Activated protein C inhibits lung injury induced by LPS via downregulating MAPK signaling

Zhou, Jian‐Ming; Hu, Ruoyu; Jing, Shengjie; Xue, Xin; Tang, Wen-hao

doi:10.3892/etm.2018.6228

Cited by 4 publications

(6 citation statements)

References 28 publications

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“…This is also associated with a reduction in LPS-induced apoptosis and adhesion of human monocytes to the endothelium [65]. A similar observation has been reported in bronchoalveolar lavage (BAL) obtained from rats treated with LPS and APC [44]. In addition to decreased cytokine levels, reduced numbers of leukocytes and neutrophils were observed in BAL fluid [44].…”

Section: Thrombomodulin and Mapk Signaling In Leukocytessupporting

confidence: 63%

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Thrombomodulin Regulation of Mitogen-Activated Protein Kinases

Giri

Cai

Panicker

et al. 2019

IJMS

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The multifaceted role of mitogen-activated protein kinases (MAPKs) in modulating signal transduction pathways in inflammatory conditions such as infection, cardiovascular disease, and cancer has been well established. Recently, coagulation factors have also emerged as key players in regulating intracellular signaling pathways during inflammation. Among coagulation factors, thrombomodulin, as a high affinity receptor for thrombin on vascular endothelial cells, has been discovered to be a potent anti-inflammatory and anti-tumorigenic signaling molecule. The protective signaling function of thrombomodulin is separate from its well-recognized role in the clotting cascade, which is to function as an anti-coagulant receptor in order to switch the specificity of thrombin from a procoagulant to an anti-coagulant protease. The underlying protective signaling mechanism of thrombomodulin remains largely unknown, though a few published reports link the receptor to the regulation of MAPKs under different (patho)physiological conditions. The goal of this review is to summarize what is known about the regulatory relationship between thrombomodulin and MAPKs.

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Section: Thrombomodulin and Mapk Signaling In Leukocytessupporting

confidence: 63%

“…In addition to decreased cytokine levels, reduced numbers of leukocytes and neutrophils were observed in BAL fluid [44]. APC mediates these anti-inflammatory and anti-apoptotic effects by inhibiting the activation of p38, ERK1/2, JNK [44], and NF-κB [66] signaling pathways.…”

Section: Thrombomodulin and Mapk Signaling In Leukocytesmentioning

confidence: 99%

Thrombomodulin Regulation of Mitogen-Activated Protein Kinases

Giri

Cai

Panicker

et al. 2019

IJMS

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“…Next, we investigated the effect of CoQ10, AES, or their combination on serum CRP, ALKP, LDH, and pulmonary MPO activities. These markers have been reported to be changed in cases of ALI [Zhou et al, 2018;Gallelli, 2019]. As illustrated in Figure 2, rats challenged with LPS exhibited a significant elevation of serum CRP level (116%), ALKP (69%), LDH (126%), and pulmonary MPO (260%) activities compared to the control group.…”

Section: Pretreatment With Coq10 And/or Aes Preserved Serum Crp Level Alkp Ldh and Pulmonary Mpo Activities In Rats Challenged With Lpsmentioning

confidence: 90%

“…Interestingly, Wang et al [2017] demonstrated that rats treated with LPS showed inflammatory reaction and increased expression of NF-κB-p65 and MAPKs (p38 MAPK and ERK1/2) through activation of TLR4/MyD88 signaling. Additionally, Zhou et al [2018] reported that both p38 MAPK and ERK are critical for LPS-induced cytokine production and lung inflammation. Further, ERK1/2 me-diates the activation of NLRP-3 inflammasome by reactive oxygen species as discussed by Harijith et al [2014].…”

Section: Discussionmentioning

confidence: 99%

Pretreatment with Coenzyme Q10 Combined with Aescin Protects against Sepsis-Induced Acute Lung Injury

