Modulation of mitogen-activated protein kinase attenuates sepsis-induced acute lung injury in acute respiratory distress syndrome rats

Fang, Wei; Cai, Shumin; Wang, Chuanlei; Sun, Xiaoxia; Li, Kun; Yan, Xiaowen; Sun, Ying; Sun, Xiaozhe; Gu, Chuan-Kai; Dai, Mingying; Wang, Huiming; Zhou, Zhen

doi:10.3892/mmr.2017.7811

Cited by 47 publications

(36 citation statements)

References 47 publications

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“…The MAPK signaling pathway is involved in both the inflammatory response and lung injury [23,24]. The expression level of mitogen-activated protein kinase kinase kinase 2 (MAP2K2), the target of bosutinib, a drug approved for the treatment of chronic myelogenous leukemia (CML), was significantly altered in cultured cells infected with H5N1 in the current study.…”

Section: Plos Pathogensmentioning

confidence: 64%

Identification of amitriptyline HCl, flavin adenine dinucleotide, azacitidine and calcitriol as repurposing drugs for influenza A H5N1 virus-induced lung injury

Huang¹,

Zhang²,

Liu³

et al. 2020

PLoS Pathog

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Infection with avian influenza A H5N1 virus results in acute lung injury (ALI) and has a high mortality rate (52.79%) because there are limited therapies available for treatment. Drug repositioning is an economical approach to drug discovery. We developed a method for drug repositioning based on high-throughput RNA sequencing and identified several drugs as potential treatments for avian influenza A H5N1 virus. Using high-throughput RNA sequencing, we identified a total of 1,233 genes differentially expressed in A549 cells upon H5N1 virus infection. Among these candidate genes, 79 drug targets (corresponding to 59 approved drugs) overlapped with the DrugBank target database. Twenty-two of the 41 commercially available small-molecule drugs reduced H5N1-mediated cell death in cultured A549 cells, and fifteen drugs that protected A549 cells when administered both pre-and post-infection were tested in an H5N1-infection mouse model. The results showed significant alleviation of acute lung injury by amitriptyline HCl (an antidepressant drug), flavin adenine dinucleotide (FAD; an ophthalmic agent for vitamin B2 deficiency), azacitidine (an antineoplastic drug) and calcitriol (an active form of vitamin D). All four agents significantly reduced the infiltrating cell count and decreased the lung injury score in H5N1 virus-infected mice based on lung histopathology, significantly improved mouse lung edema by reducing the wet-to-dry weight ratio of lung tissue and significantly improved the survival of H5N1 virus-infected mice. This study not only identifies novel potential therapies for influenza H5N1 virus-induced lung injury but also provides a highly effective and economical screening method for repurposing drugs that may be generalizable for the prevention and therapy of other diseases.

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Section: Plos Pathogensmentioning

confidence: 64%

Identification of amitriptyline HCl, flavin adenine dinucleotide, azacitidine and calcitriol as repurposing drugs for influenza A H5N1 virus-induced lung injury

Huang¹,

Zhang²,

Liu³

et al. 2020

PLoS Pathog

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“…The cause of overwhelming inflammation induced by SARS-CoV-2 is unclear, however. One particular pathway that has been previously implicated in animal models of acute lung injury and myocardial injury is the p38 MAPK system [4,5]. Upregulation of the p38 MAPK pathway activates pro-inflammatory cytokines such as IL-6, TNF-α and IL-1β [6].…”

