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F Q Cunha

Publications and source records attributed to F Q Cunha.

At least 19 recordsLinked to original sources
PubMed2007

The dual role of p55 tumour necrosis factor-alpha receptor in Actinobacillus actinomycetemcomitans-induced experimental periodontitis: host protection and tissue destruction.

Inflammatory immune reactions in response to periodontopathogens are thought to protect the host against infection, but may trigger periodontal destruction. Thus, we examined the mechanisms by which the proinflammatory cytokine tumour necrosis factor (TNF)-alpha modulates the outcome of Actinobacillus actinomycetemcomitans-induced periodontal disease in mice. Our results showed that TNF-alpha receptor p55-deficient mice [p55TNF-knock-out (KO)] developed a less severe periodontitis in response to A. actinomycetemcomitans infection, characterized by significantly less alveolar bone loss and inflammatory reaction. Real-time polymerase chain reaction (PCR) demonstrated that levels of chemokines (CXCL1, 3 and 10; CCL3 and 5) and their receptors (CXCR2 and 3, CCR5) were lower in p55TNF-KO mice, as were matrix metalloproteinase (MMP)-1, 2 and 9 and receptor activator of nuclear factor kB ligand (RANKL) mRNA levels. However, the absence of the TNF-alpha p55 results in an impairment of protective immunity to A. actinomycetemcomitans infection, characterized by increased bacterial load and higher levels of C-reactive protein during the course of disease. Such impaired host response may be the result of the reduced chemoattraction of lymphocytes, neutrophils and macrophages, and reduced inducible nitric oxide synthase expression (iNOS) and myeloperoxidase (MPO) production in periodontal tissues of p55 TNF-KO mice. Our results demonstrate the mechanisms involved determining periodontal disease severity by TNF-alpha receptor p55, and its role in providing immune protection to A. actinomycetemcomitans periodontal infection.

Actinobacillus Infections↗
PubMed2006

Eotaxin-2 in sputum cell culture to evaluate asthma inflammation.

The aim of the present study was to elucidate whether the culture of cells recovered from induced sputum may represent a suitable model to evaluate cytokine and chemokine production by airway inflammatory cells. Sputum induction was performed in 21 normal subjects and 30 asthmatic patients. A total of 21 out of the 30 asthmatic patients were taking inhaled corticosteroids, while the remaining nine were steroid-naive asthmatics. The steroid-naive group was evaluated before and after a 14-day treatment with oral prednisone (40 mg.day(-1)). The supernatant of lysed and centrifuged sputum and the supernatant of sputum cell culture were analysed. Tumour necrosis factor-alpha, interleukin (IL)-8 (CXCL8), IL-1beta, IL-13 and eotaxin-2 (CCL24) concentrations were determined by specific ELISA. Eotaxin-2 production by cell culture was higher in the asthma group (131+/-108 pg.mL(-1)) than in the control group (36+/-41 pg.mL(-1)) and treatment with oral corticosteroids eliminated this difference. In addition, reduction of eotaxin-2 levels by corticosteroid treatment was greater in cell culture (81.3% reduction) than in sputum (26.4%). There was correlation between the decrease in eotaxin-2 production and the decrease in blood eosinophil number and between eotaxin-2 and eosinophils in sputum. Eotaxin-2 may play an important role in asthma and the response to corticosteroid treatment suggests that analysis of sputum cell culture is relevant as an inflammatory parameter.

Administration, Inhalation↗
PubMed2006

A novel technique to perform direct intraganglionar injections in rats.

The present work describes a simple method for direct drug administration into the dorsal root ganglion (DRG) in anesthetized rats. This technique does not involve surgery, is easy to learn and allows behavioral testing within minutes after the injection. Based on landmarks that target the L5 DRG, an orifice was created with a guide needle through which a specially designed needle was inserted for solution injection. Its introduction into the ganglia was ensured by the triggering of an ipsilateral hindpaw reflex. The precision of the technique was checked by injections of the biological dye Pontamine Sky Blue (PSB) or C14-labeled arginine. There was no leakage of the dye to the surrounding tissues after a single 4 microl or three successive 2.5 microl injections (at 30-min intervals). Moreover, identical effects were observed with prostaglandin E2 (PGE2), morphine or glibenclamide injected intraplantarly or in the DRG, thus confirming the precision of the method and suggesting that the ganglion cells and peripheral nociceptors may display similar receptor population.

Analgesics, Opioid↗
PubMed2006

Heme oxygenase/carbon monoxide-biliverdin pathway down regulates neutrophil rolling, adhesion and migration in acute inflammation.

BACKGROUND AND PURPOSE: Heme oxygenase (HO) activity is known to down-regulate inflammatory events. Here, we address the role of HO and its metabolites, carbon monoxide (CO) and biliverdin (BVD), in leukocyte rolling, adhesion and neutrophil migration during inflammatory processes. EXPERIMENTAL APPROACH: Intravital microscopy was used to evaluate leukocyte rolling and adhesion in the mesenteric microcirculation of mice. TNFalpha and IL-1beta were determined by ELISA and HO-1 protein expression by Western blot. KEY RESULTS: Intraperitoneal challenge with carrageenan enhanced HO-1 protein expression in mesentery and bilirubin concentration in peritoneal exudates. Pretreatment of mice with a non-specific inhibitor of HO (ZnDPBG) or with a HO-1 specific inhibitor (ZnPP IX) enhanced neutrophil migration, rolling and adhesion on endothelium induced by carrageenan. In contrast, HO substrate (hemin), CO donor (DMDC) or BVD reduced these parameters. The reduction of neutrophil recruitment promoted by HO metabolites was independent of the production of chemotactic cytokines. Inhibitory effects of CO, but not of BVD, were counteracted by treatment with a soluble guanylate cyclase (sGC) inhibitor, ODQ. Furthermore, inhibition of HO prevented the inhibitory effect of a nitric oxide (NO) donor (SNAP) upon neutrophil migration, while the blockade of NO synthase (NOS) activity by aminoguanidine did not affect the CO or BVD effects. CONCLUSIONS AND IMPLICATIONS: Metabolites of HO decreased leukocyte rolling, adhesion and neutrophil migration to the inflammatory site by a mechanism partially dependent on sGC. Moreover, inhibition by NO of neutrophil migration was dependent on HO activity.

Animals↗
PubMed2006

Role of nitric oxide on pathogenesis of 5-fluorouracil induced experimental oral mucositis in hamster.

INTRODUCTION: Mucositis induced by antineoplastic drugs is an important, dose-limiting, and costly side effect of cancer therapy. AIM: To investigate the role of nitric oxide (NO) on the pathogenesis of 5-fluorouracil (5-FU)-induced oral mucositis. MATERIALS AND METHODS: Oral mucositis was induced by two intraperitoneal (i.p) administrations of 5-FU on the first and second days of the experiment (60 and 40 mg/kg, respectively) in male hamsters. Animals were treated subcutaneously with saline (0.4 ml), 1,400 W (1 mg/kg), aminoguanidine (5 or 10 mg/kg) or Nphi-Nitro-L-Arginine Methyl Ester (L-NAME) (5, 10, or 20 mg/kg) 1 h before the injections of 5-FU and daily until sacrifice, on the tenth day. Macroscopic and histopathological analyses were evaluated and graded. Tissues from the cheek pouches were harvested for measurement of myeloperoxidase (MPO) activity, nitrite level, and immunohistochemistry for induced nitric oxide synthase (iNOS). RESULTS: Treatment with 1,400 W or aminoguanidine reduced macroscopic and histological parameters of oral mucositis, and reduced the inflammatory cell infiltration as detected by histopathology and by MPO activity. In contrast, the administration of L-NAME did not significantly reverse the inflammatory alterations induced by experimental mucositis. Increased NOS activity, nitrite level and immunostaining for iNOS were detected on the check pouch tissue of animals submitted to 5-FU-induced oral mucositis on the tenth day. CONCLUSION: These results suggest an important role of NO produced by iNOS in the pathogenesis of oral mucositis induced by 5-FU.

Animals↗
PubMed2006

Atorvastatin inhibits inflammatory hypernociception.

BACKGROUND AND PURPOSE: Atorvastatin is an inhibitor of the enzyme 3-hydroxyl-3-methylglutaryl coenzyme A reductase used to prevent coronary heart disease. We have studied the analgesic effect of atorvastatin in inflammatory models in which a sequential release of mediators (bradykinin, (BK), tumour necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and the chemokine, KC/CXCL) links the stimulus with release of directly acting hypernociceptive mediators such as prostaglandin E(2) (PGE(2)). EXPERIMENTAL APPROACH: The effects of orally administered atorvastatin on inflammatory mechanical hypernociception in mouse paws were evaluated with an electronic pressure-meter. Cytokines and PGE(2) were measured by ELISA and RIA. KEY RESULTS: Treatment with atorvastatin for 3 days dose-dependently reduced hypernociception induced by lipopolysaccharide (LPS) or that following antigen challenge in sensitized animals. Atorvastatin pre-treatment reduced hypernociception induced by bradykinin and cytokines (TNF-alpha, IL-1beta and KC), and the release of IL-1beta and PGE(2) in paw skin, induced by lipopolysaccharide. The antinociceptive effect of atorvastatin on LPS-induced hypernociception was prevented by mevalonate co-treatment without affecting serum cholesterol levels. Hypernociception induced by PGE(2) was inhibited by atorvastatin, suggesting intracellular antinociceptive mechanisms for atorvastatin. The antinociceptive effect of atorvastatin upon LPS- or PGE(2)-induced hypernociception was prevented by non-selective inhibitors of nitric oxide synthase (NOS) but not by selective inhibition of inducible NOS or in mice lacking this enzyme. CONCLUSIONS AND IMPLICATIONS: Antinociceptive effects of atorvastatin depend on inhibition of cytokines and prostanoid production and on stimulation of NO production by constitutive NOS. Our study suggests that statins may constitute a novel class of analgesic drugs.

Animals↗
PubMed2006

Amifostine and glutathione prevent ifosfamide- and acrolein-induced hemorrhagic cystitis.

INTRODUCTION: Ifosfamide (IFS) is an antineoplastic alkylating agent whose major side effect is hemorrhagic cystitis (HC). This toxicity is attributed to the renal excretion of acrolein (ACR), a highly urotoxic IFS metabolite. Despite the clinical use of mesna to prevent HC, a significant percent ( approximately 33%) of patients present with at last one feature of HC, mainly hematuria. AIM: To investigate the use of two antioxidants-amifostine and glutathione-for the prevention of experimental IFS- and ACR-induced HC. MATERIALS AND METHODS: Male Swiss mice were treated intraperitoneal (i.p.) with saline (control), glutathione (125, 250 or 500 mg/kg) or amifostine (25, 50 or 100 mg/kg), and 30 min later they received a single i.p. injection of IFS at a dose of 400 mg/kg. To investigate the systemic effects of the antioxidants on ACR-induced HC, the animals were treated with saline, amifostine (50 mg/kg, i.p.) or glutathione (500 mg/kg, i.p.), and 30 min afterward with 75 mug ACR intravesically (i.ve.). In another set of experiments, the antioxidants were injected directly into the bladder, where the mice received a single i.ve injection of ACR (75 mug) plus amifostine (1.5 mg/kg) or glutathione (2 mg/kg). HC was measured 3 h after IFS or ACR injection according to bladder wet weight, macroscopic (edema and hemorrhage) and microscopic changes, i.e., edema, hemorrhage, cellular infiltration, fibrin deposition and urothelial desquamation. RESULTS: Pretreatments with amifostine or glutathione prevented IFS-induced HC in a dose-dependent manner. Furthermore, ACR-induced HC was also prevented by systemic (i.p.) or local (i.ve.) pretreatment with glutathione or amifostine. The greatest protective effect was seen with local amifostine treatment (2 mg/kg i.ve.) (P < 0.05). CONCLUSIONS: Glutathione and amifostine show a beneficial effect in experimental IFS- and ACR-induced HC. Thus, they should be investigated as an alternative treatment to prevent HC observed in patients undergoing IFS treatment.

Acrolein↗
PubMed2006

Evidence for the participation of nitric oxide in pemphigus.

