scholarly journals Identification of atypical mitogen-activated protein kinase MAPK4 as a novel regulator in acute lung injury

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Ling Mao ◽  
Ya Zhou ◽  
Longqing Chen ◽  
Lin Hu ◽  
Shiming Liu ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Survival Time ◽  
Inflammatory Cytokines ◽  
Mitogen Activated Protein Kinase ◽  
Lps Challenge ◽  
Mitogen Activated Protein ◽  
Pre Treatment ◽  
Pro Inflammatory Cytokines

Abstract Background Acute lung injury (ALI) is a serious disease with highly morbidity and mortality that causes serious health problems worldwide. Atypical mitogen activated protein kinases (MAPKs) play critical roles in the development of tissues and have been proposed as promising therapeutic targets for various diseases. However, the potential role of atypical MAPKs in ALI remains elusive. In this study, we investigated the role of atypical MAPKs family member MAPK4 in ALI using LPS-induced murine ALI model. Results We found that MAPK4 deficiency mice exhibited prolonged survival time after LPS challenge, accompanied by alleviated pathology in lung tissues, decreased levels of pro-inflammatory cytokines and altered composition of immune cells in BALF. Furthermore, the transduction of related signaling pathways, including MK5, AKT, JNK, and p38 MAPK pathways, was reduced obviously in LPS-treated MAPK4−/− mice. Notably, the expression of MAPK4 was up-regulated in lung tissues of ALI model, which was not related with MAPK4 promoter methylation, but negatively orchestrated by transcriptional factors NFKB1 and NR3C1. Further studies have shown that the expression of MAPK4 was also increased in LPS-treated macrophages. Meanwhile, MAPK4 deficiency reduced the expression of related pro-inflammatory cytokines in macrophage in response to LPS treatment. Finally, MAPK4 knockdown using shRNA pre-treatment could ameliorate the pathology of lung tissues and prolong the survival time of mice after LPS challenge. Conclusions Collectively, these findings reveal an important biological function of atypical MAPK in mediating the pathology of ALI, indicating that MAPK4 might be a novel potential therapeutic target for ALI treatment.

scholarly journals Identification of Atypical Mitogen-Activated Protein Kinase MAPK4 as A Novel Regulator in Acute Lung Injury

2020 ◽  
Author(s):  
Ling Mao ◽  
Ya Zhou ◽  
Longqing Chen ◽  
Lin Hu ◽  
Shiming Liu ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Survival Time ◽  
Inflammatory Cytokines ◽  
Mitogen Activated Protein Kinase ◽  
Lps Challenge ◽  
Mitogen Activated Protein ◽  
Pre Treatment ◽  
Pro Inflammatory Cytokines

Abstract Background: Acute lung injury (ALI) is a serious disease with highly morbidity and mortality that causes serious health problems worldwide. Atypical mitogen activated protein kinases (MAPKs) play critical roles in the development of tissues and have been proposed as promising therapeutic targets for various diseases. However, the potential role of atypical MAPKs in ALI remains elusive. In this study, we investigated the role of atypical MAPKs family member MAPK4 in ALI using LPS-induced murine ALI model. Results: We found that MAPK4 deficiency mice exhibited prolonged survival time after LPS challenge, accompanied by alleviated pathology in lung tissues, decreased levels of pro-inflammatory cytokines and altered composition of immune cells in BALF. Furthermore, the transduction of related signaling pathways, including MK5, AKT, JNK, and p38 MAPK pathways, was reduced obviously in LPS-treated MAPK4-/- mice. Notably, the expression of MAPK4 was up-regulated in lung tissues of ALI model, which was not related with MAPK4 promoter methylation, but negatively orchestrated by transcriptional factors NFKB1 and NR3C1. Further studies have shown that the expression of MAPK4 was also increased in LPS-treated macrophages. Meanwhile, MAPK4 deficiency reduced the expression of related pro-inflammatory cytokines in macrophage in response to LPS treatment. Finally, MAPK4 inhibition using shRNA pre-treatment could ameliorate the pathology of lung tissues and prolong the survival time of mice after LPS challenge. Conclusions: Collectively, these findings reveal an important biological function of atypical MAPK in mediating the pathology of ALI, indicating that MAPK4 might be a novel potential therapeutic target for ALI treatment.

scholarly journals Identification of atypical mitogen-activated protein kinase MAPK4 as a novel regulator in acute lung injury

2020 ◽  
Author(s):  
Ling Mao ◽  
Ya Zhou ◽  
Longqing Chen ◽  
Lin Hu ◽  
Shiming Liu ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Survival Time ◽  
Inflammatory Cytokines ◽  
Mitogen Activated Protein Kinase ◽  
Lps Challenge ◽  
Mitogen Activated Protein ◽  
Pre Treatment ◽  
Pro Inflammatory Cytokines

