部转染细胞因子信号传导抑制因子重组腺病毒（Ad-SOCS-1）的小鼠对毒烟吸入性肺损伤有明显高的抵抗力，小鼠存活率显著增加；2）在转染SOCS-1表达质粒的细胞，毒烟诱导的细胞凋亡和炎症反应减少；3）在转染SOCS-1表达质粒的细胞，毒烟诱导的细胞凋亡信号调节激酶1（ASK-1）表达减少。我们推测：SOCS-1通过诱导ASK-1泛素化而抑制细胞凋亡和炎症反应，从而减少毒烟吸入性肺损伤。我们提出三个目标去检验我们的推测: 1）确定ASK-1在SOCS-1抑制死亡诱导信号复合物盘诱导的细胞凋亡中的作用；2）确定ASK-1在SOCS-1抑制NALP3炎性体形成中的作用；3）确定ASK-1在毒烟诱导嘌呤P2X7受体介导的炎性体形成中的作用。重要结果：增加小鼠肺中SOCS-1表达水平减少毒烟吸入性肺损伤、提高存活率；SOCS-1超表达抑制毒烟诱导的SAEC细胞凋亡和ASK-1表达；SAEC超表达SOCS-1诱导ASK-1泛素化；SOCS-1抑制毒烟诱导的DISC形成；毒烟通过P2X7受体导致NALP3形成；SOCS-1抑制毒烟诱导的NALP3炎性体形成。相比火灾毒烟对肺的损伤，雾霾对人体的危害要小些。毒烟/雾霾吸入性肺损伤都与空气中粉尘颗粒物有关，致病机理相似，因此本项目对雾霾吸入性肺损伤的防治疗也有指导意义。