Role of p38 mitogen-activated protein kinase in antiphospholipid antibody-mediated thrombosis and endothelial cell activation

BACKGROUND: The purpose of this study was to examine whether SB 203580, a p38 mitogen-activated protein kinase (MAPK) inhibitor, is effective in reversing the pathogenic effects of antiphospholipid antibodies. METHODS: The adhesion of THP-1 monocytes to cultured endothelial cells (EC) treated with immunoglobulin G (IgG) from a patient with antiphospholipid syndrome (IgG-APS) or control IgG (IgG-NHS) in the presence and absence of SB 203580 was examined. The size of an induced thrombus in the femoral vein, the adhesion of leukocytes to EC of cremaster muscle, tissue factor (TF) activity in carotid artery and in peritoneal macrophages, the ex vivo expression of vascular cell adhesion molecule-1 (VCAM-1) in aorta preparations and platelet aggregation were studied in mice injected with IgG-APS or control IgG-NHS and with or without SB 203580. RESULTS: SB 203580 significantly reduced the increased adhesion of THP-1 to EC in vitro, the number of leukocytes adhering to EC, the thrombus size, the TF activity in carotid arteries and in peritoneal mononuclear cells, and the expression of VCAM-1 in aorta of mice, and completely abrogated platelet aggregation induced by IgG-APS. CONCLUSION: These data suggest that targeting the p38 MAPK pathway may be valuable in designing new therapy modalities for treating thrombosis in patients with APS.     

Roflumilast inhibits lipopolysaccharide-induced inflammatory mediators via suppression of nuclear factor-kappaB, p38 mitogen-activated protein kinase, and c-Jun NH2-terminal kinase activation

Roflumilast, a potent and selective phosphodiesterase 4 (PDE4) inhibitor, has been demonstrated to be an effective anti-inflammatory agent in airway inflammatory diseases. In the present study, we investigated the mechanism of anti-inflammatory effects of roflumilast in murine macrophage cell line RAW264.7 cells. Roflumilast inhibited NO, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-1beta production via suppression of their gene expressions in lipopolysaccharide (LPS)-stimulated macrophages. To elucidate the mechanism by which roflumilast inhibits the production of inflammatory mediators, we examined the effect of roflumilast on the activation of nuclear factor-kappaB (NF-kappaB) in these cells. Roflumilast inhibited the DNA binding activity of NF-kappaB by preventing inhibitor kappaBalpha phosphorylation and degradation. The phosphorylation of mitogen-activated protein (MAP) kinases, including stress-activated protein kinase/c-Jun NH2-terminal kinase (JNK) and p38 MAP kinase, was also markedly inhibited by roflumilast. Similar to the effects of roflumilast, treatment of either SB203580 [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)imidazole] or SP600125 [anthra(1,9-cd)pyrazol-6(2H)-one 1,9-pyrazoloanthrone], specific inhibitors of p38 MAP kinase and JNK, respectively, suppressed NO, TNF-alpha, and IL-1beta production. Consistent with in vitro results, administration of roflumilast recovered the survival rate of LPS-treated mice, with concurrent suppression of plasma levels of nitrite/nitrate, TNF-alpha, and IL-1beta. These results suggest that the inhibitory activity of roflumilast on the production of inflammatory mediators seems to be mediated via inhibition of NF-kappaB, p38 MAP kinase, and JNK activation in macrophages.     

p38 mitogen-activated protein kinase targets the production of proinflammatory endothelial microparticles

Summary.  Background: Endothelial microparticles (EMPs) are irregularly shaped membrane fragments shed into the circulation in patients with vascular diseases, and may themselves act to enhance the endothelial response to inflammation. On the basis of the importance of p38 mitogen-activated protein kinase (MAPK) in endothelial responses to inflammatory stimuli, we sought to define the role of p38 in EMP generation and function. Methods: Microparticle generation from cultures of human aortic endothelial cells (hAECs) treated with tumor necrosis factor-α (TNF-α) and p38 inhibition was quantified via multiple modalities. The response of target endothelial cells was assessed by treatment of cells with EMPs generated under various conditions. Results: Inhibition of p38 in hAECs, using pharmacologic agents, resulted in a 50% reduction of TNF-α-induced EMPs. Importantly, suppression of microparticles was specific to p38 MAPK pathways. EMPs triggered by TNF-α activation induced an approximately four-fold increase in soluble intercellular adhesion molecule-1 (sICAM-1) release from targeted cells. However, inhibition of p38 MAPK in the targeted cell prior to EMP treatment did not alter the sICAM1 response. Conclusions: Our findings implicate p38 MAPK signaling as significant and selective in the formation and maturation of EMPs. EMPs elicited a proinflammatory response from targeted hAECs that was dependent on the conditions under which EMPs were generated. However, our results imply a unidirectional model in which p38 MAPK is critical at the source of microparticle formation, but not the target cell response to EMPs. These findings indicate a novel mechanism by which p38 inhibition may offer therapeutic benefit in vivo via direct inhibition of EMP formation .     

