Role of preprotachykinin-A gene products on multiple organ injury in LPS-induced endotoxemia.
Endotoxemia is a life-threatening, inflammatory condition that involves multiple organ injury and dysfunction. Preprotachykinin-A (PPT-A) gene products, substance P (SP), and neurokinin-A have been shown to play an important role in neurogenic inflammation. To investigate the role of PPT-A gene products on multiple organ injury in LPS-induced endotoxemia, endotoxemia was induced by LPS administration (10 mg/kg, i.p.) in PPT-A gene-deficient mice (PPTA(-/-)) and the wild-type (WT) control mice (PPT-A+/+). I.p. administration of LPS to WT mice caused a significant increase in circulating levels of SP as well as in liver, lung, and kidney. PPT-A gene deletion significantly protected against liver, pulmonary, and renal injury following LPS-induced endotoxemia, as evidenced by tissue myeloperoxidase activities, plasma alanine aminotransferase, aspartate aminotransferase levels, and histological examination. Furthermore, PPT-A(-/-) mice had significantly attenuated chemokines, proinflammatory cytokines, and adhesion molecule levels in the liver, lung, and kidney. These results show that PPT-A gene products are critical proinflammatory mediators in endotoxemia and the associated multiple organ injury. In addition, the data suggest that deletion of the PPT-A gene protected mice against organ damage in endotoxemia by disruption in neutrophil recruitment.
Ng
Siaw Wei
SW
Cardiovascular Biology Research Group, Department of Pharmacology, National University of Singapore, Singapore.
Zhang
Huili
H
Hegde
Akhil
A
Bhatia
Madhav
M
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D015815:Cell Adhesion Molecules / Q000032:analysis; D018925:Chemokines / Q000032:analysis; D016207:Cytokines / Q000032:analysis; D019446:Endotoxemia / Q000139:chemically induced / Q000150:complications* / Q000473:pathology / Q000503:physiopathology; D007668:Kidney / Q000737:chemistry / Q000473:pathology; D008070:Lipopolysaccharides / Q000633:toxicity; D008099:Liver / Q000737:chemistry / Q000473:pathology; D008168:Lung / Q000737:chemistry / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009102:Multiple Organ Failure / Q000473:pathology / Q000503:physiopathology* / Q000517:prevention & control; D009504:Neutrophils / Q000201:enzymology; D009195:Peroxidase / Q000032:analysis; D011498:Protein Precursors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013373:Substance P / Q000032:analysis; D015320:Tachykinins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D015815:Cell Adhesion Molecules; D018925:Chemokines; D016207:Cytokines; D008070:Lipopolysaccharides; D011498:Protein Precursors; D015320:Tachykinins; C044206:preprotachykinin; D013373:Substance P; D009195:Peroxidase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase