ascorbic-acid and Peritonitis

Topics: Adult; Ascorbic Acid; Cholangitis; Clinical Trials as Topic; Erythromycin; Female; Fungi; Humans; Infant; Infections; Male; Meningitis; Meningoencephalitis; Peritonitis; Pneumonia; Staphylococcal Infections; Urine

The anticarcinogenic and anti-inflammatory properties of curcumin have been extensively investigated, identifying prostaglandin E2 synthase (mPGES)-1 and 5-lipoxygenase (5-LO), key enzymes linking inflammation with cancer, as high affinity targets. A comparative structure-activity study revealed three modifications dissecting mPGES-1/5-LO inhibition, namely (i) truncation of the acidic, enolized dicarbonyl moiety and/or replacement by pyrazole, (ii) hydrogenation of the interaryl linker, and (iii) (dihydro)prenylation. The prenylated pyrazole analogue 11 selectively inhibited 5-LO, outperforming curcumin by a factor of up to 50, and impaired zymosan-induced mouse peritonitis along with reduced 5-LO product levels. Other pro-inflammatory targets of curcumin (i.e., mPGES-1, cyclooxygenases, 12/15-LOs, nuclear factor-κB, nuclear factor-erythroid 2-related factor-2, and signal transducer and activator of transcription 3) were hardly affected by 11. The strict structural requirements for mPGES-1 and 5-LO inhibition strongly suggest that specific interactions rather than redox or membrane effects underlie the inhibition of mPGES-1 and 5-LO by curcumin.

Topics: Animals; Anti-Inflammatory Agents; Arachidonate 5-Lipoxygenase; Curcumin; Humans; Lipoxygenase Inhibitors; Male; Mice; Monocytes; Peritonitis; Structure-Activity Relationship

Macrophage reprogramming is vital for resolution of acute inflammation. Parenteral vitamin C (VitC) attenuates proinflammatory states in murine and human sepsis. However information about the mechanism by which VitC regulates resolution of inflammation is limited.. To examine whether physiological levels of VitC modulate resolution of inflammation, we used transgenic mice lacking L-gulono-γ-lactone oxidase. VitC sufficient/deficient mice were subjected to a thioglycollate-elicited peritonitis model of sterile inflammation. Some VitC deficient mice received daily parenteral VitC (200 mg/kg) for 3 or 5 days following thioglycollate infusion. Peritoneal macrophages harvested on day 3 or day 5 were examined for intracellular VitC levels, pro- and anti-inflammatory protein and lipid mediators, mitochondrial function, and response to lipopolysaccharide (LPS). The THP-1 cell line was used to determine the modulatory activities of VitC in activated human macrophages.. VitC deficiency significantly delayed resolution of inflammation and generated an exaggerated proinflammatory response to in vitro LPS stimulation. VitC sufficiency and in vivo VitC supplementation restored macrophage phenotype and function in VitC deficient mice. VitC loading of THP-1 macrophages attenuated LPS-induced proinflammatory responses.. VitC sufficiency favorably modulates macrophage function. In vivo or in vitro VitC supplementation restores macrophage phenotype and function leading to timely resolution of inflammation.

Topics: Animals; Ascorbic Acid; Blotting, Western; Cell Line; Humans; Inflammation; Lipopolysaccharides; Macrophages; Macrophages, Peritoneal; Mice; Mice, Knockout; Mice, Transgenic; Microscopy, Fluorescence; Peritonitis; Real-Time Polymerase Chain Reaction; Thioglycolates

Dual inhibition of microsomal prostaglandin E2 synthase-1 (mPGES-1) and 5-lipoxygenase (5-LO) is currently pursued as potential pharmacological strategy for treatment of inflammation and cancer. Here we present a series of 26 novel 2-aminothiazole-featured pirinixic acid derivatives as dual 5-LO/mPGES-1 inhibitors with improved potency (exemplified by compound 16 (2-[(4-chloro-6-{[4-(naphthalen-2-yl)-1,3-thiazol-2-yl]amino}pyrimidin-2-yl)sulfanyl]octanoic acid) with IC50 = 0.3 and 0.4 μM, respectively) and bioactivity in vivo. Computational analysis presumes binding sites of 16 at the tip of the 5-LO catalytic domain and within a subpocket of the mPGES-1 active site. Compound 16 (10 μM) hardly suppressed cyclooxygenase (COX)-1/2 activities, failed to inhibit 12/15-LOs, and is devoid of radical scavenger properties. Finally, compound 16 reduced vascular permeability and inflammatory cell infiltration in a zymosan-induced mouse peritonitis model accompanied by impaired levels of cysteinyl-leukotrienes and prostaglandin E2. Together, 2-aminothiazole-featured pirinixic acids represent potent dual 5-LO/mPGES-1 inhibitors with an attractive pharmacological profile as anti-inflammatory drugs.

Topics: Animals; Arachidonate 5-Lipoxygenase; Binding Sites; Drug Design; Humans; Hydrophobic and Hydrophilic Interactions; Inhibitory Concentration 50; Intramolecular Oxidoreductases; Lipoxygenase Inhibitors; Male; Mice; Microsomes; Models, Molecular; Peritonitis; Prostaglandin-E Synthases; Protein Conformation; Pyrimidines; Structure-Activity Relationship; Thiazoles; Zymosan

Neutrophil extracellular trap (NET) formation was recently identified as a novel mechanism to kill pathogens. However, excessive NET formation in sepsis can injure host tissues. We have recently shown that parenteral vitamin C (VitC) is protective in sepsis. Whether VitC alters NETosis is unknown.. We used Gulo-/- mice as they lack the ability to synthesize VitC. Sepsis was induced by intraperitoneal infusion of a fecal stem solution (abdominal peritonitis, FIP). Some VitC deficient Gulo-/- mice received an infusion of ascorbic acid (AscA, 200 mg/kg) 30 min after induction of FIP. NETosis was assessed histologically and by quantification for circulating free DNA (cf-DNA) in serum. Autophagy, histone citrullination, endoplasmic reticulum (ER) stress, NFκB activation and apoptosis were investigated in peritoneal PMNs.. Sepsis produced significant NETs in the lungs of VitC deficient Gulo-/- mice and increased circulating cf-DNA. This was attenuated in the VitC sufficient Gulo-/- mice and in VitC deficient Gulo-/- mice infused with AscA. Polymorphonuclear neutrophils (PMNs) from VitC deficient Gulo-/- mice demonstrated increased activation of ER stress, autophagy, histone citrullination, and NFκB activation, while apoptosis was inhibited. VitC also significantly attenuated PMA induced NETosis in PMNs from healthy human volunteers.. Our in vitro and in vivo findings identify VitC as a novel regulator of NET formation in sepsis. This study complements the notion that VitC is protective in sepsis settings.

Topics: Animals; Apoptosis; Ascorbic Acid; Autophagy; Endoplasmic Reticulum Stress; Histones; Humans; Hydrolases; Lung; Mice; Mice, Knockout; Neutrophils; NF-kappa B; Peritonitis; Protein-Arginine Deiminase Type 4; Real-Time Polymerase Chain Reaction; RNA, Messenger; Sepsis; Signal Transduction; Up-Regulation

Vascular leakage in multiple organs is a characteristic pathological change in sepsis. Our recent study revealed that ascorbate protects endothelial barrier function in microvascular endothelial cell monolayers through inhibiting serine/threonine protein phosphatase 2A (PP2A) activation (Han M, Pendem S, Teh SL, Sukumaran DK, Wu F, Wilson JX. Free Radic Biol Med 48: 128-135, 2010). The present study addressed the mechanism of protection by ascorbate against vascular leakage in cecal ligation and puncture (CLP)-induced septic peritonitis in mice. CLP caused NADPH oxidase activation and endothelial nitric oxide synthase (eNOS) uncoupling to produce superoxide, increased NO production by inducible NOS (iNOS) and neuronal NOS (nNOS) activity, and elevated 3-nitrotyrosine (a product of peroxynitrite) formation and PP2A activity in the hindlimb skeletal muscles at 12 h after CLP. The increase in PP2A activity was associated with decreased levels of phosphorylated serine and threonine in occludin, which was immunoprecipitated from freshly harvested endothelial cells of the septic skeletal muscles. Moreover, CLP increased the vascular permeability to fluorescent dextran and Evans blue dye in skeletal muscles. An intravenous bolus injection of ascorbate (200 mg/kg body wt), given 30 min prior to CLP, prevented eNOS uncoupling, attenuated the increases in iNOS and nNOS activity, decreased 3-nitrotyrosine formation and PP2A activity, preserved the phosphorylation state of occludin, and completely inhibited the vascular leakage of dextran and Evans blue. A delayed ascorbate injection, given 3 h after CLP, also prevented the vascular permeability increase. We conclude that ascorbate injection protects against vascular leakage in sepsis by sequentially inhibiting excessive production of NO and superoxide, formation of peroxynitrite, PP2A activation, and occludin dephosphorylation. Our study provides a scientific basis for injection of ascorbate as an adjunct treatment for vascular leakage in sepsis.

Topics: Animals; Antioxidants; Ascorbic Acid; Capillary Permeability; Cecum; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Muscle, Skeletal; NADPH Oxidases; Nitric Oxide; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Occludin; Peritonitis; Protein Phosphatase 2; Sepsis; Superoxides; Tyrosine

Bacterial infections of the lungs and abdomen are among the most common causes of sepsis. Abdominal peritonitis often results in acute lung injury (ALI). Recent reports demonstrate a potential benefit of parenteral vitamin C [ascorbic acid (AscA)] in the pathogenesis of sepsis. Therefore we examined the mechanisms of vitamin C supplementation in the setting of abdominal peritonitis-mediated ALI. We hypothesized that vitamin C supplementation would protect lungs by restoring alveolar epithelial barrier integrity and preventing sepsis-associated coagulopathy. Male C57BL/6 mice were intraperitoneally injected with a fecal stem solution to induce abdominal peritonitis (FIP) 30 min prior to receiving either AscA (200 mg/kg) or dehydroascorbic acid (200 mg/kg). Variables examined included survival, extent of ALI, pulmonary inflammatory markers (myeloperoxidase, chemokines), bronchoalveolar epithelial permeability, alveolar fluid clearance, epithelial ion channel, and pump expression (aquaporin 5, cystic fibrosis transmembrane conductance regulator, epithelial sodium channel, and Na(+)-K(+)-ATPase), tight junction protein expression (claudins, occludins, zona occludens), cytoskeletal rearrangements (F-actin polymerization), and coagulation parameters (thromboelastography, pro- and anticoagulants, fibrinolysis mediators) of septic blood. FIP-mediated ALI was characterized by compromised lung epithelial permeability, reduced alveolar fluid clearance, pulmonary inflammation and neutrophil sequestration, coagulation abnormalities, and increased mortality. Parenteral vitamin C infusion protected mice from the deleterious consequences of sepsis by multiple mechanisms, including attenuation of the proinflammatory response, enhancement of epithelial barrier function, increasing alveolar fluid clearance, and prevention of sepsis-associated coagulation abnormalities. Parenteral vitamin C may potentially have a role in the management of sepsis and ALI associated with sepsis.

Topics: Abdomen; Acute Lung Injury; Animals; Ascorbic Acid; Biomarkers; Blood Coagulation; Bronchoalveolar Lavage; Cell Line; Cytoskeletal Proteins; Humans; Inflammation; Ion Channels; Ion Transport; Lung; Male; Mice; Mice, Inbred C57BL; Neutrophils; Peritonitis; Permeability; Pulmonary Alveoli; Respiratory Mucosa; Sepsis; Sodium-Potassium-Exchanging ATPase

