Map kinase phosphatase 5 protects against sepsis-induced acute lung injury

Mitogen-activated protein kinases (MAPKs) play a critical role in inflammation. Although activation of MAPK in inflammatory cells has been studied extensively, much less is known about the inactivation of these kinases. MAPK phosphatase 5 (MKP5) is a member of the dual-specificity phosphatase family that dephosphorylates activated MAPKs. Here we report that MKP5 protects sepsis-induced acute lung injury. Mice lacking MKP5 displayed severe lung tissue damage following LPS challenge, characterized with increased neutrophil infiltration and edema compared with wild-type (WT) controls. In response to LPS, MKP5-deficient macrophages produced significantly more inflammatory factors including inflammatory cytokines, nitric oxide, and superoxide. Phosphorylation of p38 MAPK, JNK, and ERK were enhanced in MKP5-deficient macrophages upon LPS stimulation. Adoptive transfer of MKP5-deficient macrophages led to more severe lung inflammation than transfer of WT macrophages, suggesting that MKP5-deficient macrophages directly contribute to acute lung injury. Taken together, these results suggest that MKP5 is crucial to homeostatic regulation of MAPK activation in inflammatory responses.

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Estradiol attenuates LPS-induced acute lung injury via induction of aquaporins AQP1 and AQP5

European Journal of Inflammation ◽

10.1177/20587392211049197 ◽

2021 ◽

Vol 19 ◽

pp. 205873922110491

Author(s):

Xiaobo Wang ◽

Xiuyun Zhou ◽

Xiumei Xia ◽

Yili Zhang

Keyword(s):

Oxidative Stress ◽

Acute Lung Injury ◽

Lung Injury ◽

Inflammatory Responses ◽

Critical Role ◽

Weight Ratio ◽

Lung Edema ◽

Therapeutic Effects ◽

Lps Challenge ◽

And Oxidative Stress

Background Acute lung injury (ALI) is associated with increased inflammation and oxidative stress. Estradiol is produced by the ovaries and is the most active hormone of estrogen. Our aim was to investigate whether estradiol contributes to protect against lipopolysaccharide (LPS)-induced ALI via induction of aquaporins AQP1 and AQP5 and the underlying mechanisms. Methods and results For induction of ALI, LPS was applied once by intraperitoneal injection in SD rats 14 days after oophorectomy. To assess the therapeutic effects of estradiol on LPS-induced ALI, estradiol was subcutaneously injected for 1 h prior to LPS challenge. Estradiol can significantly attenuate the lung edema reflected by decreasing wet-to-dry weight ratio and permeability of lung and total protein concentration of bronchial lavage fluid (BALF). Results of histological detection showed that estradiol attenuated the lung injury reflected by reducing edema, congestion, and thickening pulmonary septal of lung tissues. In addition, estradiol attenuated TNF-α, IL-1β, and IL-6 and oxidative stress in lung tissues. Estradiol was more effective than estradiol associated with ERα antagonist or ERβ antagonist in protecting against LPS-induced ALI in rats. Mechanistically, we investigate whether estradiol regulates the expression of AQP1 and AQP5 in lung tissues. Of interest, estradiol upregulates AQP1 and AQP5 mRNA and protein expression. Taken together, these results demonstrate that estradiol can increase the expression of AQP1 and AQP5, which plays a critical role in ameliorating oxidative stress and downregulating inflammatory responses induced by LPS.Conclusion Therefore, these findings strongly suggest that AQP1 and AQP5 mediate the anti-inflammatory and antioxidant effects of estradiol.

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Src protein tyrosine kinase family and acute inflammatory responses

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00261.2005 ◽

2006 ◽

Vol 291 (2) ◽

pp. L129-L141 ◽

Cited By ~ 111

Author(s):

Daisuke Okutani ◽

Monika Lodyga ◽

Bing Han ◽

Mingyao Liu

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Tyrosine Kinase ◽

Reperfusion Injury ◽

Protein Tyrosine Kinase ◽

Inflammatory Responses ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Critical Role ◽

Protein Tyrosine

Acute inflammatory responses are one of the major underlying mechanisms for tissue damage of multiple diseases, such as ischemia-reperfusion injury, sepsis, and acute lung injury. By use of cellular and molecular approaches and transgenic animals, Src protein tyrosine kinase (PTK) family members have been identified to be essential for the recruitment and activation of monocytes, macrophages, neutrophils, and other immune cells. Src PTKs also play a critical role in the regulation of vascular permeability and inflammatory responses in tissue cells. Importantly, animal studies have demonstrated that small chemical inhibitors for Src PTKs attenuate tissue injury and improve survival from a variety of pathological conditions related to acute inflammatory responses. Further investigation may lead to the clinical application of these inhibitors as drugs for ischemia-reperfusion injury (such as stroke and myocardial infarction), sepsis, acute lung injury, and multiple organ dysfunction syndrome.