达格列净通过p38丝裂原活化蛋白激酶抑制高糖诱导的人肾小球足细胞损伤

目的 探讨达格列净通过p38丝裂原活化蛋白激酶（p38 MAPK）信号通路对D-葡萄糖诱导的人肾小球足细胞凋亡、自噬、炎症反应及氧化损伤的影响。方法 体外培养人肾小球足细胞（HGPCs），分为对照组（5 mmol/L D-葡萄糖）、D-葡萄糖组（30 mmol/L D-葡萄糖）、达格列净组（30 mmol/L D-葡萄糖＋50 μmol/L达格列净）、抑制剂组（30 mmol/L D-葡萄糖＋10 μmol/L p38 MAPK通路抑制剂SB 203580）、达格列净＋抑制剂组（30 mmol/L D-葡萄糖＋50 μmol/L达格列净＋10 μmol/L SB 203580）和达格列净＋激活剂组（30 mmol/L D-葡萄糖＋50 μmol/L达格列净＋10 μmol/L p38 MAPK通路激活剂C16-PAF）。对照组与D-葡萄糖组用D-葡萄糖干预24 h；其他组D-葡萄糖干预24 h后相应药物继续干预 24 h。采用细胞计数试剂盒-8（CCK-8）检测细胞活力；采用Hoechst 33258染色法检测细胞凋亡率；采用ELISA检测白细胞介素（IL）-1β、IL-6、肿瘤坏死因子α（TNF-α）、丙二醇（MDA）和超氧化物歧化酶（SOD）的表达水平；采用实时荧光定量PCR（RT-qPCR）检测酵母ATG6同源物（Beclin-1）、微管相关蛋白1轻链3 Ⅱ（LC3 Ⅱ）mRNA表达水平；采用Western印迹法检测Beclin-1、LC3 Ⅱ、p53、p38 MAPK及p-p38 MAPK蛋白表达。结果 与对照组相比，D-葡萄糖组细胞活力降低（P＜0.05），达格列净组细胞活力升高（P＜0.05），细胞凋亡率，IL-1β、IL-6、TNF-α、MDA、Beclin-1、LC3 ⅡmRNA和蛋白、p53和p-p38 MAPK蛋白水平升高（P＜0.05），SOD水平降低（P＜0.05）。与D-葡萄糖组相比，达格列净组和抑制剂组细胞凋亡率、IL-1β、IL-6、TNF-α、MDA、Beclin-1、LC3 ⅡmRNA和蛋白、p53和p-p38 MAPK蛋白水平降低（P＜0.05），SOD水平升高（P＜0.05）。与达格列净组相比，达格列净＋抑制剂组细胞凋亡率、IL-1β、IL-6、TNF-α、MDA、Beclin-1、LC3 Ⅱ mRNA和蛋白、p53和p-p38 MAPK蛋白水平进一步降低（P＜0.05），SOD水平进一步升高（P＜0.05）；达格列净＋激活剂组与达格列净＋抑制剂组变化趋势相反，与达格列净组差异有统计学意义（P＜0.05）。结论 达格列净可抑制高糖诱导的人HGPCs的凋亡、自噬、炎症反应及氧化损伤，其作用机制可能与抑制p38 MAPK通路信号转导相关。     

Proapoptotic effect of curcumin on human neutrophils: activation of the p38 mitogen-activated protein kinase pathway

OBJECTIVE: Despite advances in the management of sepsis and acute respiratory distress syndrome, the mortality rate remains high. Delayed apoptosis of neutrophils is associated with multiple organ failure under those conditions. Thus, development of nontoxic neutrophil apoptosis regulating molecules may provide a novel therapeutic strategy. Curcumin is a promising dietary supplement for cancer prevention. However, the effect of curcumin on human neutrophil apoptosis remains unknown. We therefore hypothesized that curcumin would produce a proapoptotic effect on neutrophils. DESIGN: Prospective, controlled, and randomized in vitro study. SETTING: Research institute laboratory. SUBJECTS: Human peripheral neutrophils obtained from normal subjects. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: In the presence or absence of curcumin, both spontaneous neutrophil apoptosis and apoptosis of neutrophils following transmigration across a human lung endothelium-epithelium bilayer were studied by morphology and terminal dUTP nucleotide end labeling analyses, respectively. Myeloperoxidase activity and migration assays were performed to determine the impact of curcumin on neutrophil function. To elucidate the potential mechanism, the p38 mitogen-activated protein kinase pathway and caspase-3 activity were examined by Western blotting and enzymatic analyses. The data demonstrate that curcumin increased constitutive neutrophil apoptosis and abrogated the transbilayer migration-induced delay in neutrophil apoptosis. Neutrophil activation was reduced by curcumin treatment as evidenced by a decrease in migration and myeloperoxidase release. A marked increase in p38 phosphorylation and caspase-3 activity was observed following curcumin exposure. In addition, inhibition of p38 mitogen-activated protein kinase with SB203580 suppressed apoptosis and caspase-3 activation induced by curcumin. Thus, activation of p38 mitogen-activated protein kinase or an increase in caspase-3 activity appears to contribute to the proapoptotic effect of human neutrophil apoptosis by curcumin. CONCLUSION: The characteristics of curcumin, including its proapoptotic effect and antidegranulation effect, make it a potential candidate for the therapy of neutrophil-induced lung injury and sepsis.     

Drugs designed to inhibit human p38 mitogen-activated protein kinase activation treat Toxoplasma gondii and Encephalitozoon cuniculi infection

We recently showed that the pyridinylimidazoles SB203580 and SB202190, drugs designed to block human p38 mitogen-activated protein kinase (MAPK) activation, also inhibited replication of the medically important intracellular parasite Toxoplasma gondii in cultured human fibroblasts through a direct effect on the parasite. We now show that additional pyridinylimidazole and imidazopyrimidine p38 MAPK inhibitors inhibit intracellular T. gondii replication in vitro and protect mice against fatal T. gondii infection. Mice surviving infection following treatment with p38 MAPK inhibitors were resistant to subsequent T. gondii challenge, demonstrating induction of protective immunity. Thus, drugs originally developed to block human p38 MAPK activation are useful for treating T. gondii infection without inducing significant immunosuppression. MAPK inhibitors combined with either of the approved anti-Toxoplasma drugs sulfadiazine and pyrimethamine resulted in improved survival among mice challenged with a fatal T. gondii inoculum. A MAPK inhibitor also treated mice infected with the Microsporidium parasite Encephalitozoon cuniculi, suggesting that MAPK inhibitors represent a novel class of agents that may have a broad spectrum of antiparasitic activity. Preliminary studies implicate a T. gondii MAPK homologue as the target of drug action, suggesting possibilities for more-selective agents.     

p38 mitogen-activated protein kinase inhibitors--mechanisms and therapeutic potentials.

The pyridinylimidazole compounds, exemplified by SB 203580, originally were prepared as inflammatory cytokine synthesis inhibitors. Subsequently, the compounds were found to be selective inhibitors for p38 mitogen-activated protein kinase (MAPK), a member of the MAPK family. SB 203580 inhibits the catalytic activity of p38 MAPK by competitive binding in the ATP pocket. Four homologues of p38 MAPK have been identified to date, and interestingly, their biochemical properties and their respective sensitivities to the inhibitors are distinct. X-ray crystallographic analysis of p38-inhibitor complexes reinforces the observations made from site-directed mutagenesis studies, thereby providing a molecular basis for understanding the kinase selectivity of these inhibitors. The p38 MAPK inhibitors are efficacious in several disease models, including inflammation, arthritis and other joint diseases, septic shock, and myocardial injury.     

Inhibition of p38 mitogen-activated protein kinase blocks activation of rat pancreatic stellate cells

Activated pancreatic stellate cells (PSCs) have recently been implicated in the pathogenesis of pancreatic fibrosis and inflammation. However, the signal transduction pathways in PSCs remain largely unknown. We examined the role of p38 mitogen-activated protein (MAP) kinase in the activation of PSCs. PSCs were isolated from rat pancreas tissue and used in their culture-activated, myofibroblast-like phenotype. Activation of p38 MAP kinase was determined by Western blotting using anti-phosphospecific antibody. The effects of two p38 MAP kinase inhibitors, 4-(4-flurophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)imidazole (SB203580) and 4-(4-flurophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)1H-imidazole (SB202190), on the parameters of PSC activation, including proliferation, expression of alpha-smooth muscle actin, alpha1(I) procollagen, and prolyl 4-hydroxylase (alpha) genes, and monocyte chemoattractant protein-1 production were evaluated. Interleukin-1beta and platelet-derived growth factor-BB activated p38 MAP kinase. Platelet-derived growth factor-induced PSC proliferation was inhibited by SB203580 and SB202190. These reagents decreased alpha-smooth muscle actin protein expression, and alpha1(I) procollagen and prolyl 4-hydroxylase (alpha) mRNA levels. Treatment with these p38 MAP kinase inhibitors also resulted in inhibition of monocyte chemoattractant protein-1 expression. In addition, SB203580 inhibited spontaneous activation of freshly isolated PSCs in culture on plastic. Thus, inhibition of p38 MAP kinase modulated profibrogenic and proinflammatory actions in PSCs, implying a potential application of p38 MAP kinase inhibitors for the treatment of pancreatic fibrosis and inflammation.     

Selective activation and functional significance of p38alpha mitogen-activated protein kinase in lipopolysaccharide-stimulated neutrophils

Activation of leukocytes by proinflammatory stimuli selectively initiates intracellular signal transduction via sequential phosphorylation of kinases. Lipopolysaccharide (LPS) stimulation of human neutrophils is known to result in activation of p38 mitogen-activated protein kinase (MAPk); however, the upstream activator(s) of p38 MAPk is unknown, and consequences of p38 MAPk activation remain largely undefined. We investigated the MAPk kinase (MKK) that activates p38 MAPk in response to LPS, the p38 MAPk isoforms that are activated as part of this pathway, and the functional responses affected by p38 MAPk activation. Although MKK3, MKK4, and MKK6 all activated p38 MAPk in experimental models, only MKK3 was found to activate recombinant p38 MAPk in LPS-treated neutrophils. Of p38 MAPk isoforms studied, only p38alpha and p38delta were detected in neutrophils. LPS stimulation selectively activated p38alpha. Specific inhibitors of p38alpha MAPk blocked LPS-induced adhesion, nuclear factor-kappa B (NF-kappaB) activation, and synthesis of tumor necrosis factor-alpha (TNF-alpha). Inhibition of p38alpha MAPk resulted in a transient decrease in TNF-alpha mRNA accumulation but persistent loss of TNF-alpha synthesis. These findings support a pathway by which LPS stimulation of neutrophils results in activation of MKK3, which in turn activates p38alpha MAPk, ultimately regulating adhesion, NF-kappaB activation, enhanced gene expression of TNF-alpha, and regulation of TNF-alpha synthesis.     

Inhibition of nuclear factor-kappaB augments antitumor activity of adenovirus-mediated melanoma differentiation-associated gene-7 against lung cancer cells via mitogen-activated protein kinase kinase kinase 1 activation

Nuclear factor-kappaB (NF-kappaB) activation promotes cell survival and growth. Reports show that chemotherapeutic agents and cytokines that are used for cancer therapy activate NF-kappaB expression in tumor cells and its suppression enhanced the antitumor activity. We hypothesized that adenovirus-mediated overexpression of melanoma differentiation-associated gene-7/interleukin-24 (Ad-mda7/IL-24) induces NF-kappaB expression and that inhibition of this expression results in enhanced tumor cell killing. Treatment of human lung tumor (H1299 and A549) cells with Ad-mda7 resulted in NF-kappaB activation in a dose- and time-dependent manner before activation of cell death pathways. To establish that inhibition of Ad-mda7-mediated NF-kappaB activation results in enhanced tumor cell killing, H1299 cells that overexpress the dominant-negative I kappa B alpha (dnI kappa B alpha) were treated with Ad-mda7 in vitro. An enhanced growth arrest and apoptosis was observed in Ad-mda7-treated H1299-dnI kappa B alpha compared with H1299-Neo cells. This Ad-mda7-mediated enhanced killing of H1299-dnI kappa B alpha cells involved cleavage of mitogen-activated protein kinase kinase kinase 1 (MEKK1) and caspase-3 in a feedback loop mechanism. The inhibition of MEKK1 or caspase-3 cleavage in H1299-dnI kappa B alpha cells resulted in reduced Ad-mda7-mediated cell killing. In vivo, the treatment of H1299-dnI kappa B alpha s.c. tumors with Ad-mda7 resulted in increased drug sensitivity and delayed the tumor growth rate compared with Ad-mda7-treated H1299-Neo tumors. Molecular analysis of Ad-mda7-treated H1299-dnI kappa B alpha tumors showed increased MEKK1 cleavage and activation of caspase-3 compared with Ad-mda7-treated H1299-Neo tumors. Our findings thus showed that the NF-kappaB activation induced by Ad-mda7 treatment of lung cancer cells is an intrinsic survival mechanism and that the inhibition of this NF-kappaB expression results in enhanced tumor cell killing.     