Pemphigus is an inflammatory autoimmune disorder of the skin. Nitric oxide (NO) is an inflammatory mediator linked to a variety of physiological and pathophysiological phenomena that include skin tumors, psoriasis, urticaria, and atopic dermatitis. Inflammatory cells present in pemphigus lesions are important sources of NO production. We investigated whether NO is involved in pemphigus. A prospective cohort study was conducted at the Dermatology Service of the Hospital Universitário Walter Cantídio of the Federal University of Ceará. All patients seen at the outpatient clinic between August 2000 and July 2001, with a clinically and histologically confirmed diagnosis of pemphigus were included. The median age was 42.5 years (range: 12-69 years) with a male to female ratio of 3:2. Total serum nitrite levels, used as a marker for NO production, were determined by the Griess reaction. Skin biopsies from pemphigus and breast surgery (control) patients were used for the detection of the inducible NO synthase (iNOS) by immunohistochemistry. Twenty-two (22) patients with pemphigus and eight (8) controls who did not differ in demographic characteristics were included. Total serum nitrite levels were significantly higher (>7 micromol/L) in pemphigus patients compared to controls (<6 micromol/L), regardless of the severity of the clinical activity of pemphigus (P < 0.0001). All pemphigus biopsies presented increased immunostaining for iNOS that was not detected in normal skin samples. These data are the first to demonstrate that pemphigus patients display increased serum NO levels that are associated with increased iNOS expression in the affected skin.

Adolescent↗
PubMed2006

A quantitative approach to measure joint pain in experimental osteoarthritis--evidence of a role for nitric oxide.

OBJECTIVES: To describe a method to study joint pain in experimental osteoarthritis (OA) and to study nitric oxide (NO) participation in experimental OA. DESIGN: Rats were subjected to anterior cruciate ligament transection (ACLT) (OA group) of the right knee and evaluated during 28 days. A sham group was false operated and a naive group received no manipulation. Joint pain was measured by recording the time the right hind paw fails to touch the surface while walking. Cell influx (CI) and nitrite levels were measured in joint exudates. Expression of inducible NO synthase (iNOS) in synovia was detected by immunostaining. For the specific purpose of pharmacological manipulation, groups received either indomethacin (2 mg/kg/day s.c. (subcutaneous)), meloxicam (6 mg/kg/day s.c.), morphine (200 microg intra-articularly), the non-selective NOS inhibitor L-N(G)-nitroarginine methyl ester (L-NAME; 30 mg/kg/bid i.p. (intra-peritoneal)) or the selective iNOS inhibitor 1400W (0.5 mg/kg/day s.c.), given 30 min prior (prophylactic) or 4 days after (therapeutic) ACLT, until sacrifice, at 7 days. The respective non-treated groups received the vehicles. RESULTS: The OA group developed joint pain, as compared to sham and control groups (P<0.05). Significantly increased nitrite levels and iNOS immunostaining were seen in the OA group. Both indomethacin and meloxicam inhibited joint pain (P<0.05). Morphine inhibited joint pain, whereas this effect was blocked by co-administration of the mu-opioid receptor naloxone. CI was similar among all groups. Prophylactic but not therapeutic L-NAME or 1400W reduced joint pain. CONCLUSION: We describe a method to quantitate joint pain associated to weight bearing in the ACLT model. The joint pain is sensitive to classical antinociceptive compounds. NO release is associated to joint pain though NOS inhibition does not inhibit ongoing pain.

Amidines↗
PubMed2006

Glutathione and the redox control system trypanothione/trypanothione reductase are involved in the protection of Leishmania spp. against nitrosothiol-induced cytotoxicity.

Glutathione is the major intracellular antioxidant thiol protecting mammalian cells against oxidative stress induced by oxygen- and nitrogen-derived reactive species. In trypanosomes and leishmanias, trypanothione plays a central role in parasite protection against mammalian host defence systems by recycling trypanothione disulphide by the enzyme trypanothione reductase. Although Kinetoplastida parasites lack glutathione reductase, they maintain significant levels of glutathione. The aim of this study was to use Leishmania donovani trypanothione reductase gene mutant clones and different Leishmania species to examine the role of these two individual thiol systems in the protection mechanism against S-nitroso-N-acetyl-D,L-penicillamine (SNAP), a nitrogen-derived reactive species donor. We found that the resistance to SNAP of different species of Leishmania was inversely correlated with their glutathione concentration but not with their total low-molecular weight thiol content (about 0.18 nmol/10(7) parasites, regardless Leishmania species). The glutathione concentration in L. amazonensis, L. donovani, L. major, and L. braziliensis were 0.12, 0.10, 0.08, and 0.04 nmol/10(7) parasites, respectively. L. amazonensis, that have a higher level of glutathione, were less susceptible to SNAP (30 and 100 microM). The IC50 values of SNAP determined to L. amazonensis, L. donovani, L. major, and L. braziliensis were 207.8, 188.5, 160.9, and 83 microM, respectively. We also observed that L. donovani mutants carrying only one trypanothione reductase allele had a decreased capacity to survive (approximately 40%) in the presence of SNAP (30-150 microM). In conclusion, the present data suggest that both antioxidant systems, glutathione and trypanothione/trypanothione reductase, participate in protection of Leishmania against the toxic effect of nitrogen-derived reactive species.