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VDR Attenuates Acute Lung Injury by Blocking Ang-2-Tie-2 Pathway and Renin-Angiotensin System

Molecular Endocrinology ◽

10.1210/me.2013-1146 ◽

2013 ◽

Vol 27 (12) ◽

pp. 2116-2125 ◽

Cited By ~ 52

Author(s):

Juan Kong ◽

Xiangdong Zhu ◽

Yongyan Shi ◽

Tianjing Liu ◽

Yunzi Chen ◽

...

Keyword(s):

Vitamin D ◽

Acute Lung Injury ◽

Angiotensin Ii ◽

Lung Injury ◽

Renin Angiotensin System ◽

Neutrophil Infiltration ◽

Angiotensin System ◽

Renin Angiotensin ◽

Lps Challenge ◽

Kinase Cascade

Acute lung injury (ALI) is a hallmark of systemic inflammation associated with high mortality. Although the vitamin D receptor (VDR) is highly expressed in the lung, its role in lung physiology remains unclear. We investigated the effect of VDR deletion on ALI using a lipopolysaccharide (LPS)-induced sepsis model. After LPS challenge VDR-null mice exhibited more severe ALI and higher mortality compared with wild-type (WT) counterparts, manifested by increased pulmonary vascular leakiness, pulmonary edema, apoptosis, neutrophil infiltration, and pulmonary inflammation, which was accompanied by excessive induction of angiopoietin (Ang)-2 and myosin light chain (MLC) phosphorylation in the lung. 1,25-Dihydroxyvitamin D blocked LPS-induced Ang-2 expression by blocking nuclear factor-κB activation in human pulmonary artery endothelial cells. The severity of lung injury seen in VDR-null mice was ameliorated by pretreatment with L1–10, an antagonist of Ang-2, suggesting that VDR signaling protects the pulmonary vascular barrier by targeting the Ang-2-Tie-2-MLC kinase cascade. Severe ALI in VDR-null mice was also accompanied by an increase in pulmonary renin and angiotensin II levels, and pretreatment of VDR-null mice with angiotensin II type 1 receptor blocker losartan partially ameliorated the severity of LPS-induced lung injury. Taken together, these observations provide evidence that the vitamin D-VDR signaling prevents lung injury by blocking the Ang-2-Tie-2-MLC kinase cascade and the renin-angiotensin system.

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Temporal changes in pulmonary expression of key procoagulant molecules in rabbits with endotoxin-induced acute lung injury: elevated expression levels of protease-activated receptors

Thrombosis and Haemostasis ◽

10.1160/th04-03-0160 ◽

2004 ◽

Vol 92 (11) ◽

pp. 966-979 ◽

Cited By ~ 27

Author(s):

Subrina Jesmin ◽

Naoyuki Matsuda ◽

Ichiro Sakuma ◽

Shigeaki Kobayashi ◽

Fumika Sakuraya ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Inflammatory Responses ◽

Tissue Injury ◽

Critical Role ◽

Control Level ◽

Temporal Changes ◽

Expression Levels ◽

Time Courses ◽

Pai 1

SummaryRecently a new concept has emerged implicating thrombin signaling as the “bridge” that connects tissue damage to hemostatic and inflammatory responses. In view of this concept, we hypothesized that induction of protease-activated receptor (PAR) expression may play a critical role in endotoxin-induced tissue injury through the cellular actions of thrombin. Thus, in this study, temporal changes in expression of key precoagulant molecules, including PARs, in lungs from rabbits rendered endotoxemic by 100 μg/kg lipopolysaccharide (LPS) were examined with measurements of variables reflecting acute lung injury (ALI). ALI induction by LPS was confirmed by blood gas derangement, lung vascular hyperpermeability, and histopathological changes, and was characterized by the deposition of fibrin in the alveolar spaces, bronchioles and vessels. Plasminogen activator inhibitor-1 (PAI-1) and tissue factor (TF) were highly expressed in lungs after LPS injection. While the peaks in levels of PAI-1 and TF were comparable (12∼13-fold from control), their expression time-courses were different: PAI-1 exhibited a bell-shaped expression pattern and peak at 6 h, whereas TF level reached maximum at 10 h. Of note, LPS induced a rapid and significant increase in levels of PAR-1 compared to control, with a peak level at 1 h (3.3-fold). Although declining thereafter, it remained significantly higher than the control level throughout the study period. Expressions of PAR-2, -3, and -4 were also increased by LPS with different time courses from PAR-1 expression. Immunofluorescence staining for PAR-1 were localized in blood vessels, bronchial epithelium, and alveolar pneumocytes after LPS. These results suggest that the increased expression levels of PARs, in addition to PAI-1 and TF, may, in part, underlie the development of ALI occurring during endotoxemia.

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Loss of caveolin-1 and adiponectin induces severe inflammatory lung injury following LPS challenge through excessive oxidative/nitrative stress

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00182.2013 ◽

2014 ◽

Vol 306 (6) ◽

pp. L566-L573 ◽

Cited By ~ 15

Author(s):

Lei Cai ◽

Fan Yi ◽

Zhiyu Dai ◽

Xiaojia Huang ◽

Yidan D. Zhao ◽

...

Keyword(s):

Lung Injury ◽

Vascular Permeability ◽

Inflammatory Responses ◽

Critical Role ◽

Sublethal Dose ◽

Myeloperoxidase Activity ◽

Double Knockout ◽

Caveolin 1 ◽

Lps Challenge ◽

Nitrative Stress

Excessive reactive oxygen/nitrogen species have been associated with the onset, progression, and outcome of sepsis, both in preclinical and clinical studies. However, the signaling pathways regulating oxidative/nitrative stress in the pathogenesis of sepsis-induced acute lung injury and acute respiratory distress syndrome are not fully understood. Employing the novel mouse model with genetic deletions of both caveolin-1 ( Cav1) and adiponectin ( ADPN) [double knockout (DKO) mice], we have demonstrated the critical role of Cav1 and ADPN signaling cross talk in regulating oxidative/nitrative stress and resulting inflammatory lung injury following LPS challenge. In contrast to the inhibited inflammatory lung injury in Cav1 −/− mice, we observed severe lung inflammation and markedly increased lung vascular permeability in DKO mice in response to LPS challenge. Accordingly, the DKO mice exhibited an 80% mortality rate following a sublethal dose of LPS challenge. At basal state, loss of Cav1 and ADPN resulted in a drastic increase of oxidative stress and resultant nitrative stress in DKO lungs. Scavenging of superoxide by pretreating the DKO mice with MnTMPYP (a superoxide dismutase mimetic) restored the inflammatory responses to LPS challenge including reduced lung myeloperoxidase activity and vascular permeability. Thus oxidative/nitrative stress collectively modulated by Cav1 and ADPN signalings is a critical determinant of inflammatory lung injury in response to LPS challenge.

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Bigelovii A Protects against Lipopolysaccharide-Induced Acute Lung Injury by Blocking NF-κB and CCAAT/Enhancer-Binding ProteinδPathways

Mediators of Inflammation ◽

10.1155/2016/9201604 ◽

2016 ◽

Vol 2016 ◽

pp. 1-12 ◽

Cited By ~ 5

Author(s):