Sustained activation of p38 mitogen-activated protein kinase contributes to the vascular response to injury

The vascular response to mechanical injury involves inflammatory and fibroproliferative processes that result in the formation of neointima and vascular remodeling. The complex cellular interactions initiated by vascular injury are coordinated and modulated by the elaboration of cytokines and growth factors. The production and transduction of many of these mediators require phosphorylation of p38 mitogen-activated protein kinase (MAPK). In the present investigation, we examined the pattern and localization of p38 MAPK activation following balloon vascular injury. The effects of long-term and selective inhibition of p38 MAPK with SB 239063 (trans-1-(4-hydroxycyclohexyl)-4-(4-fluorophenyl)-5-[2-methoxy)pyrimidin-4-yl]imidazole) were also investigated in a model of vascular injury. Western blotting and immunohistochemical staining demonstrated that phospho-p38 MAPK was increased following balloon injury of the rabbit iliofemoral artery. The p38 MAPK activation was noted as early as 15 min after balloon injury and remained elevated for at least 28 days. Phospho-p38 MAPK immunoreactivity (IR) was localized primarily in regions of dedifferentiated, smooth muscle alpha-actin-positive cells in all lamina of the vessel wall. Phospho-p38 MAPK IR was not correlated with the localization of macrophage or proliferating cells (proliferating cell nuclear antigen; PCNA +). Long-term treatment (4 weeks) with SB 239063 (50 mg/kg/day, p.o.) reduced the vascular response to injury in the hypercholesterolemic rabbit. SB 239063 had no effect on platelet-derived growth factor (PDGF)-stimulated migration or proliferation of rabbit vascular smooth muscle cells (VSMCs) in culture. However, SB 239063 produced a concentration-dependent inhibition of transforming growth factor (TGF)-beta-stimulated fibronectin production in VSMCs. In conclusion, sustained activation of p38 MAPK plays an important role in the vascular response to injury and inhibition of p38 MAPK may represent a novel therapeutic approach to limit this response.     

Selective inhibitor of p38 mitogen-activated protein kinase inhibits lipopolysaccharide-induced interleukin-8 expression in human pulmonary vascular endothelial cells

Adult respiratory distress syndrome (ARDS) characterized by permeability edema is observed in severe insults such as bacteremia sepsis. Interleukin (IL)-8, which chemoattracts and activates neutrophils, has been suggested to play an important role in the production of ARDS. Therefore, the inhibition of IL-8 production is an important strategy for the treatment of ARDS. Recent studies have revealed the role of p38 mitogen-activated protein (MAP) kinase in cytokine expression and the inhibition by a selective inhibitor of p38 MAP kinase activity of cytokine expression in a variety of cell types. However, little is known about the role of p38 MAP kinase in lipopolysaccharide (LPS)-induced IL-8 expression in pulmonary vascular endothelial cells and the effect of a selective p38 MAP kinase inhibitor on it. In the present study, we therefore attempted to clarify these issues. The results showed that LPS induced p38 MAP kinase phosphorylation and activity, and SB 203580 as a selective inhibitor of p38 MAP kinase activity inhibited p38 MAP kinase activity and IL-8 expression in LPS-stimulated pulmonary vascular endothelial cells. These results indicate that p38 MAP kinase regulates LPS-induced IL-8 expression in pulmonary vascular endothelial cells. Although it is currently not known whether SB 203580 is capable of producing beneficial effects on ARDS, a strategy of inhibiting p38 MAP kinase activity by a selective p38 MAP kinase inhibitor may apply to the therapy for ARDS.     

