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Fernando Q Cunha

Publications and source records attributed to Fernando Q Cunha.

At least 37 records · Page 2Linked to original sources
PubMed2006

Neutrophil recruitment in immunized mice depends on MIP-2 inducing the sequential release of MIP-1alpha, TNF-alpha and LTB(4).

Neutrophils are thought to play an important role in the tissue damage observed in various autoimmune diseases. Chemokines, cytokines and leukotrienes have recognized roles in the orchestration of neutrophil migration. We have recently shown that antigen-induced neutrophil migration into the peritoneum of immunized mice is mediated by macrophage-inflammatory protein (MIP)-1alpha which interacts with CCR1 and induces the sequential release of TNF-alpha and leukotriene B(4) (LTB(4)). The present study investigates the role of MIP-2 and CXCR2 in the cascade of events leading to mediator generation and neutrophil influx. Antigen challenge of immunized mice induced the expression of CXCR2 and the production of KC and MIP-2 proteins. Antigen-induced neutrophil migration was inhibited by a CXCR2 receptor antagonist (repertaxin) or an anti-MIP-2 antibody, but not by an anti-KC antibody. Administration of MIP-2 promoted a dose-dependent neutrophil migration in naive mice which was inhibited by repertaxin, anti-TNF-alpha, anti-MIP-1alpha antibodies or by MK886 (leukotriene synthesis inhibitor). MIP-2 administration induced the release of MIP-1alpha, TNF-alpha and LTB(4), and the release of the latter two was inhibited by anti-MIP-1alpha antibody treatment. Our studies highlight the intricate balance between mediator production and action during an immune-mediated inflammatory response and suggest a mediator cascade leading to neutrophil influx following antigen challenge of immunized mice: MIP-2 --> MIP-1alpha --> TNF-alpha --> LTB(4).

Animals↗
PubMed2006

Toll-like receptor 4 signaling leads to neutrophil migration impairment in polymicrobial sepsis.

OBJECTIVE: We have documented an impaired neutrophil migration toward the infectious focus in severe sepsis. This phenomenon appears to be mediated by nitric oxide, the release of which is stimulated by circulating inflammatory cytokines released by immune cells after stimulation by bacteria and/or their products. Toll-like receptor 4 (TLR4) is the major recognition receptor for lipopolysaccharide, a component of Gram-negative bacterial cell walls. In the present study, we investigated whether TLR4 is involved in the failure of neutrophil migration in mice subjected to polymicrobial or Gram-negative sepsis. DESIGN: Controlled animal study. SETTING: University research laboratory. SUBJECTS: Male C3H/HeJ (TLR4-deficient) and C3H/HePas (TLR4-normal) mice. INTERVENTIONS: Mice were subjected to sublethal or lethal polymicrobial sepsis, both induced by cecal ligation and puncture or intraperitoneal polymicrobial inoculation, and subjected to sublethal Gram-negative sepsis induced by intraperitoneal Salmonella typhimurium inoculation (GNI). Survival was monitored for 5 days. In separate experiments, mice were killed 6 hrs after sepsis induction, and intraperitoneal neutrophil migration, bacteremia, lung neutrophil sequestration, and levels of cytokines, chemokines, and nitrate were evaluated. MEASUREMENTS AND RESULTS: TLR4-deficient (C3H/HeJ) mice presented incapacity to promote neutrophil recruitment to the infectious site after sublethal GNI, resulting in high mortality. However, TLR4 signaling is not essential to display neutrophil migration in sublethal polymicrobial sepsis induced by both cecal ligation and puncture and polymicrobial inoculation models, but surprisingly, it is crucial to establish the impairment of neutrophil migration in lethal polymicrobial sepsis, since TLR4-deficient mice that underwent lethal cecal ligation and puncture or polymicrobial inoculation did not present failure of neutrophil migration to infectious focus. As a consequence, these animals presented low bacteremia and a high survival rate and did not display systemic inflammation, determined by high levels of circulating cytokines and lung neutrophil sequestration and chemokine production. CONCLUSION: These results highlight the harmful role of TLR4 signaling in polymicrobial severe sepsis.

Animals↗
PubMed2006

Turbulent flow/low wall shear stress and stretch differentially affect aorta remodeling in rats.

OBJECTIVE: The present investigation was carried out to evaluate the relationship between local hemodynamic forces and intimal and medial remodeling in the proximal and distal segments of the arterial walls of rats in relation to severe infradiaphragmatic stenosis of the aorta. METHODS: Young male rats were divided randomly into an operated group, animals submitted to surgical abdominal aorta stenosis, and a sham-operated group, a control group of animals submitted to sham operation to simulate abdominal aorta stenosis. RESULTS AND CONCLUSIONS: Constricted aortas showed two distinct adaptive remodeling responses to hemodynamic stimuli induced by infradiaphragmatic coarctation. The first is remodeling in the hypertensive prestenotic segment with increased circumferential wall tension (CWT), associated with normal tensile stress, laminar flow/normal wall shear stress characterized by enlarged heterogeneous endothelial cells, elongated in the direction of the blood flow, diffusely distributed neointimal plaques, appearing as discrete bulging towards the vascular lumen and medial thickening. Our findings suggest that increased CWT caused by hypertension play a pivotal role in the remodeling of the prestenotic segment through biomechanical effects on oxidative stress and increased expression of transforming growth factor beta. The second is remodeling in the normotensive poststenotic segment with turbulent flow/low wall shear stress and normal CWT and tensile stress characterized by groups of endothelial cells with phenotypic alterations and focally distributed neointimal plaques, similar but many of them larger than those found in the prestenotic segments. Further studies are needed to determine how the mechanical forces of turbulent flow/low shear stress are detected and transduced into chemical signaling by the cells of the artery walls and then converted into pathophysiologically relevant phenotypic changes.