Chunguang Yan ◽

Fuqin Guan ◽

Yanfei Shen ◽

Huifang Tang ◽

Dong Yuan ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

P38 Mapk ◽

Inflammatory Mediators ◽

Neutrophil Infiltration ◽

Therapeutic Approaches ◽

Lps Challenge ◽

Enhancer Binding Protein ◽

Underlying Mechanisms

Optimal methods are applied to acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS), but the mortality rate is still high. Accordingly, further studies dedicated to identify novel therapeutic approaches to ALI are urgently needed. Bigelovii A is a new natural product and may exhibit anti-inflammatory activity. Therefore, we sought to investigate its effect on lipopolysaccharide- (LPS-) induced ALI and the underlying mechanisms. We found that LPS-induced ALI was significantly alleviated by Bigelovii A treatment, characterized by reduction of proinflammatory mediator production, neutrophil infiltration, and lung permeability. Furthermore, Bigelovii A also downregulated LPS-stimulated inflammatory mediator expressionsin vitro. Moreover, both NF-κB and CCAAT/enhancer-binding proteinδ(C/EBPδ) activation were obviously attenuated by Bigelovii A treatment. Additionally, phosphorylation of both p38 MAPK and ERK1/2 (upstream signals of C/EBPδactivation) in response to LPS challenge was also inhibited by Bigelovii A. Therefore, Bigelovii A could attenuate LPS-induced inflammation by suppression of NF-κB, inflammatory mediators, and p38 MAPK/ERK1/2—C/EBPδ, inflammatory mediators signaling pathways, which provide a novel theoretical basis for the possible application of Bigelovii A in clinic.

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USP9X promotes LPS-induced pulmonary epithelial barrier breakdown and hyperpermeability by activating an NF-κBp65 feedback loop

AJP Cell Physiology ◽

10.1152/ajpcell.00094.2019 ◽

2019 ◽

Vol 317 (3) ◽

pp. C534-C543 ◽

Cited By ~ 1

Author(s):

Yijin Xiang ◽

Shaoyan Zhang ◽

Jia Lu ◽

Wen Zhang ◽

Min Cai ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Cell Viability ◽

Western Blotting ◽

Critical Role ◽

Alveolar Epithelial Cells ◽

Inflammatory Factors ◽

Epithelial Barrier ◽

Pyrrolidine Dithiocarbamate ◽

Barrier Breakdown

NF-κB is a central regulator of inflammatory and immune responses and has been shown to regulate transcription of several inflammatory factors as well as promote acute lung injury. However, the regulation of NF-κB signaling in acute lung injury has yet to be investigated. Human pulmonary alveolar epithelial cells (HPAEpiC) were treated with LPS to establish an acute lung injury model in vitro in which LPS stimulation resulted in pulmonary epithelial barrier breakdown and hyperpermeability. Cell viability was measured by CCK-8, and the transepithelial permeability was examined by measurement of transepithelial electrical resistance (TEER) and the transepithelial flux. Expression of ubiquitin-specific peptidase 9 X-linked (USP9X), zonula occludens (ZO-1), occludin and NF-κBp65, and the secretion of TNF-α and IL-1β were measured by Western blotting and ELISA, respectively. For in vivo studies, mice were intraperitoneally injected with LPS and/or NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC). Lung tissues were harvested for hematoxylin-eosin staining and Western blotting, and bronchoalveolar lavage fluid (BALF) was harvested for ELISA. We found that treatment with LPS in HPAEpiC inhibited cell viability and induced the expression of USP9X. Interestingly, knockdown of USP9X and treatment with PDTC suppressed LPS-induced HPAEpiC injury. USP9X overexpression promoted NF-κB activation, while NF-κB inactivation inhibited USP9X transcription and HPAEpiC injury induced by USP9X overexpression. Furthermore, LPS also induced the expression of USP9X in lungs, which was inhibited by PDTC. Taken together, these results demonstrate a critical role of USP9X-NF-κBp65 loop in mediating LPS-induced acute lung injury and may serve as a potential therapeutic target in acute lung injury.

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Pterostilbene 4′-β-Glucoside Attenuates LPS-Induced Acute Lung Injury via Induction of Heme Oxygenase-1

Oxidative Medicine and Cellular Longevity ◽

10.1155/2018/2747018 ◽

2018 ◽

Vol 2018 ◽

pp. 1-16 ◽

Cited By ~ 6

Author(s):

Jeongmin Park ◽

Yingqing Chen ◽

Min Zheng ◽

Jinhyun Ryu ◽

Gyeong Jae Cho ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Heme Oxygenase ◽

