transforming-growth-factor-beta and Multiple-Organ-Failure

Topics: Fibrosis; Humans; Multiple Organ Failure; Transforming Growth Factor beta

It has been well demonstrated that TNF-alpha is integral to the pathogenesis of multiple organ dysfunction syndrome (MODS). In this study, we investigate the effects of etanercept (10 mg/kg, s.c.), a specific TNF-alpha-soluble inhibitor, on the acute phase and late mortality in a murine model of MODS of nonseptic origin induced by zymosan (500 mg/kg, suspended in saline solution, i.p.). Etanercept was administered 1 h after the injection of zymosan. Animals were killed after 18 h. In another set of experiments, mice were monitored for systemic toxicity, loss of body weight, and mortality for 12 days. Sham-treated and TNF receptor 1 (TNFR1)-deficient animals were used as control. Treatment of mice with Etanercept and TNFR1 gene deletion decreased the peritoneal exudation and the migration of neutrophils caused by zymosan. In addition, pharmacological and genetic neutralization of TNF-alpha attenuated pancreas and ileum injury (histology), the increase in myeloperoxidase activity in the ileum and in the lung, and the formation of TNF-alpha and IL-1beta. Immunohistochemical analysis for TNF-alpha, transforming growth factor beta, and vascular endothelial growth factor revealed a positive staining in pancreas and ileum sections. The degree of immunostaining was markedly reduced after etanercept treatment and in TNFR1 knockout mice. Furthermore, TNF-alpha neutralization decreased the potent apoptotic stimulus induced by zymosan. All of these findings ultimately led to an amelioration of organ functions at 18 h and to a better survival rate at 12 days. Therefore, we demonstrate that etanercept reduces acute tissue injury and mortality associated to MODS of nonseptic origin in mice.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; bcl-2-Associated X Protein; Etanercept; Fas Ligand Protein; Immunoglobulin G; Inflammation; Mice; Mice, Knockout; Multiple Organ Failure; Peritonitis; Proto-Oncogene Proteins c-bcl-2; Receptors, Tumor Necrosis Factor; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A; Zymosan

Direct hemoperfusion (DHP) with polymixin B-immobilized fiber (PMX) has been reported to be effective for patients with septic shock. The aim of this study was to clarify the mechanism of PMX-DHP effect on septic shock.. The following parameters were measured in septic shock patients who were treated with PMX-DHP: survival rate, sepsis-related organ failure assessment (SOFA) score, acute physiology and chronic health evaluation II (APACHE-II) score, and plasma concentrations of cannabinoids [anandamide (ANA) and 2-arachidonyl glyceride (2-AG)], cytokines [interleukin (IL)-6, IL-8, IL-10], transforming growth factor beta (TGF-beta), and calcitonin gene-related peptide (CGRP)]. The primary end point was mortality from all causes at day 28 after intensive care unit (ICU) admission or discharge.. The survival rate of all patients at 28 days after ICU admission was 37.5% (9/24). The survival group showed significantly lower SOFA and APACHE-II scores than the nonsurvival group after PMX-DHP treatment (P = 0.008 and 0.028, respectively). The improved SOFA score group showed a better survival rate than the nonimproved SOFA score group (71.4% versus 23.5%, P = 0.028). Plasma ANA level significantly decreased after PMX-DHP treatment both in the improved SOFA score group and in the survival group. The level of 2-AG, however, showed no significant change in either group.. ANA, an intrinsic cannabinoid that induces hypotension in septic shock, is inferred to be the main mechanism of the PMX-DHP effect. Removal of ANA by PMX-DHP could be key to successful septic shock treatment.

Topics: Adult; Aged; APACHE; Arachidonic Acids; Calcitonin Gene-Related Peptide; Endocannabinoids; Female; Hemoperfusion; Humans; Male; Middle Aged; Multiple Organ Failure; Polymyxin B; Polyunsaturated Alkamides; Prognosis; Prospective Studies; Shock, Septic; Survival Rate; Transforming Growth Factor beta

Despite the strides made toward understanding cardiac abnormalities in obesity-induced hypertension, the composition and concentration of cardiac extracellular matrix (ECM) components resulting from diet-induced obesity are largely unknown. Previous studies from our laboratory have demonstrated differential expression of collagens, growth factors, and homocysteine (Hcy) in pressure overload models of cardiac hypertrophy. The hypothesis of the present study was that left ventricular hypertrophy (LVH) from the combined pressure and volume overload of obesity induced cardiac fibrosis in part by increasing Hcy, increasing transforming growth factor-beta1 (TGF-beta1), and decreasing decorin. Using the rabbit model, we examined the changes in cardiac collagen accumulation, plasma Hcy, left ventricular (LV) TGF-beta1, and LV decorin after 12 weeks of developing obesity. Cardiac fibrosis was analyzed by trichrome stain for collagens. Total collagens types I and III, TGF-beta1, and decorin were analyzed in tissue homogenates by immunoblots and quantitated with a densitometer. After 12 weeks, rabbits eating a high-fat diet had greater body weight (5.38 +/- 0.3 kg v 3.73 +/- 0.6 kg) and greater LV weight (5.08 +/- 0.05 g v 3.86 +/- 0.17 g) compared with lean rabbits. Heart rate was also significantly higher in obese than in lean rabbits (221 +/- 8 v 173 +/- 5 beats/min). Plasma concentrations of circulating Hcy were 16.9 +/- 2.4 micromol/L and 24.3 +/- 1.8 micromol/L in lean and obese rabbits, respectively. Compared with lean rabbits, obese rabbits had increased interstitial and perivascular collagen, a 4-fold increase in the medial/lumen ratio of coronary vessels, a 1.75-fold increase in cardiac collagen I, and a 1.5-fold increase in cardiac collagen III levels. Levels of TGF-beta1 were increased 1.75-fold, whereas decorin levels were significantly reduced in obese compared with lean rabbits. In conclusion, a high-fat diet, even over a period as short as 12 weeks, causes fibrosis in coronary vessels as well as accumulation of collagen in the cardiac interstitium. The accumulation of cardiac collagen was associated with induction of Hcy and TGF-beta1 and with suppression of decorin.

