Ghrelin Attenuates Sepsis-induced Acute Lung Injury and Mortality in Rats

Abstract

Rationale: Our study has shown that plasma levels of ghrelin, a stomach-derived peptide, are significantly reduced in sepsis, and that ghrelin administration improves organ blood flow via a nuclear factor (NF)-kB-dependent pathway. However, it remains unknown whether ghrelin has any protective effects on severe sepsis-induced acute lung injury (ALI) and, if so, whether inhibition of NF-kB plays any role in it. Objectives: To test the hypothesis that ghrelin reduces severe sepsisinduced ALI and mortality through inhibition of NF-kB. Methods: Sepsis was induced in rats by cecal ligation and puncture (CLP). Five hours after CLP, a bolus intravenous injection of 2 nmol of ghrelin was followed by continuous infusion of 12 nmol of ghrelin via a minipump for 15 hours. Samples were harvested 20 hours post-CLP (i.e., severe sepsis). Pulmonary levels of ghrelin and proinflammatory cytokines were measured by ELISA. NF-kB p65 and IkBa expression and NF-kB activity were measured by Western blot analysis and ELISA, respectively. Pulmonary blood flow was measured with radioactive microspheres. In additional animals, the necrotic cecum was excised 20 hours post-CLP and 10-day survival was recorded. Measurements and Main Results: Pulmonary levels of ghrelin decreased significantly 20 hours post-CLP. Ghrelin administration restored pulmonary levels of ghrelin, reduced lung injury, increased pulmonary blood flow, down-regulated proinflammatory cytokines, inhibited NF-kB activation, and improved survival in sepsis. Administration of a specific ghrelin receptor antagonist worsened the survival rate after CLP and cecal excision. Conclusions: Ghrelin can be developed as a novel treatment for severe sepsis-induced ALI. The protective effect of ghrelin is mediated through inhibition of NF-kB.

Ghrelin Gene Products in Acute and Chronic Inflammation

“…In healthy human subjects, LPS administration induced a biphasic change in circulating ghrelin levels, with a rapid increase reaching the maximum after the pick of TNF-a and a subsequent decrease with the nadir 5 h after LPS administration (Vila et al 2007). In rodent models of sepsis, induced either by LPS injection or caecal ligation and perforation, ghrelin treatment reduced the level of pro-inflammatory cytokines both in circulation and in tissues impacted by sepsis, such as lung and kidney (Peng et al 2012;Wang et al 2009;Wu et al 2007b). It has been shown that ghrelin protective effects are mediated by the activation of the vagal nerve (Wu et al 2007a), inhibition of sympathetic nervous system, seen as reduced gut-derived norepinephrine release (Jacob et al 2010;Wu et al 2007c), and inhibition of NF-jB pathway (Peng et al 2012;Wu et al 2007b).…”

“…In rodent models of sepsis, induced either by LPS injection or caecal ligation and perforation, ghrelin treatment reduced the level of pro-inflammatory cytokines both in circulation and in tissues impacted by sepsis, such as lung and kidney (Peng et al 2012;Wang et al 2009;Wu et al 2007b). It has been shown that ghrelin protective effects are mediated by the activation of the vagal nerve (Wu et al 2007a), inhibition of sympathetic nervous system, seen as reduced gut-derived norepinephrine release (Jacob et al 2010;Wu et al 2007c), and inhibition of NF-jB pathway (Peng et al 2012;Wu et al 2007b). In addition, ghrelin exerts its protective action through inhibition of high-mobility group box release (Chorny et al 2008;Wu et al 2009) and through an antimicrobial activity (Chorny et al 2008).…”

Clinical application of ghrelin administration for gastric cancer patients undergoing gastrectomy

“…Ghrelin has several physiological functions in addition to the secretion of GH, including the promotion of the appetite signal that antagonizes leptin in the hypothalamus [17], stimulation of gastrointestinal activity (e.g., peristalsis, gastric acid secretion, and pancreatic excretion through the vagal nerves) [18], and regulation of fat metabolism [19] (Table 1). Ghrelin also mitigates proinflammatory cytokine production and attenuates the stress signal [20]. Ghrelin exists as two major molecular forms: acyl ghrelin and des-acyl ghrelin.…”

“…GH regulates IGF-I levels, promotes anabolism, and increases muscle strength. Ghrelin enhances lipolysis via GH and stimulates protein synthesis, myoblast differentiation, and muscle growth via IGF-1 Antiinflammatory action [20,63,64] Ghrelin inhibits the activation of NF-jB, a transcription factor known to control the production of multiple proinflammatory cytokines during inflammatory insults Stimulation of gastrointestinal peristalsis [18] Ghrelin acts on motor neurons in the myenteric plexus, activates a vago-vagal reflex, or may stimulate central pathways Augmentation of cardiac output and reduction of blood pressure [26] Ghrelin improves myocardial structure and function in chronic heart failure (CHF) via its GH-releasing effects Inhibition of insulin secretion [65,66] Ghrelin has obesogenic/diabetogenic properties. These properties may be direct effects of ghrelin on pancreatic islet function and/or indirect effects through the modulation of GH secretion Application of ghrelin administration 201…”

Human Ghrelin Ameliorates Organ Injury and Improves Survival after Radiation Injury Combined with Severe Sepsis

“…It has been linked to the regulation of pituitary hormone secretion, feeding, energy homeostasis, gastrointestinal function, cardiovascular system, and immune system (16)(17)(18). Our recent studies have shown that circulating levels of ghrelin decreased significantly in a rat model of polymicrobial sepsis induced by cecal ligation and puncture (CLP), and ghrelin administration decreases inflammatory responses, improves organ blood flow, attenuates tissue injury, and reduces mortality under such conditions (18)(19)(20)(21). However, it remains unknown whether ghrelin ameliorates sepsis-induced organ injury and mortality after radiation exposure.…”