Lung, Spleen, and Kidney Are the Major Places for Inducible Nitric Oxide Synthase Expression in Endotoxic Shock: Role of P38 Mitogen-Activated Protein Kinase in Signal Transduction of Inducible Nitric Oxide Synthase Expression

Bacterial lipopolysaccharide (LPS) is known to induce endotoxic shock with inducible nitric oxide (NO) synthase (iNOS) expression and NO production. However, the major place for NO production in shock remains unclear. Although there is some literature about p38 mitogen-activated protein kinase (MAPK) in regulating LPS-induced iNOS expression, the results are contradictory. To interpret the precise cell mechanism and the role of p38 MAPK in the expression of iNOS during endotoxic shock, we carried out the following investigations. A severe endotoxic shock model was reproduced in mice 6 h after LPS injection. The plasma NO level was increased in a dose- and time-dependent manner after LPS stimulation and was suppressed by administration of SB203580 [4-(4-fluorophenyl)-2-4-methylsulfonylphenyl-5-(4-pyridyl) imidazole], a highly specific inhibitor of p38 MAPK. The iNOS expression was increased in many organs, including heart, liver, spleen, lung, gut, and kidney in endotoxic shock. Among them, the highest expression of iNOS mRNA and protein was in the lung, moderate expression was in the spleen and kidney, and the lowest expression was in the heart, gut, and liver. The level of expression in lung was 5.5 times that of iNOS mRNA and was 3.1 times that of iNOS protein than in heart, and 1.6 and 1.8 times that of iNOS mRNA and 1.7 and 1.4 times that of iNOS protein than in spleen and kidney, respectively. The p38 MAPK activity increased after LPS injection, and SB203580 markedly reduced LPS-induced expressions of iNOS protein and mRNA in the lung. The results indicates that lung, spleen, and kidney are the major places for iNOS expression in endotoxic shock and are important therapeutic target organs for attenuating NO production in shock treatment.

[1]  J. Ward,et al.  Hemorrhage-Induced Vascular Hyporeactivity to Norepinephrine in Select Vasculatures of Rats and the Roles of Nitric Oxide and Endothelin , 2003, Shock.

[2]  Yong Jiang,et al.  New Approach to Treatment of Shock—Restitution of Vasoreactivity , 2002, Shock.

[3]  Wensheng Yan,et al.  Role of p38 MAPK in ICAM-1 Expression of Vascular Endothelial Cells Induced by Lipopolysaccharide , 2002, Shock.

[4]  W. Schobersberger,et al.  In vitro modulation of inducible nitric oxide synthase gene expression and nitric oxide synthesis by procalcitonin , 2001, Critical care medicine.

[5]  D. Geller,et al.  MOLECULAR REGULATION OF THE HUMAN INDUCIBLE NITRIC OXIDE SYNTHASE (iNOS) GENE , 2000, Shock.

[6]  D. Annane,et al.  Compartmentalised inducible nitric-oxide synthase activity in septic shock , 2000, The Lancet.

[7]  W. Buurman,et al.  Regulation of lipopolysaccharide-induced NO synthase expression in the major organs in a mouse model. The roles of endogenous interferon-gamma, tumor necrosis factor-alpha and interleukin-10. , 2000, European cytokine network.

[8]  Y. Nakajima,et al.  S-nitroso-N-acetylpenicillamine (SNAP) During Hemorrhagic Shock Improves Mortality as a Result of Recovery From Vascular Hyporeactivity , 2000, Anesthesia and analgesia.

[9]  Y. Nakajima,et al.  S-Nitroso-N-acetylpenicillamine (SNAP) during hemorrhagic shock improves mortality as a result of recovery from vascular hyporeactivity. , 2000 .

[10]  P. Cohen,et al.  Involvement of mitogen-activated protein kinase homologues in the regulation of lipopolysaccharide-mediated induction of cyclo-oxygenase-2 but not nitric oxide synthase in RAW 264.7 macrophages. , 1999, Cellular signalling.

[11]  C. Chen,et al.  p38 but not p44/42 mitogen-activated protein kinase is required for nitric oxide synthase induction mediated by lipopolysaccharide in RAW 264.7 macrophages. , 1999, Molecular pharmacology.