Topics: Animals; Collagen; Coronary Vessels; Extracellular Matrix; Female; Homocysteine; Hypertrophy; Multiple Organ Failure; Myocardium; Obesity; Rabbits; Transforming Growth Factor beta; Transforming Growth Factor beta1

TGF-beta1 plays a central role in maintaining normal immune function and deficiency of this potent immunosuppressive molecule is linked to uncontrolled inflammation, cachexia, and multiorgan failure as seen in the TGF-beta1 null mouse. Infiltration of inflammatory cells into vital organs of the null mouse is accompanied by increased gene expression of inflammatory cytokines, including TNF-alpha and IL-1beta, as well as inducible NO synthase, each regulated by NF-kappaB. Treatment with the proteasome inhibitor MG132 to prevent NF-kappaB activation dramatically reduced NO production and expression of inflammatory cytokines. This inflammatory phenotype with NF-kappaB activation in the TGF-beta1 null mouse, in the absence of any identifiable pathogen, suggested activation of innate immune responses. Because Toll-like receptors (TLR) are essential in the activation of innate immunity, we examined inflamed tissue from TGF-beta1 null and wild-type mice for expression of TLR4, the receptor that interacts with bacterial cell wall LPS to initiate an NF-kappaB-dependent signaling pathway, leading to gene transcription of inflammatory mediators. Increased TLR4 mRNA expression observed in TGF-beta1 null mice as well as in mice lacking the TGF-beta transcription factor Smad3 was associated with LPS hyperresponsiveness leading to increased expression of inflammatory cytokines and NO and endotoxemia. Furthermore, mice lacking both TGF-beta1 and a functional TLR4 were resistant to endotoxin shock. Constitutive and/or environmental activation of TLR4 and downstream elements, in the absence of TGF-beta suppression, may impact on innate and adaptive immunity and contribute to massive uncontrolled inflammation.

Topics: Animals; Endotoxemia; Immunity, Innate; Inflammation; Injections, Intraperitoneal; Lipopolysaccharides; Membrane Glycoproteins; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Knockout; Multiple Organ Failure; NF-kappa B; Nitric Oxide; Phenotype; Receptors, Cell Surface; Signal Transduction; Toll-Like Receptor 4; Toll-Like Receptors; Transforming Growth Factor beta; Transforming Growth Factor beta1; Up-Regulation

The objectives of this study were to examine the prevalence of genetic variation for cytokine production (tumor necrosis factor [TNF]-alpha, interleukin-10, transforming growth factor-beta1) in patients with multiple organ dysfunction syndrome, to measure circulating cytokine levels and relate these to genotype, and to identify the relationship between genetic variation and outcome.. Prospective analysis.. Intensive care unit of a university teaching hospital.. Eighty-eight critically ill patients with multiple organ dysfunction syndrome.. The frequency of the different interleukin-10 genotypes (corresponding to high, intermediate, and low interleukin-10 production ) were significantly different between controls and multiple organ dysfunction syndrome patients. High interleukin-10 producers were under-represented in the multiple organ dysfunction syndrome group: This genotype occurred in 30% of controls but in only 6% of patients ( <.001). There was no relationship between interleukin-10 genotype and mortality. The frequency of TNF-alpha genotypes was also significantly different between patients and controls. Intermediate TNF-alpha producers were under-represented (5.7% vs. 23%) and high TNF-alpha producers over-represented (35.2% vs. 16%) in the patient group (p <.001). TNF-alpha genotype was not related to mortality. The distribution of TNF-beta genotypes (homozygous B1, homozygous B2, and heterozygotes) was also different between controls and patients (p =.008). The B2/B2 genotype (associated with high TNF-alpha production) tended to occur less frequently in the intensive care unit population (31% vs. 50%) and was associated with a higher mortality rate than either the B1/B1 or B1/B2 genotypes (48% vs. 11% and 33% respectively, p=.115). The combination of proinflammatory (TNF-alpha/TNF-beta) and anti-inflammatory (interleukin-10/transforming growth factor-beta1) cytokine genotypes was associated with prolonged patient survival time. Patients predisposed to produce a balanced cytokine response (e.g., intermediate interleukin-10/TNF-alpha producers) demonstrated the longest survival times, although overall mortality was no different.. A genetic predisposition to high interleukin-10 production or intermediate TNF-alpha production may be protective of admission to the intensive care unit, although once admitted, any protection provided by these genotypes seems to be lost. TNF-beta genotype conferred no advantage to patients with multiple organ dysfunction syndrome, the TNFB2 allele being associated with increased mortality. The combination of proinflammatory and anti-inflammatory cytokine genotypes supports the idea that a balanced cytokine response is favorable and was associated with prolonged patient survival time.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Cytokines; Female; Genetic Predisposition to Disease; Genetic Variation; Genotype; Humans; Interleukin-10; Male; Middle Aged; Multiple Organ Failure; Polymerase Chain Reaction; Polymorphism, Genetic; Prospective Studies; Systemic Inflammatory Response Syndrome; Transforming Growth Factor beta; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha