title: Role of preprotachykinin-A gene products on multiple organ injury in LPS-induced endotoxemia.
abstract: 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.
authors.affiliation: Cardiovascular Biology Research Group, Department of Pharmacology, National University of Singapore, Singapore.
authors.forename: Siaw Wei
authors.initials: SW
authors.lastname: Ng
authors.forename: Huili
authors.initials: H
authors.lastname: Zhang
authors.forename: Akhil
authors.initials: A
authors.lastname: Hegde
authors.forename: Madhav
authors.initials: M
authors.lastname: Bhatia
mesh_terms: 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*
chemical_list: 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