Growth hormone increases lung microvascular injury in lipopolysaccharide peritonitis rats: possible involvement of NF-kappaB activation in circulating neutrophils.

AIM To investigate the effects of growth hormone (GH) on NF-kappaB activity in neutrophils and neutrophils-mediated organ injury induced by lipopolysaccharide (LPS) in rats. METHODS Male Wistar rats challenged with or without LPS (5 mg/kg) were treated with varied doses of GH (0.5, 1.0, and 2.0 mg/kg) for 2 or 4 h. NF-kappaB activities in circulating neutrophils were measured with electrophoretic mobility shift assays (EMSA), and I-kappaB levels in circulating neutrophils were detected by Western blot. Lung neutrophils sequestration and lung microvascular permeability were measured at 4 h after LPS challenge. RESULTS Circulating neutrophils in LPS challenged rats had increased NF-kappaB activity and decreased I-kappaB level as compared with controls. GH dramatically increased NF-kappaB activity and I-kappaB degradation induced by LPS challenge in neutrophils. Also, subsequently, GH treatment increased lung neutrophils sequestration and lung microvascular injury induced by LPS. CONCLUSION These results suggest that treatment of GH is harmful, instead of beneficial, to LPS-induced organ injury. Increased neutrophils' NF-kappaB activity and lung neutrophils sequestration are critical in vivo mechanisms mediating GH action on LPS-induced organ injury.

[1]  T. Zhu,et al.  Signal transduction via the growth hormone receptor. , 2001, Cellular signalling.

[2]  N. Webster,et al.  Increased nuclear factor κB activation in critically ill patients who die , 2000 .

[3]  E. Abraham.  NF-κB activation , 2000 .

[4]  R. Shenkar,et al.  Mechanisms of lung neutrophil activation after hemorrhage or endotoxemia: roles of reactive oxygen intermediates, NF-kappa B, and cyclic AMP response element binding protein. , 1999, Journal of immunology.

[5]  A. Malik,et al.  Pyrrolidine dithiocarbamate prevents I-kappaB degradation and reduces microvascular injury induced by lipopolysaccharide in multiple organs. , 1999, Molecular pharmacology.

[6]  E. Chilvers,et al.  Neutrophil priming: pathophysiological consequences and underlying mechanisms. , 1998, Clinical science.

[7]  S. Ghosh,et al.  Signal transduction through NF-κB , 1998 .

[8]  D. Männel,et al.  Role of NFkappaB in the mortality of sepsis. , 1997, The Journal of clinical investigation.

[9]  L. Balteskard,et al.  Growth hormone impaired compensation of hemorrhagic shock after trauma and sepsis in swine. , 1996, The Journal of trauma.

[10]  B. Groner,et al.  Participation of JAK and STAT Proteins in Growth Hormone-induced Signaling (*) , 1996, The Journal of Biological Chemistry.

[11]  P. Cole,et al.  Growth hormone is a human macrophage activating factor. Priming of human monocytes for enhanced release of H2O2. , 1995, Journal of immunology.

[12]  D. Geissler,et al.  Priming of normal human neutrophils by recombinant human growth hormone , 1991, British journal of haematology.

[13]  A. Malik,et al.  Decreased oxidant buffering impairs NF-kappaB activation and ICAM-1 transcription in endothelial cells. , 2001, Shock.

[14]  P. Kelly,et al.  Growth Hormone Exerts Antiapoptotic and Proliferative Effects through Two Different Pathways Involving Nuclear Factor-κB and Phosphatidylinositol 3-Kinase** This work was supported by INSERM, a grant from Association pour la Recherche sur le Cancer, and USPHS Grant CA-36355 from the NIH. , 2001, Endocrinology.

[15]  P. Kelly,et al.  Growth hormone exerts antiapoptotic and proliferative effects through two different pathways involving nuclear factor-kappaB and phosphatidylinositol 3-kinase. , 2001, Endocrinology.

[16]  G. Van den Berghe,et al.  Increased mortality associated with growth hormone treatment in critically ill adults. , 2000, The New England journal of medicine.

[17]  R. Shenkar,et al.  Protein Cyclic AMP Response Element Binding B , and κ Reactive Oxygen Intermediates , NF-After Hemorrhage or Endotoxemia : Roles of Mechanisms of Lung Neutrophil Activation , 1999 .

[18]  D. Männel,et al.  Role of NF k B in the Mortality of Sepsis , 1997 .

[19]  A. Benzer,et al.  Improvement of septic syndrome after administration of recombinant human growth hormone (rhGH)? , 1991, The Journal of trauma.

[20]  W. Stenson,et al.  Quantitative assay for acute intestinal inflammation based on myeloperoxidase activity. Assessment of inflammation in rat and hamster models. , 1984, Gastroenterology.