[12]  P. Bollaert,et al.  Beneficial effects of L-canavanine, a selective inhibitor of inducible nitric oxide synthase, on lactate metabolism and muscle high energy phosphates during endotoxic shock in rats. , 1999, Shock.

[13]  S. Hussain,et al.  Contribution of macrophages to pulmonary nitric oxide production in septic shock. , 1998, American journal of respiratory and critical care medicine.

[14]  John C. Lee,et al.  Extracellular Signal-Regulated Kinase and p38 Subgroups of Mitogen-Activated Protein Kinases Regulate Inducible Nitric Oxide Synthase and Tumor Necrosis Factor-α Gene Expression in Endotoxin-Stimulated Primary Glial Cultures , 1998, The Journal of Neuroscience.

[15]  M. Andresen,et al.  [Nitric oxide in respiratory diseases]. , 1997, Revista medica de Chile.

[16]  D. Christiani,et al.  Expression of inducible nitric oxide synthase by macrophages in rat lung. , 1997, American journal of respiratory and critical care medicine.

[17]  M. Arkovitz,et al.  LOW‐LEVEL EXPRESSION AND LIMITED ROLE FOR THE INDUCIBLE ISOFORM OF NITRIC OXIDE SYNTHASE IN THE VASCULAR HYPOREACTIVITY AND MORTALITY ASSOCIATED WITH CECAL LIGATION AND PUNCTURE IN THE RAT , 1996, Shock.

[18]  T. Ogihara,et al.  Nitric oxide induces upregulation of Fas and apoptosis in vascular smooth muscle. , 1996, Hypertension.

[19]  C. Thiemermann,et al.  The multiple organ dysfunction syndrome caused by endotoxin in the rat: attenuation of liver dysfunction by inhibitors of nitric oxide synthase , 1995, British journal of pharmacology.

[20]  S. Erzurum,et al.  Continuous nitric oxide synthesis by inducible nitric oxide synthase in normal human airway epithelium in vivo. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[21]  W. Pryor,et al.  The chemistry of peroxynitrite: a product from the reaction of nitric oxide with superoxide. , 1995, The American journal of physiology.

[22]  Csaba Szabó,et al.  Aminoguanidine attenuates the delayed circulatory failure and improves survival in rodent models of endotoxic shock , 1995, British journal of pharmacology.

[23]  C. Thiemermann,et al.  Beneficial effects and improved survival in rodent models of septic shock with S-methylisothiourea sulfate, a potent and selective inhibitor of inducible nitric oxide synthase. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[24]  J. Stamler,et al.  Constitutive and inducible nitric oxide synthase gene expression, regulation, and activity in human lung epithelial cells. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[25]  S Moncada,et al.  Nitric oxide synthases in mammals. , 1994, The Biochemical journal.

[26]  J. Stamler,et al.  Nitric oxide synthase in human and rat lung: immunocytochemical and histochemical localization. , 1993, American journal of respiratory cell and molecular biology.

[27]  S. Moncada,et al.  Nitric oxide: physiology, pathophysiology, and pharmacology. , 1991, Pharmacological reviews.

[28]  Q. Huang,et al.  Peroxynitrite leads to arteriolar smooth muscle cell membrane hyperpolarization and low vasoreactivity in severe shock. , 2000, Clinical hemorheology and microcirculation.

[29]  J. Liu,et al.  The role of membrane potential and calcium kinetic changes in the pathogenesis of vascular hyporeactivity during severe shock. , 2000, Chinese medical journal.

[30]  M. Hecker,et al.  Regulation of inducible nitric oxide synthase gene expression in vascular smooth muscle cells. , 1999, General pharmacology.

[31]  S. Uh,et al.  Evaluation of the role of mitogen-activated protein kinases in the expression of inducible nitric oxide synthase by IFN-gamma and TNF-alpha in mouse macrophages. , 1999, Journal of immunology.

[32]  C. Szabó.  Alterations in nitric oxide production in various forms of circulatory shock. , 1995, New horizons.