Role of Serotonin in MODS: Deficiency of Serotonin Protects Against Zymosan-Induced Multiple Organ Failure in Mice.
Zymosan-induced multiple organ dysfunction syndrome (MODS) is a multifactorial pathology that involves the deterioration of function of several organs. 5-Hydroxytryptamine (5-HT) is a small monoamine molecule that is primarily known for its role as a neurotransmitter. Previous studies have shown that 5-HT could serve as an important inflammatory mediator in the peripheral immune system. In the present study, we investigated the effect of 5-HT on the development of non-septic shock caused by zymosan in mice. Tryptophan hydroxylase 1-knockout mice (TPH1, leading to the absence of 5-HT), TPH1 + 5-hydroxytryptophan (precursor of 5-HT) treatment mice, wild-type (TPH1) mice, and wild-type plus p-chlorophenylalanine (PCPA, TPH1 inhibitor) treatment mice received zymosan intraperitoneally at a dose of 500 mg/kg. Organ failure and systemic inflammation in the mice were assessed 18 h after the administration of zymosan. Deficiency of 5-HT caused a significant reduction of the 1) peritoneal exudate formation, 2) neutrophil infiltration, 3) MODS, 4) nitrosative stress, and 5) cytokine formation. In addition, at the end of the observation period (7 days), deficiency of 5-HT in the mice was shown to be able to alleviate the severe illness characterized as systemic toxicity, significant loss of body weight, and high mortality caused by zymosan. In conclusion, the lack of 5-HT by genetic knockout or by pharmacologic inhibition of the TPH1 enzyme significantly attenuated zymosan-induced MODS.
Departments of *Hepatobiliary Surgery and †Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiaotong University; and ‡Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an Shaanxi, People's Republic of China.
Jingyao
J
Zhang
Qing
Q
Pang
Sidong
S
Song
Ruiyao
R
Zhang
Sushun
S
Liu
Zichao
Z
Huang
Qifei
Q
Wu
Yang
Y
Liu
Chang
C
Liu
D006916:5-Hydroxytryptophan / Q000008:administration & dosage; D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D010134:Fenclonine / Q000008:administration & dosage; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009102:Multiple Organ Failure / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D018384:Oxidative Stress; D010538:Peritonitis / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D020011:Protective Agents / Q000008:administration & dosage; D012701:Serotonin / Q000172:deficiency / Q000502:physiology*; D012769:Shock / Q000150:complications / Q000209:etiology / Q000503:physiopathology; D014365:Tryptophan Hydroxylase / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics; D015054:Zymosan / Q000633:toxicity
D016207:Cytokines; D004791:Enzyme Inhibitors; D020011:Protective Agents; D012701:Serotonin; D015054:Zymosan; D006916:5-Hydroxytryptophan; C487801:Tph1 protein, mouse; D014365:Tryptophan Hydroxylase; D010134:Fenclonine