Animals↗
PubMed2006

Failure of neutrophil migration to infectious focus and cardiovascular changes on sepsis in rats: Effects of the inhibition of nitric oxide production, removal of infectious focus, and antimicrobial treatment.

Recently, we demonstrated that mice under lethal sepsis present failure of neutrophil migration (FNM) to infectious focus, which is mediated by nitric oxide. The aims of the present study were to investigate whether FNM is also observed in severe sepsis induced by cecal ligation and puncture in rats and the effects of the prevention of nitric oxide production and of the elimination of the infectious focus through peritoneal lavage or by antimicrobial treatment on FNM and disease outcome. Rats were submitted to several septic stimuli (low, moderate, and severe) by cecal ligation and puncture. Severe septic stimulus animals presented FNM to the peritoneal cavity that was accompanied by large numbers of bacteria in the peritoneal cavity, blood, and liver and lung tissues; high cytokines (tumor necrosis factor alpha, interleukin [IL] 1beta, IL-6, cytokine-induced neutrophil chemoattractant 1, and IL-10) concentrations in the infection site, sera, and lung tissues; marked hypotension; and high mortality rate. The exhaustive lavage of the peritoneal cavity to reduce the infectious focus did not ameliorate the disease outcome. The association of lavage procedure with aminoguanidine treatment re-established neutrophil migration, but only delayed the death of the animals. In contrast, the antimicrobial treatment of severe septic stimulus animals with sulfamethoxazole and trimethoprim significantly improved the survival rate of the severe septic stimulus but did not re-establish neutrophil migration. However, the association of aminoguanidine plus sulfamethoxazole and trimethoprim brought about a significant increase in the survival rate and re-established neutrophil migration to infectious focus; reduced the colony-forming units in the peritoneal cavity, blood, and lung tissues; and caused an improvement in the cardiovascular performance. The results showed, for the first time, that the pharmacological prevention of FNM to the infectious focus associated with the antimicrobial therapy could be a new beneficial strategy for the treatment of sepsis syndrome.

Animals↗
PubMed2006

Cytokine pattern determines the progression of experimental periodontal disease induced by Actinobacillus actinomycetemcomitans through the modulation of MMPs, RANKL, and their physiological inhibitors.

OBJECTIVE: Inflammatory and immune reactions raised in response to periodontopathogens are thought to trigger periodontal tissue destruction. We therefore investigated the expression of matrix metalloproteinases (MMPs) and the osteoclastogenic factor RANKL (receptor activator of nuclear factor-kappaB ligand), their respective inhibitors TIMPs (tissue inhibitors of metalloproteinases) and OPG (osteoprotegerin) and their possible correlation with the expression of inflammatory and regulatory cytokines in the course of experimental periodontal disease in mice. METHODS: We characterized the time course of leukocyte migration and alveolar bone loss in C57BL/6 mice infected with Actinobacillus actinomycetemcomitans. Quantitative polymerase chain reaction (RealTime PCR) and ELISA were performed to determine the expression of MMPs, TIMPs, RANKL, OPG and cathepsin K, interleukin-1beta, tumor necrosis factor-alpha, interferon-gamma, interleukin-12, interleukin-4 and interleukin-10 in periodontal tissue samples harvested throughout the course of experimental disease. RESULTS: Oral inoculation of A. actinomycetemcomitans results in an intense and widespread migration of leukocytes to the gingival tissues, besides marked alveolar bone resorption. Our data also demonstrate two distinct patterns of MMP/TIMP and RANKL/OPG expression in the course of experimental periodontal disease. The expression of MMPs (MMP-1, 2 and 9) and RANKL was correlated with the expression of interleukin-1beta, tumor necrosis factor-alpha and interferon-gamma, in a time period characterized by the intense increase of inflammatory reaction and alveolar bone loss. On the other hand, interleukin-4 and interleukin-10 were associated with higher expression of TIMPs (TIMP 1, 2 and 3) and OPG, with a lower expression of MMPs and RANKL, and with reduced rates of increase of cellular infiltration in periodontal tissues and alveolar bone loss. CONCLUSIONS: It is possible that the pattern of cytokines produced in periodontal tissues determines the progression and the severity of experimental periodontal disease, controlling the breakdown of soft and bone tissues through the balance between MMPs/TIMP and RANKL/OPG expression in gingival tissues.

Actinobacillus Infections↗
PubMed2006

Effect of novel A2A adenosine receptor agonist ATL 313 on Clostridium difficile toxin A-induced murine ileal enteritis.

Clostridium difficile is a spore-forming, anaerobic, gram-positive bacillus that releases two main virulence factors: toxins A and B. Toxin A plays an important pathogenic role in antibiotic-induced diarrhea and pseudomembranous colitis, a condition characterized by intense mucosal inflammation and secretion. Agonist activity at A2A adenosine receptors attenuates inflammation and damage in many tissues. This study evaluated the effects of a new selective A2A adenosine receptor agonist (ATL 313) on toxin A-induced injury in murine ileal loops. ATL 313 (0.5 to 5 nM) and/or the A2A adenosine receptor antagonist (ZM241385; 5 nM) or phosphate-buffered saline (PBS) were injected into ileal loops immediately prior to challenge with toxin A (1 to 10 microg/loop) or PBS. Intestinal fluid volume/length and weight/length ratios were calculated 3 h later. Ileal tissues were collected for the measurement of myeloperoxidase, adenosine deaminase activity, tumor necrosis factor alpha (TNF-alpha) production, histopathology, and detection of cell death by the TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling) method. Toxin A significantly increased volume/length and weight/length ratios in a dose-dependent fashion. ATL 313 treatment significantly (P < 0.05) reduced toxin A-induced secretion and edema, prevented mucosal disruption, and neutrophil infiltration as measured by myeloperoxidase activity. ATL 313 also reduced the toxin A-induced TNF-alpha production and adenosine deaminase activity and prevented toxin A-induced cell death. These protective effects of ATL 313 were reversed by ZM241385. In conclusion, the A2A adenosine receptor agonist, ATL 313, reduces tissue injury and inflammation in mice with toxin A-induced enteritis. The finding of increased ileal adenosine deaminase activity following the administration of toxin A is new and might contribute to the pathogenesis of the toxin A-induced enteritis by deaminating endogenous adenosine.

Adenosine A2 Receptor Agonists↗
PubMed2006

Macrophage populations and cardiac sympathetic denervation during L-NAME-induced hypertension in rats.

The rat model of hypertension induced by prolonged treatment with Nomega-nitro-L-arginine methyl ester (L-NAME) has been extensively used. However, the effects on cardiac autonomic innervation are unknown. Here, the cardiac sympathetic innervation is analyzed in parallel with myocardial lesions and leukocyte infiltration during L-NAME (40 mg/Kg body weight/day, orally) treatment. The occurrence of cardiomyocyte hypertrophy, a controversial matter, is also addressed. Degenerating cardiomyocytes and focal inflammation occurred one day after treatment. Inflammatory lesions became gradually more frequent until day 7. At day 14 fibroblast-like cells were outstanding. Interstitial and perivascular connective tissue increased from day 28 on. In the left ventricle, cardiomyocyte hypertrophy occurred only around the damaged area during the first 14 days. After 28 days, it became more widespread. In the right ventricle, the hypertrophic cardiomyocytes were restricted to damaged areas. Significant reduction of the noradrenergic nerve terminals occurred from day 3 to 28. The area occupied by ED1+ (hematogenous) macrophages increased until day 7, and dropped to control levels by day 10. ED2+ (resident) macrophages increased from day 3 to 7 and remained higher than control values up to day 77. Animals receiving both L- NAME and aminoguanidine (AG), an inducible nitric oxide synthase (iNOS) inhibitor (65 mg/Kg body weight/day, orally), showed significant decrease in the nitrite serum levels, sympathetic denervation and macrophage infiltration at day 7. No denervation was detectable at day 14 of double treatment, using subcutaneous AG. Our findings favor a role for ED1+ macrophages and iNOS in the hypertension-induced denervation process.

