Protective effect of C4a against hyperoxic lung injury via a macrophage-dependent but not a neutrophil/lymphocyte-dependent signaling pathway

Mechanical ventilation (MV) may lead to ventilator-induced lung injury (VILI). Previous research has shown that dexmedetomidine attenuates pulmonary inﬂammation caused by MV, but the underlying mechanisms remain unclear. Our study aims to test whether dexmedetomidine has a protective effect against VILI and to explore the possible molecular mechanisms using the rat model. Thirty adult male Wistar rats weighing 200-250 g were randomly assigned to 5 groups (n = 6): control, low tidal volume MV (LMV), high tidal volume (HVT) MV (HMV), HVT MV + dexmedetomidine (DEX), HVT MV + dexmedetomidine + yohimbine (DEX+Y). Rats were euthanized after being ventilated for 4 hours. Pathological changes, lung wet/dry (W/D) weight ratio, lung myeloperoxidase (MPO) activity, levels of inflammatory cytokines (i.e., interleukin [IL]-1β, tumor necrosis factor alpha [TNF-α], and IL-6) in the bronchoalveolar lavage fluid (BALF) and lung tissues, expression of Toll-like receptor 4 (TLR4) and nuclear factor (NF)-κB, and activation of NF-κB in lung tissues were measured. Compared with HMV, DEX group showed fewer pathological changes, lower W/D ratios and decreased MPO activity of the lung tissues and lower concentrations of the inflammatory cytokines in the BALF and lung tissues. Dexmedetomidine significantly inhibited the expression of TLR4 and NF-κB and activation of NF-κB. Yohimbine partly alleviated the effects of dexmedetomidine. Dexmedetomidine reduced the inflammatory response to HVT-MV and had a protective effect against VILI, with the inhibition of the TLR4/NF-κB signaling pathway, at least partly via α2-adrenoceptors.

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Protective effect of resveratrol against acute lung injury induced by lipopolysaccharide via inhibiting the myd88-dependent Toll-like receptor 4 signaling pathway

Molecular Medicine Reports ◽

10.3892/mmr.2014.2226 ◽

2014 ◽

Vol 10 (1) ◽

pp. 101-106 ◽

Cited By ~ 31

Author(s):

ZHUO ZHANG ◽

NI CHEN ◽

JIN-BO LIU ◽

JIAN-BO WU ◽

JING ZHANG ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Protective Effect ◽

Signaling Pathway ◽

Toll Like Receptor ◽

Toll Like Receptor 4

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α7nAChR Agonist Activates the Nrf2/HO-1 Signaling Pathway to Reduce Acute Lung Injury Induced by Endotoxic Shock

10.21203/rs.3.rs-135045/v1 ◽

2020 ◽

Author(s):

Yanmei Zhang ◽

Minghui Lun ◽

Lingfei Wang ◽

Zeqing Huang

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Protective Effect ◽

Partial Pressure ◽

Signaling Pathway ◽

Inflammatory Responses ◽

Endotoxic Shock ◽

B Cell Lymphoma ◽

Heme Oxygenase 1 ◽

Nuclear Factor

Abstract Objective: Alpha 7 nicotinic acetylcholine receptors (α7nAChRs) can inhibit the activation of macrophages and the production of pro-inflammatory cytokines and exert inhibitory effects on systemic and local inflammatory responses. The objective of this study was to observe the protective effect of α7nAChR agonist against acute lung injury (ALI) caused by endotoxic shock, and to explore the regulatory mechanism of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway. Methods: A total of 40 Sprague-Dawley rats were randomly divided into sham operation group (Sham group, n=10), endotoxic shock-induced ALI model group (ALI group, n=10), ALI + α7nAChR agonist (PHA568487, 3134, Tocris Bioscience, USA) group (PHA group, n=10) and ALI + α7nAChR agonist + Nrf2 inhibitor (ML385, HY-100523, MCE, USA) group (ML group, n=10). The rats received a tail vein injection of LPS to initiate ALI. Six hrs after injection, arterial blood was analyzed for blood gases and lung wet weight/dry weight (W/D) was determined. Lung histopathology was determined by H&E staining and apoptosis quantified by TUNEL. Levels of intercellular adhesion molecule-1 (ICAM-1), TNF-α, IL-1β, malondialdehyde (MDA), myeloperoxidase (MPO), superoxide dismutase (SOD), choline acetyltransferase (ChAT) and acetylcholine esterase (AchE) in bronchoalveolar lavage fluid were measured via ELISA. Western blotting revealed levels of nuclear factor kappa-B (NF-κB), B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), phosphatidylin-ositol-3-kinase (PI3K), protein kinase B (Akt), phosphorylated Akt (p-Akt), HO-1, Nrf2, thioredoxin reductase 1 (Trx-1) and glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Results: It was found that α7nAChR agonist increased the partial pressure of oxygen (PaO2) and pH, reduced the partial pressure of carbon dioxide (PaCO2) and W/D ratio, alleviated pulmonary edema and oxidative stress injury, and suppressed inflammatory responses. At the same time, it activated PI3K to phosphorylate Akt, inhibited cell apoptosis, and protected the lung tissues of ALI rats. Moreover, α7nAChR agonist facilitated nuclear translocation of Nrf-2 and up-regulated HO-1 and Trx-1 expression. Nrf-2 activity was required for the protective effect of α7nAChR . Conclusion: α7nAChR agonist can improve endotoxic shock-induced ALI by activating the cholinergic anti-inflammatory pathway and the Nrf2/HO-1 signaling pathway.

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