Therapeutic Effect Of Recombinant Human Growth Hormone On Rat Sepsis And Its Possible Mechanism

Sepsis, an uncontrolled inflammatory response, is a common and severe syndrome, which could result in multiple organ dysfunction and multiple organ failure. Pathogenesis of sepsis is quite complex and its therapy is still dissatisfactory, and sepsis remains the leading cause of mortality in critical illness by now. Growth hormone is an important anabolic hormone. It has been showed that recombinant human growth hormone (rhGH) could enhance protein synthesis, promote tissue recovery, improve host defenses and decrease stress response, etc. Some results showed that rhGH had positive effects on critical illness. However, some studies showed that high doses of rhGH increased mortality of critical illness. So, the use of rhGH in sepsis therapy remains controversial. It is not yet clear whether low doses of rhGH have therapeutic effects on sepsis.In this study E. coli was injected intraperitoneally to produce ratssepsis models. Female Sprague-Dawley rats were divided randomly into 3groups: control group (group C) with nothing procedure, sepsis group(group S), injected intraperitoneally with a bolus of E. coli (1 XlO^cfu-I/'jlSml/kg), treated group (group T) received a bolus injection ofE.coli, and then followed by rhGH intramuscular injection (2.25 U-kg'^d"1).Group S and group T were further divided into Id and 3d subgroups,respectively. ?Mean arterial pressure(MAP), microcirculation of intestineand survival rate in 72h, ?levels of lipopolysaccharide(LPS), growthhormone(GH), insulin-like growth factor-1 (IGF-1), inflammatory mediatorssuch as TNF a and IL-1 P, anti-inflammatory mediators such as IL-10 inplasma, ?content of thiobarbituric acid reactive substances (TBARS) andnitric oxide (NO), activities of superoxide dismutase (SOD) and induciblenitric oxide synthase(iNOS) in plasma and bronchial alveolar lavagefluid(BALF), ?expression of ICAM-1 at levels of protein and mRNA andnuclear positive rate of NF-kB in lung tissue, ?expression of IGF-1mRNA in liver, ?expression of Bcl-2 protein in intestine and bacteriatranslocation,efc. were determined dynamically by means of reversetranscriptional polymerase chain reaction (RT-PCR), radioimmunoassay(RIA), immunohistochemical staining and other corresponding methods.The present study was to investigate the therapeutic effects of low doses ofrhGH on circulatory function, intestinal mucosal barrier and acute lunginjury of rat sepsis and its possible mechanism.The results showed that low doses of rhGH could: (1) attenuate the hypotension induced by sepsis and improve circulatory function, (2) maintain intestinal mucosal barrier and ameliorate bacteria/LPS translocation, (3) ameliorate acute lung injury, (4) increase survival rate in 72h and improve the outcome of sepsis.These results suggested that low doses of rhGH treatment showed desirable beneficial effects on rat sepsis, which may involve the following mechanism: (1) rhGH maintained a balance of inflammatory cytokines network by inhibiting the production and release of inflammatory mediators such as TNF a and maintaining the level of anti-inflammatory mediators such as IL-10.(2)rhGH improved circulatory function by diminishing levels of LPS and inflammatory cytokines in circulation. (3) rhGH maintained intestinal mucosal barrier by the roles of GH and IGF-1 and anti-apoptotic effects, and ameliorated bacteria/LPS translocation. (4) rhGH inhibited the production of free radicals and reduced damage mediated by oxidant free radicals, enhanced the clearance of free radicals and increased antioxidant potential. (5) rhGH reduced the expression of ICAM-1 at levels of protein and mRNA in lung tissue and influenced the adhesion, accumulation and activation of polymorphnuclear neutrophils (PMN). (6) rhGH inhibited activation of NF- k B in lung and regulated the transcription of ICAM-1,etc.(7) rhGH elevated percentage of PMN in blood and peritoneal cavity, upregulated release response and phagocytosis of PMN, enhanced host defense and minimized the spread of bacteria and prevented translocation of bacteria/LPS from the gut lumen into circulation.