Immunomodulatory role of leptin treatment in experimental sepsis caused by gram negative bacteria
To investigate the effect of leptin treatment on circulating inflammatory cytokines and on tissue damage in experimental rat model of gram-negative sepsis. Materials and methods: Adult male Wistar rats, 28 in total, were randomly divided into 4 groups (n = 7): sham, leptin, sepsis, and sepsis group treated with leptin (sepsis+leptin). Sepsis was induced by intraperitoneal (ip) injection of 2 × 1010 CFU of Escherichia coli ATCC 25922. Leptin and sepsis+leptin groups received a single dose ip 0.1 mg/kg leptin, while sham group received 1 mL of ip saline. Rats were sacrificed 24 h after the induction of sepsis. Blood samples, lung, and kidney tissues were collected for analysis. Results: The sepsis group had significantly higher serum TNF-a, IL-6, and endothelin levels than the sham group (P = 0.05, P < 0.001, P = 0.003, respectively). The sepsis+leptin group had significantly lower IL-6 and endothelin levels (P = 0.001 and P = 0.020, respectively), and higher lung and kidney tissue myeloperoxidase activities when compared with the sepsis group (P = 0.039, P = 0.033, respectively). Conclusion: According to our results, leptin has a profound influence on sepsis, and to some extent it restricts the inflammatory events in sepsis.
Immunomodulatory role of leptin treatment in experimental sepsis caused by gram negative bacteria
To investigate the effect of leptin treatment on circulating inflammatory cytokines and on tissue damage in experimental rat model of gram-negative sepsis. Materials and methods: Adult male Wistar rats, 28 in total, were randomly divided into 4 groups (n = 7): sham, leptin, sepsis, and sepsis group treated with leptin (sepsis+leptin). Sepsis was induced by intraperitoneal (ip) injection of 2 × 1010 CFU of Escherichia coli ATCC 25922. Leptin and sepsis+leptin groups received a single dose ip 0.1 mg/kg leptin, while sham group received 1 mL of ip saline. Rats were sacrificed 24 h after the induction of sepsis. Blood samples, lung, and kidney tissues were collected for analysis. Results: The sepsis group had significantly higher serum TNF-a, IL-6, and endothelin levels than the sham group (P = 0.05, P < 0.001, P = 0.003, respectively). The sepsis+leptin group had significantly lower IL-6 and endothelin levels (P = 0.001 and P = 0.020, respectively), and higher lung and kidney tissue myeloperoxidase activities when compared with the sepsis group (P = 0.039, P = 0.033, respectively). Conclusion: According to our results, leptin has a profound influence on sepsis, and to some extent it restricts the inflammatory events in sepsis.
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- Hotchkiss RS, Karl IE. Cytokine blockade in sepsis—Are two better than one? Crit Care Med 2001; 29: 671-2.
- Kellum JA, Kong L, Fink MP, Weissfeld LA, Yealy DM, Pinsky MR et al. Understanding the infl ammatory cytokine response in pneumonia and sepsis: results of the Genetic and Infl ammatory Markers of Sepsis (GenIMS) Study. Arch Intern Med 2007; 167: 1655-63. 3. Zhang Y, Proenca R, Maff ei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature 1994; 372: 425-32.
- Otero M, Lago R, Lago F, Casanueva FF, Dieguez C, Gómez- Reino JJ et al. Leptin, from fat to infl ammation: old questions and new insights. FEBS Lett 2005; 579: 295-301.
- Fantuzzi G, Faggioni R. Leptin in the regulation of immunity, infl ammation, and hematopoiesis. J Leukoc Biol 2000; 68: 437- 46.
- Tschöp J, Nogueiras R, Haas-Lockie S, Kasten KR, Castañeda TR, Huber N et al. CNS leptin action modulates immune response and survival in sepsis. J Neurosci 2010; 30: 6036-47.
- Gultekin FA, Kerem M, Tatlicioglu E, Aricioglu A, Unsal C, Bukan N. Leptin treatment ameliorates acute lung injury in rats with cerulein-induced acute pancreatitis. World J Gastroenterol 2007; 13: 2932-38.
- Hacioglu A, Algin C, Pasaoglu O, Pasaoglu E, Kanbak G. Protective eff ect of leptin against ischemia-reperfusion injury in the rat small intestine. BMC Gastroenterol 2005; 5: 37.
- Gülen S, Dinçer S. Eff ects of leptin on oxidative stress in healthy and Streptozotocin-induced diabetic rats. Mol Cell Biochem 2007; 302: 59-65.
- Giacometti A, Ghiselli R, Cirioni O, Mocchegiani F, D’Amato G, Orlando F et al. Th erapeutic effi cacy of the magainin analogue MSI-78 in diff erent intra-abdominal sepsis rat models. J Antimicrob Chemother 2004; 54: 654-60.
- Koike K, Moore EE, Moore FA, Read RA, Carl VS, Banerjee A. Gut ischemia/reperfusion produces lung injury independent of endotoxin. Crit Care Med 1994; 22: 1438-44.