Postnatal glucocorticoid therapy in premature infants diminishes chronic lung disease, but it also increases the risk of hypertension in adulthood. Since glucocorticoid excess leads to overproduction of free radicals and endothelial dysfunction, this study tested the hypothesis that adverse effects on cardiovascular function of postnatal glucocorticoids are secondary to oxidative stress. Therefore, combined postnatal treatment of glucocorticoids with antioxidants may diminish unwanted effects.. Male rat pups received a course of dexamethasone (Dex), or Dex with vitamins C and E (DexCE), on postnatal days 1-6 (P1-6). Controls received vehicle (Ctrl) or vehicle with vitamins (CtrlCE). At P21, femoral vascular reactivity was determined via wire myography. Dex, but not DexCE or CtrlCE, increased mortality relative to Ctrl (81.3 versus 96.9 versus 90.6 versus 100% survival, respectively; P<0.05). Constrictor responses to phenylephrine (PE) and thromboxane were enhanced in Dex relative to Ctrl (84.7+/-4.8 versus 67.5+/-5.7 and 132.7+/-4.9 versus 107.0+/-4.9% Kmax, respectively; P<0.05); effects that were diminished in DexCE (58.3+/-7.5 and 121.1+/-4.3% Kmax, respectively; P<0.05). Endothelium-dependent dilatation was depressed in Dex relative to Ctrl (115.3+/-11.9 versus 216.9+/-18.9, AUC; P<0.05); however, this effect was not restored in DexCE (68.3+/-8.3, AUC). Relative to Ctrl, CtrlCE alone diminished PE-induced constriction (43.4+/-3.7% Kmax) and the endothelium-dependent dilatation (74.7+/-8.7 AUC; P<0.05).. Treatment of newborn rats with dexamethasone has detrimental effects on survival and peripheral vasoconstrictor function. Coadministration of dexamethasone with antioxidant vitamins improves survival and partially restores vascular dysfunction. Antioxidant vitamins alone affect peripheral vascular function.

Topics: Animals; Animals, Newborn; Antioxidants; Ascorbic Acid; Body Weight; Cardiovascular Diseases; Dexamethasone; Dose-Response Relationship, Drug; Female; Femoral Artery; Glucocorticoids; In Vitro Techniques; Male; Nitric Oxide Donors; Nitroprusside; Peritonitis; Potassium; Random Allocation; Rats; Rats, Wistar; Survival Rate; Time Factors; Vasoconstriction; Vitamin E

Probiotics and antioxidants could be alternatives to antibiotics in the prevention of bacterial infections in cirrhosis. The aim of the present study was to determine the effect of Lactobacillus johnsonii La1 and antioxidants on intestinal flora, endotoxemia, and bacterial translocation in cirrhotic rats.. Twenty-nine Sprague-Dawley rats with cirrhosis induced by CCl(4) and ascites received Lactobacillus johnsonii La1 10(9)cfu/day in vehicle (antioxidants: vitamin C+glutamate) (n=10), vehicle alone (n=11), or water (n=8) by gavage. Another eight non-cirrhotic rats formed the control group. After 10 days of treatment, a laparotomy was performed to determine microbiological study of ileal and cecal feces, bacterial translocation, endotoxemia, and intestinal malondialdehyde (MDA) levels as index of intestinal oxidative damage.. Intestinal enterobacteria and enterococci, bacterial translocation (0/11 and 0/10 vs. 5/8, P<0.01), and ileal MDA levels (P<0.01) were lower in cirrhotic rats treated with antioxidants alone or in combination with Lactobacillus johnsonii La1 compared to cirrhotic rats receiving water. Only rats treated with antioxidants and Lactobacillus johnsonii La1 showed a decrease in endotoxemia with respect to cirrhotic rats receiving water (P<0.05).. Antioxidants alone or in combination with Lactobacillus johnsonii La1 can be useful in preventing bacterial translocation in cirrhosis.