Abstract Background: Acute lung injury (ALI) is a serious disease with highly morbidity and mortality that causes serious health problems worldwide. Atypical mitogen activated protein kinases (MAPKs) play critical roles in the development of tissues and have been proposed as promising therapeutic targets for various diseases. However, the potential role of atypical MAPKs in ALI remains elusive. In this study, we investigated the role of atypical MAPKs family member MAPK4 in ALI using LPS-induced murine ALI model. Results: We found that MAPK4 deficiency mice exhibited prolonged survival time after LPS challenge, accompanied by alleviated pathology in lung tissues, decreased levels of pro-inflammatory cytokines and altered composition of immune cells in BALF. Furthermore, the transduction of related signaling pathways, including MK5, AKT, JNK, and p38 MAPK pathways, was reduced obviously in LPS-treated MAPK4 -/- mice. Notably, the expression of MAPK4 was up-regulated in lung tissues of ALI model, which was not related with MAPK4 promoter methylation, but negatively orchestrated by transcriptional factors NFKB1 and NR3C1. Further studies have shown that the expression of MAPK4 was also increased in LPS-treated macrophages. Meanwhile, MAPK4 deficiency reduced the expression of related pro-inflammatory cytokines in macrophage in response to LPS treatment. Finally, MAPK4 knockdown using shRNA pre-treatment could ameliorate the pathology of lung tissues and prolong the survival time of mice after LPS challenge. Conclusions: Collectively, these findings reveal an important biological function of atypical MAPK in mediating the pathology of ALI, indicating that MAPK4 might be a novel potential therapeutic target for ALI treatment.

scholarly journals NFKB1/NR3C1-MAPK4 axis regulates the pathology of acute lung injury

2020 ◽  
Author(s):  
Ling Mao ◽  
Ya Zhou ◽  
Lin Hu ◽  
Shiming Liu ◽  
Juanjuan Zhao ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Survival Time ◽  
Signaling Pathways ◽  
Inflammatory Cells ◽  
Survival Ratio ◽  
Lps Challenge ◽  
Serious Disease ◽  
Pro Inflammatory Cytokines

Abstract BackgroundAcute lung injury (ALI) is a serious disease with highly morbidity and mortality that causes serious health problems worldwide. MAPK4, a member of atypical MAPK family, has been implicated in the development of cancer. Herein, the current study aimed to investigate the possible role of MAPK4 in the pathology of ALI to identify potential candidates for ALI therapy.MethodsMurine ALI model was established in WT or MAPK4-/- mice and the expressions of MAPK4 were measured. The survival ratio of ALI model mice was observed. Moreover, the changes of pathologic injury and infiltration of inflammatory cells, as well as the related signaling pathways, in lung tissues were analyzed. Furthermore, the possible molecular mechanism of MAPK4 expression in ALI was analyzed by massARRAY and EMSA assay. Finally, the effect of MAPK4 silencing using shRNA interference on the pathology of ALI was identified.ResultsData showed that MAPK4 was up-regulated in lung tissues in LPS-induced murine ALI model. Importantly, MAPK4 deficiency mice exhibited prolonged survival time after LPS challenge, accompanied by alleviated inflammatory injury in lung tissues characterized with reduced production of pro-inflammatory cytokines, infiltration of immune cells and altered transduction of related signaling pathways. Besides, massARRAY results showed no aberrant change in CpG methylation levels between control and ALI mice. Bioinformatics analysis and EMSA assay showed that transcriptional factor NFKB1 and NR3C1 could negatively regulate the expression of MAKP4. Finally, MAPK4-shRNA treatment could ameliorate the pathology of lung tissues and prolong the survival time of mice after LPS challenge.ConclusionsOur data demonstrated that MAPK4, orchestrated by NFKB1 and NR3C1, could regulate the pathology of ALI, indicating that MAPK4 might be a new therapeutic target for ALI treatment.

scholarly journals Mitogen-activated protein kinase phosphatase 2, MKP-2, regulates early inflammation in acute lung injury

2012 ◽  
Vol 303 (3) ◽  
pp. L251-L258 ◽  
Author(s):  
Timothy T. Cornell ◽  
Andrew Fleszar ◽  
Walker McHugh ◽  
Neal B. Blatt ◽  
Ann Marie Le Vine ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Protein Kinase ◽  
Lung Injury ◽  
Neutrophil Infiltration ◽  
Mitogen Activated Protein Kinase ◽  
Molecular Response ◽  
Proinflammatory Response ◽  
Mapk Pathways ◽  
Mitogen Activated Protein

Acute lung injury (ALI) is mediated by an early proinflammatory response resulting from either a direct or indirect insult to the lung mediating neutrophil infiltration and consequent disruption of the alveolar capillary membrane ultimately leading to refractory hypoxemia. The mitogen-activated protein kinase (MAPK) pathways are a key component of the molecular response activated by those insults triggering the proinflammatory response in ALI. The MAPK pathways are counterbalanced by a set of dual-specific phosphatases (DUSP) that deactivate the kinases by removing phosphate groups from tyrosine or threonine residues. We have previously shown that one DUSP, MKP-2, regulates the MAPK pathway in a model of sepsis-induced inflammation; however, the role of MKP-2 in modulating the inflammatory response in ALI has not been previously investigated. We utilized both MKP-2-null (MKP-2−/−) mice and MKP-2 knockdown in a murine macrophage cell line to elucidate the role of MKP-2 in regulating inflammation during ALI. Our data demonstrated attenuated proinflammatory cytokine production as well as decreased neutrophil infiltration in the lungs of MKP-2−/− mice following direct, intratracheal LPS. Importantly, when challenged with a viable pathogen, this decrease in neutrophil infiltration did not impact the ability of MKP-2−/− mice to clear either gram-positive or gram-negative bacteria. Furthermore, MKP-2 knockdown led to an attenuated proinflammatory response and was associated with an increase in phosphorylation of ERK and induction of a related DUSP, MKP-1. These data suggest that altering MKP-2 activity may have therapeutic potential to reduce lung inflammation in ALI without impacting pathogen clearance.

scholarly journals Essential Role of Visfatin in Lipopolysaccharide and Colon Ascendens Stent Peritonitis-Induced Acute Lung Injury

2019 ◽  
Vol 20 (7) ◽  
pp. 1678 ◽  
Author(s):  
Yi-Chen Lee ◽  
Chun-Yu Lin ◽  
Yen-Hsu Chen ◽  
Wen-Chin Chiu ◽  
Yen-Yun Wang ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Epithelial Cell ◽  
Lung Injury ◽  
Cell Lines ◽  
Inflammatory Cytokines ◽  
Bronchial Epithelial Cell ◽  
Bronchial Epithelial ◽  
Epithelial Cell Lines ◽  
Nfκb Pathway ◽  
Pro Inflammatory Cytokines

Acute lung injury (ALI) is a life-threatening syndrome characterized by acute and severe hypoxemic respiratory failure. Visfatin, which is known as an obesity-related cytokine with pro-inflammatory activities, plays a role in regulation of inflammatory cytokines. The mechanisms of ALI remain unclear in critically ill patients. Survival in ALI patients appear to be influenced by the stress generated by mechanical ventilation and by ALI-associated factors that initiate the inflammatory response. The objective for this study was to understand the mechanisms of how visfatin regulates inflammatory cytokines and promotes ALI. The expression of visfatin was evaluated in ALI patients and mouse sepsis models. Moreover, the underlying mechanisms were investigated using human bronchial epithelial cell lines, BEAS-2B and NL-20. An increase of serum visfatin was discovered in ALI patients compared to normal controls. Results from hematoxylin and eosin (H&E) and immunohistochemistry staining also showed that visfatin protein was upregulated in mouse sepsis models. Moreover, lipopolysaccharide (LPS) induced visfatin expression, activated the STAT3/NFκB pathway, and increased the expression of pro-inflammatory cytokines, including IL1-β, IL-6, and TNF-α in human bronchial epithelial cell lines NL-20 and BEAS-2B. Co-treatment of visfatin inhibitor FK866 reversed the activation of the STAT3/NFκB pathway and the increase of pro-inflammatory cytokines induced by LPS. Our study provides new evidence for the involvement of visfatin and down-stream events in acute lung injury. Further studies are required to confirm whether the anti-visfatin approaches can improve ALI patient survival by alleviating the pro-inflammatory process.

scholarly journals Management of Acute Lung Injury: Palmitoylethanolamide as a New Approach

2021 ◽  
Vol 22 (11) ◽  
pp. 5533
Author(s):  
Alessio Filippo Peritore ◽  
Ramona D’Amico ◽  
Rosalba Siracusa ◽  
Marika Cordaro ◽  
Roberta Fusco ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
B Cells ◽  
Lung Injury ◽  
Weight Ratio ◽  
Dry Weight ◽  
Mitogen Activated Protein Kinase ◽  
Histopathological Analysis ◽  
Nuclear Factor ◽  
Intratracheal Administration ◽  
Mitogen Activated Protein

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are common and devastating clinical disorders with high mortality and no specific therapy. Lipopolysaccharide (LPS) is usually used intratracheally to induce ALI in mice. The aim of this study was to examine the effects of an ultramicronized preparation of palmitoylethanolamide (um-PEA) in mice subjected to LPS-induced ALI. Histopathological analysis reveals that um-PEA reduced alteration in lung after LPS intratracheal administration. Besides, um-PEA decreased wet/dry weight ratio and myeloperoxidase, a marker of neutrophils infiltration, macrophages and total immune cells number and mast cells degranulation in lung. Moreover, um-PEA could also decrease cytokines release of interleukin (IL)-6, interleukin (IL)-1β, tumor necrosis factor (TNF)-α and interleukin (IL)-18. Furthermore, um-PEA significantly inhibited the phosphorylation of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation in ALI, and at the same time decreased extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38/MAPK) expression, that was increased after LPS administration. Our study suggested that um-PEA contrasted LPS-induced ALI, exerting its potential role as an adjuvant anti-inflammatory therapeutic for treating lung injury, maybe also by p38/NF-κB pathway.

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