Bortezomib induces apoptosis in esophageal squamous cell carcinoma cells through activation of the p38 mitogen-activated protein kinase pathway

Esophageal squamous cell carcinoma (ESCC) is an exceptionally drug-resistant tumor with a 5-year survival rate <5%. From an initial drug screen, we identified bortezomib as having robust activity in ESCC lines. Mechanistically, bortezomib induced a G2-M-phase cell cycle arrest and p53-independent apoptosis associated with caspase cleavage and Noxa induction. Bortezomib also showed excellent activity in organotypic culture and in vivo models of ESCC. Biochemically, bortezomib treatment activated the p38 and c-Jun NH2-termnial kinase stress-activated mitogen-activated protein kinase (MAPK) pathways and induced phospho-H2AX activity. Although H2AX is known to cooperate with c-Jun NH2-termnial kinase to induce apoptosis following UV irradiation, knockdown of H2AX did not abrogate bortezomib-induced apoptosis. Instead, blockade of p38 MAPK signaling, using either small interfering RNA or a pharmacologic inhibitor, reversed bortezomib-induced apoptosis and the up-regulation of Noxa. Radiation therapy is known to activate the p38 MAPK pathway and is a mainstay of ESCC treatment strategies. In a final series of studies, we showed that the coadministration of bortezomib with irradiation led to enhanced p38 MAPK activity and a significant reduction in colony formation. We therefore suggest that p38 MAPK pathway activation is an excellent potential therapeutic strategy in ESCC. It is further suggested that bortezomib could be added to existing ESCC therapeutic regimens.     

Glucose or diabetes activates p38 mitogen-activated protein kinase via different pathways

Hyperglycemia can cause vascular dysfunctions by multiple factors including hyperosmolarity, oxidant formation, and protein kinase C (PKC) activation. We have characterized the effect of hyperglycemia on p38 mitogen-activated protein (p38) kinase activation, which can be induced by oxidants, hyperosmolarity, and proinflammatory cytokines, leading to apoptosis, cell growth, and gene regulation. Glucose at 16.5 mM increased p38 kinase activity in a time-dependent manner compared with 5.5 mM in rat aortic smooth muscle cells (SMC). Mannitol activated p38 kinase only at or greater than 22 mM. High glucose levels and a PKC agonist activated p38 kinase, and a PKC inhibitor, GF109203X, prevented its activation. However, p38 kinase activation by mannitol or tumor necrosis factor-α was not inhibited by GF109203X. Changes in PKC isoform distribution after exposure to 16.5 mM glucose in SMC suggested that both PKC-β2 and PKC-δ isoforms were increased. Activities of p38 kinase in PKC-δ– but not PKC-β1–overexpressed SMC were increased compared with control cells. Activation of p38 kinase was also observed and characterized in various vascular cells in culture and aorta from diabetic rats. Thus, moderate hyperglycemia can activate p38 kinase by a PKC-δ isoform–dependent pathway, but glucose at extremely elevated levels can also activate p38 kinase by hyperosmolarity via a PKC-independent pathway.     

参与骨关节炎的P38丝裂原活化蛋白激酶信号转导通路

背景：p38丝裂原活化蛋白激酶信号转导通路属于丝裂原活化蛋白激酶家族成员,在骨关节炎的发生发展中发挥重要作用。目的：对骨关节炎病理进程中 p38丝裂原活化蛋白激酶信号转导通路相关作用机制的研究进展进行综述。方法：由第一作者用计算机检索中国期刊全文数据库和 PubMed 数据库,检索词分别为“p38丝裂原活化蛋白激酶信号通路、骨关节炎、关节软骨、软骨细胞”和“p38MAPK signal transduction pathway, osteoarthritis, Articular cartilage,Chondrocyte”。从 p38丝裂原活化蛋白激酶信号通路简介,p38丝裂原活化蛋白激酶在骨关节炎中的作用,p38丝裂原活化蛋白激酶阻断剂在骨关节炎中的应用3方面进行总结。共检索到可应用文献90篇,按纳入标准对文献进行筛选,共纳入46篇文章。结果与结论：p38丝裂原活化蛋白激酶信号通路与软骨细胞的肥大化和钙化、软骨细胞的凋亡、软骨基质金属蛋白酶的合成、软骨炎性细胞因子的产生等有密切关系,对骨关节炎的发生发展有重要影响。p38丝裂原活化蛋白激酶通过多种复杂的机制参与骨关节炎的形成和发展,对其起到极其重要的作用,因此阻断 p38丝裂原活化蛋白激酶信号通路可能成为骨关节炎治疗的新靶点。