Topics: Animals; Antioxidants; Ascites; Ascorbic Acid; Bacterial Translocation; Combined Modality Therapy; Disease Models, Animal; Endotoxemia; Glutamic Acid; Intestinal Mucosa; Lactobacillus; Liver Cirrhosis; Male; Malondialdehyde; Oxidative Stress; Peritonitis; Probiotics; Rats; Rats, Sprague-Dawley

Inflammation-induced disease as seen with trauma and infection can lead to increased lung oxidant activity resulting in cell membrane lipid peroxidation. Acute zymosan-induced peritonitis in rats produces lung inflammation, edema, and lipid peroxidation. We determined whether administered alpha-tocopherol (vitamin E), the key antioxidant protection against cell membrane lipid peroxidation, would improve this process.. Male Wistar rats were given 0.75 mg/kg of intraperitoneal zymosan, volume resuscitated, monitored, and killed at 4 or 24 hours. Lung histologic changes and levels of conjugated dienes, a marker of lipid peroxidation, were used to monitor injury. The levels of vitamin E, vitamin C, and catalase were used to monitor antioxidant defenses. The effect of administering alpha-tocopherol (50 mg/kg) by gavage immediately after zymosan on the degree of the lung injury was then determined.. Twenty-four hours after zymosan was administered, the vitamin E levels in plasma were significantly decreased, but lung tissue vitamin E levels were maintained, whereas tissue catalase and vitamin E levels decreased. Lung tissue-conjugated diene levels, alveolar edema, and neutrophil count were significantly increased. alpha-Tocopherol treatment increased the postzymosan plasma vitamin E levels by 50%. Lung tissue vitamin E levels did not increase; however, the degree of lung injury and lipid peroxidation was significantly attenuated. Tissue catalase levels were also maintained.. We conclude that alpha-tocopherol given at the onset of a progressing inflammatory injury can protect the lung from oxidant damage and attenuate the degree of lung injury.

Topics: Acute Disease; Animals; Ascorbic Acid; Catalase; Lipid Peroxidation; Lung; Male; Peritonitis; Pulmonary Edema; Rats; Rats, Wistar; Vitamin E; Zymosan

Acute zymosan-induced peritonitis in rats produces lung inflammation and lipid peroxidation. The effect of this process on plasma and lung tissue ascorbic acid was determined, as was the effect of infusing 150 mg/kg of ascorbic acid immediately after zymosan on the degree of lung insult. Ascorbic acid levels were significantly decreased in plasma and lung tissue at 24 h after zymosan, and lung tissue conjugated diene and neutrophil content was also significantly increased. Vitamin C infusion increased postzymosan plasma levels by 50% over normal control levels. However, lung tissue ascorbic acid was still decreased, and no decrease in the lung injury process was noted. Added ascorbic acid also did not prevent a decrease in plasma vitamin E with the peritonitis. We conclude that the amount of ascorbic acid given in this study did not diminish the lung oxidant inflammatory changes. An insufficient dose or inadequate time for plasma ascorbic acid to equilibrate with the lung cytosol are possible explanations for the lack of attenuation of lung oxidant stress.

Topics: Acute Disease; Animals; Antioxidants; Ascorbic Acid; Ascorbic Acid Deficiency; Inflammation; Lipid Peroxidation; Lung; Male; Oxidation-Reduction; Peritonitis; Pulmonary Edema; Rats; Rats, Wistar; Vitamin E; Vitamin E Deficiency; Zymosan

Topics: Acute Disease; Ascorbic Acid; Blood Transfusion; Humans; Norepinephrine; Peritonitis; Pyrimidines; Suppuration; Vitamin B Complex

Topics: Adult; Ascorbic Acid; Chronic Disease; Escherichia coli Infections; Female; Humans; Infections; Lung Diseases; Male; Middle Aged; Osteomyelitis; Peritonitis; Pleural Diseases; Pneumonia; Staphylococcal Infections; Streptococcal Infections; Suppuration; Surgical Wound Infection; Tetracycline; Thiamine

Topics: Anti-Bacterial Agents; Ascorbic Acid; Blood; Blood Protein Electrophoresis; Blood Proteins; Drug Therapy; Endocarditis; Endocarditis, Bacterial; Humans; Meningitis; Meningoencephalitis; Oximetry; Peritonitis; Ristocetin; Sepsis; Urine