- Faggioni R, Feingold KR and Grunfeld C. Leptin regulation of the immune response and the immunodefi ciency of malnutrition. FASEB J 2001; 14: 2565–71.
- Cano V, Merino B, L Ezquerra L, Somoza B and Ruiz-Gayo M. A cholecystokinin-1 receptor agonist (CCK-8) mediates increased permeability of brain barriers to leptin British Journal of Pharmacology 2008; 154: 1009-15.
- Siegmund B, Lear-Kaul KC, Faggioni R, Fantuzzi G. Leptin defi ciency, not obesity, protects mice from Con A-induced hepatitis. Eur J Immunol 2002; 32: 552-60.
- Faggioni R, Fantuzzi G, Gabay C, Moser A, Dinarello CA, Feingold KR et al. Leptin defi ciency enhances sensitivity to endotoxin-induced lethality. Am J Physiol 1999; 276: 136-42.
- Takahashi N, Waelput W, Guisez Y. Leptin is an endogenous protective protein against the toxicity exerted by tumor necrosis factor. J Exp Med 1999; 189: 207-12.
- Fantuzzi G. Adipose tissue, adipokines, and infl ammation. Allergy Clin Immunol 2005; 115: 911-19.
- Wesche-Soldato DE, Swan RZ, Chung CS, Ayala A. Th e apoptotic pathway as a therapeutic target in sepsis. Curr Drug Targets 2007; 8: 493-500.
- Bruno A, Conus S, Schmid I, Simon HU. Apoptotic pathways are inhibited by leptin receptor activation in neutrophils. J Immunol 2005; 174: 8090-96.
- Tian Z, Sun R, Wei H, Gao B. Impaired natural killer (NK) cell activity in leptin receptor defi cient mice: leptin as a critical regulator in NK cell development and activation. Biochem Biophys Res Commun 2002; 298: 297-302.
- Watson AM, Poloyac SM, Howard G, Blouin RA. Eff ect of leptin on cytochrome P-450, conjugation, and antioxidant enzymes in the ob/ob mouse. Drug Metab Dispos 1999; 27: 695-700.
- Koh KK, Park SM, Quon MJ. Leptin and cardiovascular disease: response to therapeutic interventions. Circulation 2008; 117: 3238-49.
- Shapiro NI, Khankin EV, Van Meurs M, Shih SC, Lu S, Yano M et al. Leptin exacerbates sepsis-mediated morbidity and mortality. J Immunol 2010; 185: 517-24.
- Piechota M, Banach M, Irzmanski R, Barylski M, Piechota- Urbanska M, Kowalski J et al. Plasma endothelin-1 levels in septic patients. J Intensive Care Med 2007; 22: 232-39.
- Adiarto S, Emoto N, Iwasa N, Yokoyama M. Obesity-induced upregulation of myocardial endothelin-1 expression is mediated by leptin. Biochem Biophys Res Commun 2007; 353: 623-27.
- van der Veen BS, de Winther MPJ, Heeringa P. Myeloperoxidase: Molecular mechanisms of action and their relevance to human health and disease. Antioxidants & Redox Signaling 2009; 11: 2899-2937.
- Klebanoff SJ. Myeloperoxidase: friend and foe. J Leukoc Biol 2005; 77: 598-625.
- Hirche TO, Gaut JP, Heinecke JW, Belaaouaj A. Myeloperoxidase plays critical roles in killing Klebsiella pneumoniae and inactivating neutrophil elastase: eff ects on host defense. J Immunol 2005; 174: 1557-65.
- Orlova EG, Shirshev SV. Th e eff ect of leptin on the microbiocidal activity of monocytes in humans. Fiziol Cheloveka 2007; 33: 109-13.
- Lin J, Yan GT, Xue H, Hao XH, Zhang K, Wang LH. Leptin protects vital organ functions aft er sepsis through recovering tissue myeloperoxidase activity: an anti-infl ammatory role resonating with indomethacin. Peptides 2007; 28: 1553-60.
- Yan GT, Lin J, Hao XH, Xue H, Zhang K, Wang LH. Heart- type fatty acid-binding protein is a useful marker for organ dysfunction and leptin alleviates sepsis-induced organ injuries by restraining its tissue levels. Eur J Pharmacol 2009; 616: 244- 50.
- Bornstein SR, Licinio J, Tauchnitz R, Engelmann L, Negrao AB, Gold P et al. Plasma leptin levels are increased in survivors of acute sepsis: associated loss of diurnal rhythm, in cortisol and leptin secretion. J Clin Endocrinol Metab 1998; 83: 280-83.
- Valerio A, Dossena M, Bertolotti P, Boroni F, Sarnico I, Faraco G et al. Leptin is induced in the ischemic cerebral cortex and exerts neuroprotection through NF-kappaB/c-Rel-dependent transcription. Stroke 2009; 40: 610-17.
- Signore AP, Zhang F, Weng Z, Gao Y, Chen J. Leptin neuroprotection in the CNS: mechanisms and therapeutic potentials. J Neurochem 2008; 106: 1977-90.