Animals↗
PubMed2006

Trypanosoma cruzi infection and/or administration of the nonsteroidal anti-inflammatory nimesulide increase the number of colonic crypts overexpressing metallothioneins in rat colon carcinogenesis.

Trypanosoma cruzi infection and nonsteroidal anti-inflammatory drugs inhibit colorectal carcinogenesis by mechanisms not completely known and metallothionein proteins (MTs) may be involved in this process. Sixty-six male Wistar rats weighing 90 to 120 g were randomly divided into seven groups (GI to GVII). GI, GII and GIII animals were subcutaneously infected with 200,000 trypomastigote forms of the Y strain of T. cruzi. After 8 weeks, GI, GII, GIV, and GVI were injected with one weekly subcutaneous dose of 12 mg/kg dimethylhydrazine for 4 weeks. In sequence, GI, GIV and GV were treated with nimesulide (10 mg/kg per dose, five times per week for 8 weeks). Groups I, III, IV, and VI had 12 animals, and each of the other groups had 6 animals. All the animals were euthanized 8 weeks after the last dimethylhydrazine injection. The colons were fixed and processed for MT immunohistochemistry. The index of MT-overexpressing colonic crypts (MTEC) was estimated as the percentage of MT-stained crypts in relation to the total number of crypts scored. Five hundred crypts per animal were scored. Data were analyzed by the Kruskal-Wallis test followed by the Dunn test. There was an increase in MTEC index in the groups either infected with T. cruzi or treated with nimesulide or both infected and treated when compared to control (401, 809, and 1011%, respectively). We suggest that the increased formation of MTEC may be related to the protection against carcinogenesis provided both by T. cruzi infection and nimesulide.

Animals↗
PubMed2006

A model of hemorrhagic cystitis induced with acrolein in mice.

Acrolein is a urinary metabolite of cyclophosphamide and ifosfamide, which has been reported to be the causative agent of hemorrhagic cystitis induced by these compounds. A direct cytotoxic effect of acrolein, however, has not yet been demonstrated. In the present study, the effects of intravesical injection of acrolein and mesna, the classical acrolein chemical inhibitor, were evaluated. Male Swiss mice weighing 25 to 35 g (N = 6 per group) received saline or acrolein (25, 75, 225 microg) intravesically 3, 6, 12, and 24 h before sacrifice for evaluation of bladder wet weight, macroscopic and histopathological changes by Gray's criteria, and 3 and 24 h for assessment of increase in vascular permeability. In other animals, mesna was administered intravesically (2 mg) or systemically (80 mg/kg) 1 h before acrolein. Intravesical administration of acrolein induced a dose- and time-dependent increase in vascular permeability and bladder wet weight (within 3 h: 2.2- and 21-fold increases in bladder wet weight and Evans blue dye exuded, respectively, at doses of 75 microg/bladder), as confirmed by Gray's criteria. Pretreatment with mesna (2-mercaptoethanesulfonic acid), which interacts with acrolein resulting in an inactive compound, inhibited all changes induced by acrolein. Our results are the first demonstration that intravesical administration of acrolein induces hemorrhagic cystitis. This model of acrolein-induced hemorrhagic cystitis in mice may be an important tool for the evaluation of the mechanism by which acrolein induces bladder lesion, as well as for investigation of new uroprotective drugs.

Acrolein↗
PubMed2006

Neutrophil function in severe sepsis.

Sepsis and septic shock continue to be a major cause of morbidity and mortality in critically ill patients. During the onset of sepsis, several inflammatory mediators, including cytokines, chemokines and nitric oxide are released systemically and mediate most of the pathophysiological events present in sepsis and septic shock, such as cardiovascular dysfunction and target-organ lesions. Polymorphonuclear leukocytes are critical effector cells during the inflammatory process and their migration to the infection focus is extremely important for the local control of bacterial growth and consequently for the prevention of bacterial dissemination. In experimental models and in human sepsis a profound failure of neutrophil migration to the infection focus is observed. It seems that the failure of neutrophil migration is dependent on toll-like receptor 4 (TLR4) and mediated by cytokines and chemokines, which induce the production of nitric oxide that inhibits neutrophil adhesion to venular endothelium and also the neutrophil chemotactic ability.

Animals↗