Section: Introductionmentioning

confidence: 99%

p38 MAPK inhibition: A promising therapeutic approach for COVID-19

Grimes

2020

Journal of Molecular and Cellular Cardiology

231

253

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COVID-19, caused by the SARS-CoV-2 virus, is a major source of morbidity and mortality due to its inflammatory effects in the lungs and heart. The p38 MAPK pathway plays a crucial role in the release of pro-inflammatory cytokines such as IL-6 and has been implicated in acute lung injury and myocardial dysfunction. The overwhelming inflammatory response in COVID-19 infection may be caused by disproportionately upregulated p38 activity, explained by two mechanisms. First, angiotensin-converting enzyme 2 (ACE2) activity is lost during SARS-CoV-2 viral entry. ACE2 is highly expressed in the lungs and heart and converts Angiotensin II into Angiotensin 1-7. Angiotensin II signals proinflammatory, pro-vasoconstrictive, pro-thrombotic activity through p38 MAPK activation, which is countered by Angiotensin 1-7 downregulation of p38 activity. Loss of ACE2 upon viral entry may tip the balance towards destructive p38 signaling through Angiotensin II. Second, SARS-CoV was previously shown to directly upregulate p38 activity via a viral protein, similar to other RNA respiratory viruses that may hijack p38 activity to promote replication. Given the homology between SARS-CoV and SARS-CoV-2, the latter may employ a similar mechanism. Thus, SARS-CoV-2 may induce overwhelming inflammation by directly activating p38 and downregulating a key inhibitory pathway, while simultaneously taking advantage of p38 activity to replicate. Therapeutic inhibition of p38 could therefore attenuate COVID-19 infection. Interestingly, a prior preclinical study showed protective effects of p38 inhibition in a SARS-CoV mouse model. A number of p38 inhibitors are in the clinical stage and should be considered for clinical trials in serious COVID-19 infection.

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“…15 Suppression of MAPK via blockade of the phosphorylation of p38 as well as c-Jun NH2-terminal kinase (JNK) in lung tissues has been demonstrated to have alleviatory effects in cases of ALI. 16 Investigations have been made suggesting that the regulation of PAK1 may act to influence the activation of the MAPK pathway. 17 Hence, based on the exploration of existing literature, we subsequently asserted the hypothesis that miR-542-5p may represent a novel basis and mode of target therapy for ALI in cases of SAP, contributing to the treatment of ALI in mice with SAP through inhibiting the activation of the MAPK signaling pathway by binding to PAK1.…”

Section: Introductionmentioning

confidence: 99%

Retracted: microRNA‐542‐5p protects against acute lung injury in mice with severe acute pancreatitis by suppressing the mitogen‐activated protein kinase signaling pathway through the negative regulation of P21‐activated kinase 1

Wang

et al. 2018

J of Cellular Biochemistry

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Severe acute pancreatitis (SAP) is a condition associated with high rates of mortality and lengthy hospital stays. In the current study, SAP mouse models were established in BALB/c wild-type and P21-activated kinase 1 (PAK1) knockdown mice with the objective of determining the expression of microRNA-542-5p (miR-542-5p) and the subsequent elucidation of the mechanism by which it influences acute lung injury (ALI) by mediating mitogen-activated protein kinase (MAPK) signaling and binding to PAK1. The targeting relationship between miR-542-5p and PAK1 was verified using the bioinformatics prediction website and by the means of a dual-luciferase reporter assay. Following the SAP model establishment, the mice were assigned into various groups with the introduction of different mimic and inhibitors in an attempt to investigate the effects involved with miR-542-5p on inflammatory reactions among mice with SAP-associated ALI. Our results indicated that PAK1 was targeted and negatively mediated by miR-542-5p. Mice with SAP-associated ALI exhibited an increased wet-to-dry weight ratio, myeloperoxidase activity, serum amylase activity, TNF-α, interleukin-1 beta (IL-1β), and intercellular adhesion molecule-1 (ICAM-1) contents, p-p38MAPK, p-ERK1/2, and p-JNK protein levels as well as PAK1 positive expression, while decreased miR-542-5p levels were observed. Functionally, overexpression of miR-542-5p improves ALI in mice with SAP via inhibition of the MAPK signaling pathway by binding to PAK1.Based on the evidence from experimental models, miR-542-5p was shown to improve ALI among mice with SAP, while suggesting that the effect may be related to the inactivation of the MAPK signaling pathway and downregulation of PAK1 gene. Thus, miR-542-5p could serve as a promising target for ALI treatment.

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Modulation of mitogen-activated protein kinase attenuates sepsis-induced acute lung injury in acute respiratory distress syndrome rats

Cited by 47 publications

References 47 publications

Identification of amitriptyline HCl, flavin adenine dinucleotide, azacitidine and calcitriol as repurposing drugs for influenza A H5N1 virus-induced lung injury

Identification of amitriptyline HCl, flavin adenine dinucleotide, azacitidine and calcitriol as repurposing drugs for influenza A H5N1 virus-induced lung injury

p38 MAPK inhibition: A promising therapeutic approach for COVID-19

Retracted: microRNA‐542‐5p protects against acute lung injury in mice with severe acute pancreatitis by suppressing the mitogen‐activated protein kinase signaling pathway through the negative regulation of P21‐activated kinase 1

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