title: Deficiency of Smad3 results in enhanced inducible nitric oxide synthase-mediated hypotension in lipopolysaccharide-induced endotoxemia.
abstract: BACKGROUND
  Smad3 is a principal intracellular mediator of signaling for transforming growth factor β, a cytokine involved in pleiotropic pathophysiological processes including inflammation and immunity. The function of Smad3 in regulating inducible nitric oxide synthase (iNOS) expression and septic shock has not been characterized.
  
  
  METHODS
  Smad3(-/-) (referred hereafter as KO) and wild-type (WT) mice were injected intraperitoneally with lipopolysaccharide (LPS) to induce the septic hypotension. Mortality, blood pressure, and plasma levels of nitrite were measured. The iNOS messenger RNA and protein levels in lung, kidney, and spleen were also analyzed.
  
  
  RESULTS
  Mice lacking functional Smad3 respond to LPS with greater mortality than their WT littermates. The high mortality of KO mice is accompanied by enhanced hypotension after intraperitoneal injection of LPS. Both KO and WT mice displayed an increase in plasma nitrite during the experimental period; however, LPS administration caused more dramatic changes in KO mice than WT mice. Likewise, the iNOS messenger RNA and protein levels in lung, kidney, and spleen were more strongly increased in KO mice than in WT mice after LPS administration.
  
  
  CONCLUSIONS
  Defects in the Smad3 gene may increase susceptibility to the development of septic hypotension because of enhanced iNOS production.
authors: Department of Burn & Burn Center, Changhai Hospital, Second Military Medical University, Shanghai, China.
authors: Kai-Yang
authors: KY
authors: Lv
authors: Department of Neurosurgery, General Hospital of Jinan Military Command of Chinese PLA, Jinan, Shandong, China.
authors: Qi-Sheng
authors: QS
authors: Zhong
authors: Department of Critical Care and Emergency Medicine, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors: Xue-Feng
authors: XF
authors: Liu
authors: Department of Burn & Burn Center, Changhai Hospital, Second Military Medical University, Shanghai, China.
authors: Shi-Hui
authors: SH
authors: Zhu
authors: Department of Burn & Burn Center, Changhai Hospital, Second Military Medical University, Shanghai, China.
authors: Shi-Chu
authors: SC
authors: Xiao
authors: Department of Burn & Burn Center, Changhai Hospital, Second Military Medical University, Shanghai, China.
authors: Guang-Yi
authors: GY
authors: Wang
authors: Department of Burn & Burn Center, Changhai Hospital, Second Military Medical University, Shanghai, China.
authors: Bing
authors: B
authors: Ma
authors: Department of Burn & Burn Center, Changhai Hospital, Second Military Medical University, Shanghai, China. Electronic address: netmee@163.com.
authors: Zhao-Fan
authors: ZF
authors: Xia
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000139:chemically induced / Q000378:metabolism* / Q000401:mortality; D005260:Female; D007022:Hypotension / Q000139:chemically induced / Q000378:metabolism* / Q000401:mortality; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000097:blood; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D018805:Sepsis / Q000139:chemically induced / Q000378:metabolism* / Q000401:mortality; D051900:Smad3 Protein / Q000172:deficiency / Q000235:genetics*
chemical_list: D008070:Lipopolysaccharides; D012333:RNA, Messenger; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse
keywords: Endotoxemia; Hypotension; NO; Septic shock; Smad3; iNOS