Critical role for integrin-β4 in the attenuation of murine acute lung injury by simvastatin

The statins are a class of 3-hydroxy-3-methylglutaryl-coenzyme A-reductase inhibitors that are recognized to have pleiotropic properties. We previously reported the attenuation of LPS-induced murine acute lung injury (ALI) by simvastatin in vivo and identified relevant effects of simvastatin on endothelial cell (EC) signaling, activation, and barrier function in vitro. In particular, simvastatin induces the upregulation of integrin-β4, which in turn inhibits EC inflammatory responses via attenuation of MAPK signaling. The role of integrin-β4 in murine ALI protection by simvastatin, however, is unknown. We initially confirmed a time- and dose-dependent effect of simvastatin on increased integrin-β4 mRNA expression in human lung EC with peak protein expression evident at 16 h. Subsequently, reciprocal immunoprecipitation demonstrated an attenuation of LPS-induced integrin-β4 tyrosine phosphorylation by simvastatin (5 μM, 16 h). Increased expression of EC inflammatory cytokines [IL-6, IL-8, monocyte chemoattractant protein (MCP)-1, regulated on activation normal T cell expressed and secreted (RANTES)] by LPS (500 ng/ml, 4 h) was also significantly attenuated by simvastatin pretreatment (5 μM, 16 h), but this effect was reversed by cotreatment with an integrin-β4-blocking antibody. Finally, although simvastatin (20 mg/kg) conferred significant protection in murine ALI as evidenced by decreased bronchoalveolar lavage fluid cell counts, protein, inflammatory cytokines (IL-6, IL-1β, MCP-1, RANTES), decreased Evans blue dye albumin extravasation in lung tissue, and changes on lung histology, these effects were reversed by the integrin-β4-blocking antibody (IV, 1 mg/kg, 2 h before LPS). These findings support integrin-β4 as an important mediator of ALI protection by simvastatin and implicate signaling by integrin-β4 as a novel therapeutic target in patients with ALI.

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Protective effect of adenosine receptors against lipopolysaccharide-induced acute lung injury

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00086.2013 ◽

2014 ◽

Vol 306 (6) ◽

pp. L497-L507 ◽

Cited By ~ 32

Author(s):

Joyce N. Gonzales ◽

Boris Gorshkov ◽

Matthew N. Varn ◽

Marina A. Zemskova ◽

Evgeny A. Zemskov ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Inflammatory Cytokines ◽

Adenosine Receptors ◽

Blue Dye ◽

Protective Effects ◽

Extracellular Adenosine ◽

Lps Challenge ◽

Cell Counts ◽

The Usa

Acute lung injury and acute respiratory distress syndrome (ALI/ARDS) affect 200,000 people a year in the USA. Pulmonary vascular and specifically endothelial cell (EC) barrier compromise is a hallmark of these diseases. We have recently shown that extracellular adenosine enhances human pulmonary (EC) barrier via activation of adenosine receptors (ARs) in cell cultures. On the basis of these data, we hypothesized that activation of ARs might exert barrier-protective effects in a model of ALI/ARDS in mice. To test this hypothesis, we examined the effects of pre- and posttreatment of adenosine and 5′- N-ethylcarboxamidoadenosine (NECA), a nonselective stable AR agonist, on LPS-induced lung injury. Mice were given vehicle or LPS intratracheally followed by adenosine, NECA, or vehicle instilled via the internal jugular vein. Postexperiment cell counts, Evans Blue Dye albumin (EBDA) extravasation, levels of proteins, and inflammatory cytokines were analyzed. Harvested lungs were used for histology and myeloperoxidase studies. Mice challenged with LPS alone demonstrated an inflammatory response typical of ALI. Cell counts, EBDA extravasation, as well as levels of proteins and inflammatory cytokines were decreased in adenosine-treated mice. Histology displayed reduced infiltration of neutrophils. NECA had a similar effect on LPS-induced vascular barrier compromise. Importantly, posttreatment with adenosine or NECA recovers lung vascular barrier and reduces inflammation induced by LPS challenge. Furthermore, adenosine significantly attenuated protein degradation of A2A and A3 receptors induced by LPS. Collectively, our results demonstrate that activation of ARs protects and restores vascular barrier functions and reduces inflammation in LPS-induced ALI.

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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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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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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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ID: 109: PARKIN MEDIATES ENDOTHELIAL PRO-INFLAMMATORY RESPONSES IN ACUTE LUNG INJURY

Journal of Investigative Medicine ◽

10.1136/jim-2016-000120.106 ◽

2016 ◽

Vol 64 (4) ◽

pp. 963.1-963

Author(s):

E Letsiou ◽

H Wang ◽

P Belvitch ◽

S Dudek ◽

S Sammani

Keyword(s):

Acute Lung Injury ◽

Endothelial Dysfunction ◽

Lung Injury ◽

Kinase Inhibitor ◽

Inflammatory Responses ◽

Neutrophil Adhesion ◽

Protein Levels ◽

Cell Counts

IntroductionAcute lung injury (ALI) and its more severe form, the Acute Respiratory Distress Syndrome (ARDS), are serious conditions resulting from direct or indirect lung injury that occur in critically ill patients and are associated with an unacceptable mortality of up to 40%. A key biological event in the pathogenesis of ALI/ARDS is the dysfunction of the lung endothelium (EC), which is triggered by a variety of inflammatory insults leading to damaged EC, vascular leak, and excessive inflammation. Recently, we demonstrated that an Abl family tyrosine kinase inhibitor, imatinib, protects against LPS-induced endothelial dysfunction by inhibiting c-Abl kinase through mechanisms that remain largely unknown. In the present study, we identified parkin, a novel c-Abl substrate, as a critical mediator of endothelial dysfunction in ALI.MethodsIn vitro Human pulmonary artery endothelial cells (EC) were transfected with siRNA for parkin and then challenged with LPS (1 µg/ml, 3 hrs). Inflammatory mediators were determined in cell lysates and supernatants by Western blotting and ELISA respectively. In vivo C57BL/6 (WT) and parkin deficient (PARK2 KO) male mice (8–12 wks, n=5–8) were subjected to LPS (intratracheally, 1 mg/kg) or PBS (controls), and allowed to recover prior to harvest 18 hrs later. Leakage of proteins into the alveolar space was assessed by measuring the protein levels in the bronchoalveolar lavage (BAL). To assess lung inflammation, neutrophil cell counts, myeloperoxidase (MPO) activity, and IL-6 levels were determined in BAL.ResultsIn human lung EC, down-regulation of parkin by siRNA reduces LPS-induced VCAM-1 expression (adhesion molecule involved in neutrophil adhesion to EC) (by 35%, p<0.05), IL-8 (neutrophil chemoattractant) (by 59%, p<0.01), and IL-6 (inflammatory cytokine) release (by 79%, p<0.01). PARK2 KO mice exhibit less ALI after LPS compared to WT. In PARK2 KO, BAL protein levels were reduced by 27% (p=0.0024) compared to WT mice. LPS-induced neutrophil recruitment into the alveoli of PARK2 KO was attenuated by 47% compared to WT (p=0.0019). BAL MPO activity (marker of neutrophil activation) and BAL IL-6 levels were also significantly lower in PARK2 KO by 52% (p=0.03) and 28% (p=0.0061) respectively.ConclusionThese results suggest that endothelial parkin mediates EC activation and neutrophil adhesion/migration after LPS, and therefore it may represent a new potential therapeutic target in ALI/ARDS.

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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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Genetic disruption of protein kinase Cδ reduces endotoxin-induced lung injury

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00169.2012 ◽

2012 ◽

Vol 303 (10) ◽

pp. L880-L888 ◽

Cited By ~ 22

Author(s):

Havovi Chichger ◽

Katie L. Grinnell ◽

Brian Casserly ◽

Chun-Shiang Chung ◽

Julie Braza ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Pulmonary Edema ◽

Barrier Function ◽

Inflammatory Responses ◽

Critical Role ◽

Endothelial Barrier ◽

Mouse Lung ◽

Barrier Dysfunction ◽

Transient Overexpression

The pathogenesis of acute lung injury and acute respiratory distress syndrome is characterized by sequestration of leukocytes in lung tissue, disruption of capillary integrity, and pulmonary edema. PKCδ plays a critical role in RhoA-mediated endothelial barrier function and inflammatory responses. We used mice with genetic deletion of PKCδ (PKCδ−/−) to assess the role of PKCδ in susceptibility to LPS-induced lung injury and pulmonary edema. Under baseline conditions or in settings of increased capillary hydrostatic pressures, no differences were noted in the filtration coefficients ( kf) or wet-to-dry weight ratios between PKCδ+/+ and PKCδ−/− mice. However, at 24 h after exposure to LPS, the kf values were significantly higher in lungs isolated from PKCδ+/+ than PKCδ−/− mice. In addition, bronchoalveolar lavage fluid obtained from LPS-exposed PKCδ+/+ mice displayed increased protein and cell content compared with LPS-exposed PKCδ−/− mice, but similar changes in inflammatory cytokines were measured. Histology indicated elevated LPS-induced cellularity and inflammation within PKCδ+/+ mouse lung parenchyma relative to PKCδ−/− mouse lungs. Transient overexpression of catalytically inactive PKCδ cDNA in the endothelium significantly attenuated LPS-induced endothelial barrier dysfunction in vitro and increased kf lung values in PKCδ+/+ mice. However, transient overexpression of wild-type PKCδ cDNA in PKCδ−/− mouse lung vasculature did not alter the protective effects of PKCδ deficiency against LPS-induced acute lung injury. We conclude that PKCδ plays a role in the pathological progression of endotoxin-induced lung injury, likely mediated through modulation of inflammatory signaling and pulmonary vascular barrier function.

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Oleanolic Acid Acetate Exerts Anti-Inflammatory Activity via IKKα/β Suppression in TLR3-Mediated NF-κB Activation

Molecules ◽

10.3390/molecules24214002 ◽

2019 ◽

Vol 24 (21) ◽

pp. 4002 ◽

Cited By ~ 1

Author(s):

Hyung Jin Lim ◽

Hyun-Jae Jang ◽

Mi Hwa Kim ◽

Soyoung Lee ◽

Seung Woong Lee ◽

...

Keyword(s):

Signaling Pathway ◽

Oleanolic Acid ◽

Inflammatory Cytokines ◽

Inflammatory Responses ◽

Critical Role ◽

Mapk Signaling ◽

Dependent Manner ◽

Nuclear Factor ◽

Anti Inflammatory ◽

Tlr3 Signaling

Oleanolic acid acetate (OAA), a major triterpenoid compound of Vigna angularis (azuki bean, V. angularis), has been shown to downregulate inflammatory responses in macrophages. Here, we show the molecular basis for the effect of OAA on Toll-like receptor (TLR) downstream signaling. OAA treatment significantly inhibited the secretion of embryonic alkaline phosphatase (SEAP) induced by polyinosinic acid (poly(I), TLR3 ligand) in a dose-dependent manner and without cytotoxicity in THP1-XBlue cells. In addition, OAA downregulated the gene expression of poly(I) induced pro-inflammatory cytokines and chemokines genes such as MCP-1, IL-1β, IL-8, VCAM-1 and ICAM-1. Furthermore, we found that the inhibition activity of OAA was accompanied by decreased activation of not only nuclear factor-kappa B (NF-κB) signaling but also mitogen-activated protein kinase (MAPK) signaling upon stimulation with the TLR3 agonist. Interestingly, the interaction of OAA with IκB kinase α/β (IKKα/β) strongly attenuated the production of certain proteins and inflammatory cytokines in the TLR3 signaling pathway, such as nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IkBα), extracellular regulated kinases (ERK), and p38, in an in vitro model. The action of OAA was regulated by TLR3, demonstrating that TLR3 plays a critical role in mediating the physiologically-relevant anti-inflammatory action of OAA and that the interaction with IKKα/β is modulated through TLR3. These results reveal new insight into the understanding of the regulatory mechanisms of the downstream TLR3 signaling pathway and consequent inflammatory responses that are involved in the development and progression of inflammatory diseases.

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

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00277.2011 ◽

2012 ◽

Vol 302 (9) ◽

pp. L866-L874 ◽

Cited By ~ 34

Author(s):

Feng Qian ◽

Jing Deng ◽

Benjamin N. Gantner ◽

Richard A. Flavell ◽

Chen Dong ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Inflammatory Responses ◽

Critical Role ◽

Inflammatory Cells ◽

Neutrophil Infiltration ◽

Inflammatory Factors ◽

Lps Challenge ◽

Map Kinase Phosphatase ◽

Severe Lung

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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Histatin-1 Attenuates LPS-Induced Inflammatory Signaling in RAW264.7 Macrophages

International Journal of Molecular Sciences ◽

10.3390/ijms22157856 ◽

2021 ◽

Vol 22 (15) ◽

pp. 7856

Author(s):

Sang Min Lee ◽

Kyung-No Son ◽

Dhara Shah ◽

Marwan Ali ◽

Arun Balasubramaniam ◽

...

Keyword(s):

Molecular Mechanisms ◽

Cytokine Production ◽

Inflammatory Responses ◽

Critical Role ◽

Mapk Signaling ◽

Response To Treatment ◽

No Production ◽

Inflammatory Signaling ◽

Raw264.7 Macrophages ◽

Inflammatory Mediator Production

Macrophages play a critical role in the inflammatory response to environmental triggers, such as lipopolysaccharide (LPS). Inflammatory signaling through macrophages and the innate immune system are increasingly recognized as important contributors to multiple acute and chronic disease processes. Nitric oxide (NO) is a free radical that plays an important role in immune and inflammatory responses as an important intercellular messenger. In addition, NO has an important role in inflammatory responses in mucosal environments such as the ocular surface. Histatin peptides are well-established antimicrobial and wound healing agents. These peptides are important in multiple biological systems, playing roles in responses to the environment and immunomodulation. Given the importance of macrophages in responses to environmental triggers and pathogens, we investigated the effect of histatin-1 (Hst1) on LPS-induced inflammatory responses and the underlying molecular mechanisms in RAW264.7 (RAW) macrophages. LPS-induced inflammatory signaling, NO production and cytokine production in macrophages were tested in response to treatment with Hst1. Hst1 application significantly reduced LPS-induced NO production, inflammatory cytokine production, and inflammatory signaling through the JNK and NF-kB pathways in RAW cells. These results demonstrate that Hst1 can inhibit LPS-induced inflammatory mediator production and MAPK signaling pathways in macrophages.

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