Ali

Ahmed

Eltrawy

et al. 2021

Cells Tissues Organs

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Sepsis-associated acute lung injury (ALI) is a critical condition characterized by severe inflammatory response and mitochondrial dysfunction. Coenzyme Q10 (CoQ10) and aescin (AES) are well-known for their anti-inflammatory activities. However, their effects on lipopolysaccharide (LPS)-induced lung injury have not been explored yet. Here, we asked whether combined pretreatment with CoQ10 and AES synergistically prevents LPS-induced lung injury. Fifty male rats were randomized into 5 groups: (1) control; (2) LPS-treated, rats received a single i.p. injection of LPS (8 mg/kg); (3) CoQ10-pretreated, (4) AES-pretreated, or (5) combined-pretreated; animals received CoQ10 (100 mg/kg), AES (5 mg/kg), or both orally for 7 days before LPS injection. Combined CoQ10 and AES pretreatment significantly reduced lung injury markers; 52.42% reduction in serum C-reactive protein (CRP), 53.69% in alkaline phosphatase (ALKP) and 60.26% in lactate dehydrogenase (LDH) activities versus 44.58, 37.38, and 48.6% in CoQ10 and 33.81, 34.43, and 39.29% in AES-pretreated groups, respectively. Meanwhile, combination therapy significantly reduced interleukin (IL)-1β and tumor necrosis factor (TNF)-α expressions compared to monotherapy (p < 0.05). Additionally, combination therapy prevented LPS-induced histological and mitochondrial abnormalities greater than separate drugs. Western blotting indicated that combination therapy significantly suppressed nucleotide-binding oligomerization domain (NOD)-like receptors-3 (NLRP-3) inflammasome compared to separate drugs (p < 0.05). Further, combination therapy significantly decreased the expression of signaling cascades, p38 mitogen-activated protein kinases (p38 MAPK), nuclear factor kappa B (NF-κB)-p65, and extracellular-regulated kinases 1/2 (ERK1/2) versus monotherapy (p < 0.05). Interestingly, combined pretreatment significantly downregulated high mobility group box-1 (HMGB1) by 72.93%, and toll-like receptor 4 (TLR4) by −0.93-fold versus 61.92%, −0.83-fold in CoQ10 and 38.67%, −0.70-fold in AES pretreatment, respectively. Our results showed for the first time that the enhanced anti-inflammatory effect of combined CoQ10 and AES pretreatment prevented LPS-induced ALI via suppression of NLRP-3 inflammasome through regulation of HMGB1/TLR4 signaling pathway and mitochondrial stabilization.

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“…After treatment with LPS for 24 h, the rats were anesthetized using 1% pentobarbital (50 mg/kg, intraperitoneally injection) and sacrificed by cervical dislocation. After exposing the chest cavity and intubating the trachea, PBS was slowly dropped into the lung bronchus, and the BALF was collected for further analysis, as described previously (16).…”

Section: Animals and Regentsmentioning

confidence: 99%

Apelin‑36 protects against lipopolysaccharide‑induced acute lung injury by inhibiting the ASK1/MAPK signaling pathway

Wang

Yang

et al. 2020

Mol Med Rep

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Apelin-36 is able to mediate a range of effects on various diseases, and is upregulated in lipopolysaccharide (LPS)-induced acute lung injury (ALI). However, to the best of our knowledge, whether apelin-36 is able to regulate LPS-induced ALI has yet to be investigated. The present study aimed to investigate the role of apelin-36 in LPS-induced ALI, and the putative underlying mechanisms. Rats were assigned to one of four treatment groups: The Control group, apelin-36 group, LPS group and LPS + apelin-36 group. At 4 h after intratracheal instillation of LPS (5 mg/kg), rats were intraperitoneally treated with 10 nmol/kg apelin-36. Subsequently, pathological manifestations and the extent of inflammation and apoptosis of the lung tissues were assessed. Untransfected and apoptosis signal-regulating kinase 1 (ASK1)-overexpressing Beas-2B cells were treated with LPS in the absence or presence of apelin-36, and subsequently the levels of inflammation and apoptosis were assessed. The results obtained showed that the level of apelin-36 was increased in the bronchoalveolar lavage fluid (BALF) of LPS-treated rats. Co-treatment with apelin-36 alleviated LPS-induced lung injury and pulmonary edema, reduced the levels of pro-inflammatory cytokines, including interleukin-6, monocyte chemoattractant protein-1 and tumor necrosis factor-α, in BALF, and inhibited apoptosis in the lung tissues. The presence of apelin-36 also blocked the activation of LPS-induced ASK1, p38, c-Jun N-terminal kinase and extracellular signal-regulated kinase in lung tissues. In vitro studies performed with Beas-2B cells showed that the addition of apelin-36 led to an increase in the cell viability of LPS-induced Beas-2B cells in a concentration-dependent manner. Additionally, co-treatment with 1 µM apelin-36 prevented LPS-induced inflammation and apoptosis. However, overexpression of ASK1 significantly reversed the inhibitory effects of apelin-36 on LPS-induced inflammation and apoptosis. Taken together, the results of the present study demonstrated that apelin-36 was able to protect against LPS-induced lung injury both in vivo and in vitro, and these actions may be dependent on inhibition of the ASK1/mitogen-activated protein kinase signaling pathway.

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Activated protein C inhibits lung injury induced by LPS via downregulating MAPK signaling

Cited by 4 publications

References 28 publications

Thrombomodulin Regulation of Mitogen-Activated Protein Kinases

Thrombomodulin Regulation of Mitogen-Activated Protein Kinases

Pretreatment with Coenzyme Q10 Combined with Aescin Protects against Sepsis-Induced Acute Lung Injury

Apelin‑36 protects against lipopolysaccharide‑induced acute lung injury by inhibiting the ASK1/MAPK signaling pathway

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