Inflammatory Responses ◽

Critical Role ◽

Mouse Lung ◽

Heme Oxygenase 1 ◽

Ros Production ◽

Protective Effects ◽

Anti Inflammatory

Heme oxygenase-1 (HO-1) can exert anti-inflammatory and antioxidant effects. Acute lung injury (ALI) is associated with increased inflammation and influx of proinflammatory cells and mediators in the airspaces and lung parenchyma. In this study, we demonstrate that pterostilbene 4′-β-glucoside (4-PG), the glycosylated form of the antioxidant pterostilbene (PTER), can protect against lipopolysaccharide- (LPS-) orPseudomonas aeruginosa- (P. aeruginosa-) induced ALI when applied as a pretreatment or therapeutic post-treatment, via the induction of HO-1. To determine whether HO-1 mediates the antioxidant and anti-inflammatory effects of 4-PG, we subjected mice genetically deficient inHmox-1to LPS-induced ALI and evaluated histological changes, HO-1 expression, and proinflammatory cytokine levels in bronchoalveolar lavage (BAL) fluid. 4-PG exhibited protective effects on LPS- orP. aeruginosa-induced ALI by ameliorating pathological changes in lung tissue and decreasing proinflammatory cytokines. In addition, HO-1 expression was significantly increased by 4-PG in cells and in mouse lung tissues. The glycosylated form of pterostilbene (4-PG) was more effective than PTER in inducing HO-1 expression. Genetic deletion ofHmox-1abolished the protective effects of 4-PG against LPS-induced inflammatory responses. Furthermore, we found that 4-PG decreased both intracellular ROS levels and mitochondrial (mt) ROS production in a manner dependent on HO-1. Pharmacological application of the HO-1 reaction product carbon monoxide (CO), but not biliverdin or iron, conferred protection inHmox-1-deficient macrophages. Taken together, these results demonstrate that 4-PG can increase HO-1 expression, which plays a critical role in ameliorating intracellular and mitochondrial ROS production, as well as in downregulating inflammatory responses induced by LPS. Therefore, these findings strongly suggest that HO-1 mediates the antioxidant and anti-inflammatory effects of 4-PG.

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Diversity of Th1/Th2 immunity in mice with acute lung injury induced by the H1N1 influenza virus and lipopolysaccharides

The Journal of Infection in Developing Countries ◽

10.3855/jidc.10338 ◽

2019 ◽

Vol 13 (06) ◽

pp. 536-544

Author(s):

Jian-xing Liu ◽

Ying Zhang ◽

Miao An ◽

Qing-guang Wu ◽

Ya Zhao ◽

...

Keyword(s):

Oxidative Stress ◽

Influenza Virus ◽

Acute Lung Injury ◽

Lung Injury ◽

Inflammatory Cells ◽

Cell Polarization ◽

Th2 Cells ◽

Lung Edema ◽

Lps Challenge ◽

Th Cell

Introduction: The polarization of T helper (Th) cells plays an important role in the inflammatory response, pathogen removal, and tissue damage processes of infectious acute lung injury (ALI). However, Th cell polarization in viral- or bacterial-mediated ALI is not well defined. Herein, an influenza virus (A/FM/1/47, H1N1) and lipopolysaccharide (LPS) were chosen to induce ALI in mice, and the resultant diversity of Th-cell polarization was explored. Methodology: BALB/c mice were challenged intranasally with the influenza virus or LPS. Edema of the lung, infiltration of inflammatory cells (macrophages, neutrophils, and lymphocytes), oxidative stress, and signature cytokines of Th1 and Th2 cells were detected at 2 days post virus or LPS challenge. Results: The mice exhibited increased capillary permeability accompanied by lung edema and protein-rich alveolar exudation after virus or LPS challenge. Additionally, excessive infiltration of inflammatory cells, robust oxidative stress, and cytokine production were observed in both mouse groups. However, there was conspicuous disparity in the inflammatory cell infiltration and cytokines between the virus- and LPS-challenged mice, where the infiltration in virus-challenged mice was mainly of macrophages and accompanied by robust Th1 cytokine elevation, whereas the infiltration in LPS-challenged mice was primarily of neutrophils and accompanied by robust Th2 cytokine elevation. Conclusions: The Th cell polarization was skewed depending on whether ALI was induced by the influenza virus or LPS. The polarization in the virus-challenged mice was primarily toward a Th1 response, whereas that in the LPS-challenged mice was mainly toward Th2.

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

10.21203/rs.2.20071/v1 ◽

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.

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