Mechanical Ventilation Exacerbates Poly (I:C) Induced Acute Lung Injury: Central Role for Caspase-11 and Gut-Lung Axis.
Mechanical Ventilation Exacerbates Poly (I:C) Induced Acute Lung Injury: Central Role for Caspase-11 and Gut-Lung Axis.
复制标题
机械通气加剧 Poly (I:C) 引起的急性肺损伤：Caspase-11 和肠肺轴的核心作用
DOI：
10.3389/fimmu.2021.693874
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发表时间：
2021
影响因子：
7.3
通讯作者：
Li Q
中科院分区：
文献类型：
--
作者：
Jin S;Ding X;Yang C;Li W;Deng M;Liao H;Lv X;Pitt BR;Billiar TR;Zhang LM;Li Q
适度潮气量通气（MTV）加重肺损伤的机制尚不清楚。我们假设通过肠-肺轴的全身性内毒素血症将导致涉及多聚肌苷酸-多聚胞苷酸（Poly（I：C））（dsRNA和MTV的合成类似物）的两次打击模型中的非典型和典型炎性小体活化和焦亡，并且这将与急性肺损伤（ALI）相关。方法小鼠气管内注射Poly（I：C），6 h后机械通气4 h，同时给予无损伤的MTV（10 ml/kg）。肠和肺泡毛细血管通透性的变化进行了测量。通过伊文思蓝白蛋白渗透性、支气管肺泡灌洗液（BALF）或血浆中的蛋白质和IL-1家族浓度以及野生型（WT）、全身基因消融的caspase-11（caspase-11-/-），caspase-1/caspase-11双敲除（半胱天冬酶-1/11-/-）、gasdermin D（GSDMD）-/-、核苷酸结合结构域富含亮氨酸重复序列的蛋白3（NLRP 3）-/-和晚期糖基化终产物特异性受体（AGEs）-/-小鼠。结果非损伤性MTV加重了与Poly（I：C）给药相关的轻度肺损伤。这包括肺泡-毛细血管屏障破坏以及BALF中白细胞介素（IL）-6、高迁移率族蛋白1（HMGB-1）、IL-1β和血浆中IL-18水平升高。联合（Poly（I：C）-MTV）损伤与胃肠道通透性增加和血浆及BALF中内毒素增加有关。Poly（I：C）-MTV损伤对半胱天冬酶-11缺失敏感，除了成熟和IL-18的释放（其本身对NLRP 3的缺失敏感）之外，没有半胱天冬酶-1的进一步贡献。联合损伤导致caspase-1和caspase-11的大量增加。GSDMD基因消融减轻复合损伤模型中肺泡毛细血管破裂和细胞因子释放。结论：先前注意到的轻度Poly（I：C）诱导的ALI的加重与肠道通透性增加有关，导致全身性内毒素血症。肠-肺轴导致在该二次打击模型中肺非典型（胞质介导的半胱天冬酶-11活化）和典型（半胱天冬酶-1）炎性体（NLRP 3）介导的ALI的活化，导致GSDMD敏感性肺泡毛细血管屏障破坏、焦亡（肺泡巨噬细胞）和细胞因子成熟和释放（IL-1β; IL-18）。药理学策略旨在破坏肠和肺之间的沟通，抑制炎性小体或GSDMD在焦亡可能是有用的ALI。
Background The mechanisms by which moderate tidal volume ventilation (MTV) exacerbates preexisting lung injury are unclear. We hypothesized that systemic endotoxemia via the gut-lung axis would lead to non-canonical and canonical inflammasome activation and pyroptosis in a two-hit model involving polyinosinic-polycytidylic acid (Poly(I:C)), a synthetic analog of dsRNA and MTV and that this would associate with acute lung injury (ALI). Methods Anesthetized mice were administered Poly(I:C) intratracheally and then 6 h later, they were mechanically ventilated for 4 h with otherwise non-injurious MTV (10ml/kg). Changes in intestinal and alveolar capillary permeability were measured. Further documentation of ALI was assessed by evans blue albumin permeability, protein and IL-1 family concentration in bronchoalveolar lavage fluid (BALF) or plasma, and histopathology in cohorts of wildtype (WT), whole body genetically ablated caspase-11 (caspase-11-/-), caspase-1/caspase-11 double knockout (caspase-1/11-/-), gasdermin D (GSDMD)-/-, nucleotide-binding domain leucine-rich repeat-containing protein 3 (NLRP3)-/- and advanced glycosylation end product-specific receptor (RAGE) -/- mice. Results Non-injurious MTV exacerbated the mild lung injury associated with Poly(I:C) administration. This included the disruption of alveolar-capillary barrier and increased levels of interleukin (IL)-6, high mobility group proteins 1 (HMGB-1), IL-1β in BALF and IL-18 in plasma. Combined (Poly(I:C)-MTV) injury was associated with increase in gastrointestinal permeability and endotoxin in plasma and BALF. Poly(I:C)-MTV injury was sensitive to caspase-11 deletion with no further contribution of caspase-1 except for maturation and release of IL-18 (that itself was sensitive to deletion of NLRP3). Combined injury led to large increases in caspase-1 and caspase-11. Genetic ablation of GSDMD attenuated alveolar-capillary disruption and release of cytokines in combined injury model. Conclusions The previously noted exacerbation of mild Poly(I:C)-induced ALI by otherwise non-injurious MTV is associated with an increase in gut permeability resulting in systemic endotoxemia. The gut-lung axis resulted in activation of pulmonary non-canonical (cytosolic mediated caspase-11 activation) and canonical (caspase-1) inflammasome (NLRP3) mediated ALI in this two-hit model resulting in GSDMD sensitive alveolar capillary barrier disruption, pyroptosis (alveolar macrophages) and cytokine maturation and release (IL-1β; IL-18). Pharmacologic strategies aimed at disrupting communication between gut and lung, inhibition of inflammasomes or GSDMD in pyroptosis may be useful in ALI.
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