Signaling pathways and mediators in LPS-induced lung inflammation in diabetic rats: role of insulin.
Diabetic patients are more susceptible to infections, and their inflammatory response is impaired. This is restored by insulin treatment. In the present study, we investigated the effect of insulin on LPS-induced signaling pathways and mediators in the lung of diabetic rats. Diabetic male Wistar rats (alloxan, 42 mg/kg i.v., 10 days) and control rats received intratracheal instillation of LPS (750 microg/0.4 mL) or saline. Some diabetic rats were given neutral protamine Hagedorn insulin (4 IU s.c.) 2 h before LPS. After 6 h, bronchoalveolar lavage was performed for the release of mediators, and lung tissue was homogenized for analysis of LPS-induced signaling pathways. Relative to control rats, diabetic rats exhibited a significant reduction in the LPS-induced phosphorylation of extracellular signal-regulated kinase (64%), p38 (70%), protein kinase B (67%), and protein kinase C alpha (57%) and delta (65%) and in the expression of iNOS (32%) and cyclooxygenase 2 (67%) in the lung homogenates. The bronchoalveolar lavage fluid concentrations of NO (47%) and IL-6 (49%) were also reduced in diabetic rats, whereas the cytokine-induced neutrophil chemoattractant 2 (CINC-2) levels were increased 23%, and CINC-1 was not different from control animals. Treatment of diabetic rats with insulin completely or partially restored all these parameters. In conclusion, data presented show that insulin regulates mitogen-activated protein kinase, phosphatidylinositol 3'-kinase, protein kinase C pathways, expression of the inducible enzymes, cyclooxygenase 2 and iNOS, and levels of IL-6 and CINC-2 in LPS-induced lung inflammation in diabetic rats. These results suggest that the protective effect of insulin in sepsis could be due to modulation of cellular signal transduction factors.
Department of Immunology, Institute of Biomedical Sciences, School of Medicine, University of São Paulo, Brazil. martinsj@usp.br
Joilson O
JO
Martins
Matheus
M
Ferracini
Denise B C
DB
Anger
Daniel O
DO
Martins
Luciano F
LF
Ribeiro
Paulina
P
Sannomiya
Sonia
S
Jancar
D000818:Animals; D015153:Blotting, Western; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D054360:Chemokine CXCL1 / Q000378:metabolism; D019743:Chemokines, CXC / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology* / Q000627:therapeutic use*; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity*; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D011014:Pneumonia / Q000139:chemically induced* / Q000188:drug therapy* / Q000378:metabolism; D051571:Protein Kinase C-alpha / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects
D054360:Chemokine CXCL1; D019743:Chemokines, CXC; C513297:Cxcl1 protein, rat; C513294:Cxcl3 protein, rat; D007328:Insulin; D015850:Interleukin-6; D008070:Lipopolysaccharides; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D051571:Protein Kinase C-alpha; D048049:Extracellular Signal-Regulated MAP Kinases