Adaptation, Physiological↗
PubMed2006

Anti-inflammatory and anti-nociceptive activity of risedronate in experimental pain models in rats and mice.

1. The antinociceptive effect of risedronate in experimental pain models in rats and mice was investigated in the present study. 2. Rats received zymosan intra-articularly (i.art.) into the right knee joint and the nociceptive response was assessed using the articular incapacitation test. Joint washouts were used for determining cell influx, tumour necrosis factor (TNF)-alpha and leukotriene (LT) B4 levels. 3. Mice received either zymosan (1 mg) or acetic acid (0.6%) i.p. and the nociceptive response was measured as the number of writhings between 0 and 30 min after the stimuli. Control animals received i.p. injections of saline. 4. Groups were pretreated with risedronate (5-500 microg/kg, s.c.) and compared with vehicle (saline)-treated (NT) animals. One group of rats was cotreated with the micro-opioid receptor antagonist naloxone (2 mg/kg, s.c.) prior to risedronate, followed by 1 mg zymosan i.art. 5. Risedronate, at 100 and 500 microg/kg, significantly and dose-dependently inhibited the nociceptive response in the writhings test (P < 0.05), inhibiting responses to acetic acid by 65.4 and 49.2%, respectively, and to zymosan by 72.9 and 71.9%, respectively. 6. Pretreatment with risedronate also significantly (P < 0.05) and dose-dependently inhibited the articular incapacitation in zymosan-arthritis. 7. Risedronate, at 50 microg/kg, significantly inhibited TNF-alpha release as compared with the NT group (39.4 +/- 9.8 vs 145.6 +/- 43.3 pg/mL TNF-alpha, respectively). 8. Risedronate, at 50 and 100 microg/kg, significantly inhibited LTB4 release into the joints compared with the NT group (2883.1 +/- 73.2, 1911.5 +/- 205.3 and 4709.9 +/- 237.2 pg/mL, respectively). These effects of risedronate were associated with a significant reduction in the inflammatory cell infiltration. 9. Cotreatment with risedronate and naloxone did not reverse the antinociceptive effects of risedronate in zymosan-arthritis. 10. This is the first demonstration that risedronate displays intrinsic antihypernociceptive activity. This effect is associated with reduced cell infiltration and inhibition of TNF-alpha and LTB4 release and is not linked to an endogenous opioid-release mechanism.

Acetic Acid↗
PubMed2006

Peripheral antinociceptive effect of pertussis toxin: activation of the arginine/NO/cGMP/PKG/ ATP-sensitive K channel pathway.

The aim of the present study was to determine the effect of pertussis toxin (PTX) on inflammatory hypernociception measured by the rat paw pressure test and to elucidate the mechanism involved in this effect. In this test, prostaglandin E(2) (PGE(2)) administered subcutaneously induces hypernociception via a mechanism associated with neuronal cAMP increase. Local intraplantar pre-treatment (30 min before), and post-treatment (5 min after) with PTX (600 ng/paw1, in 100 microL) reduced hypernociception induced by prostaglandin E(2) (100 ng/paw, in 100 microL, intraplantar). Furthermore, local intraplantar pre-treatment (30 min before) with PTX (600 ng/paw, in 100 microL) reduced hypernociception induced by DbcAMP, a stable analogue of cAMP (100 microg/paw, in 100 microL, intraplantar), which indicates that PTX may have an effect other than just G(i)/G(0) inhibition. PTX-induced analgesia was blocked by selective inhibitors of nitric oxide synthase (L-NMMA), guanylyl cyclase (ODQ), protein kinase G (KT5823) and ATP-sensitive K(+) channel (Kir6) blockers (glybenclamide and tolbutamide). In addition, PTX was shown to induce nitric oxide (NO) production in cultured neurons of the dorsal root ganglia. In conclusion, this study shows a peripheral antinociceptive effect of pertussis toxin, resulting from the activation of the arginine/NO/cGMP/PKG/ATP-sensitive K(+) channel pathway.

Adenosine Triphosphate↗
PubMed2005

Failure of neutrophil chemotactic function in breast cancer patients treated with chemotherapy.

Neutrophil migration is a key host event against infection. Chemotherapy may alter neutrophil function and favor increased risk of infection. Herein, we investigated the effect of chemotherapy on the migration capacity of circulating neutrophils obtained from breast cancer patients and mechanisms involved in this event. Breast cancer women (n=23) at disease stage I-III and healthy control women (n=25) were prospectively enrolled. No differences in the in vitro migratory responses towards the chemotactic stimuli N-formyl- L-methionyl- L-leucyl- L-phenylalanine (fMLP), leukotriene B(4) (LTB(4)) and interleukin (IL)-8 were observed in purified neutrophils from controls and patients, in a microchemotaxis chamber assay. However, the migration capacity evaluated upon chemotherapy (5-fluoruracil, adriamycin and cyclophosphamide, 21-day intervals between cycles, total leukocyte count >/=2,000/mm(3)), on the day immediately before the beginning of the sixth cycle, showed that patient neutrophils (n=14) failed to migrate in response to fMLP compared to response observed upon diagnosis. Considering patients (n=8) with documented bacterial infection between cycles, the number of migrated neutrophils (mean+/-SD) compared to response at diagnosis was markedly reduced upon chemotherapy to either fMLP (30.1+/-8.26 vs. 2.81+/-1.28) or LTB(4) (15.72+/-4.8 vs. 2.8+/-1.64) stimuli respectively. Treatment of control neutrophils with sera of chemotherapy-treated patients with infective episodes, to test for the presence of circulating immunosuppressive factors, significantly reduced the migratory capacity of healthy neutrophils to fMLP, LTB(4) and IL-8, in a dose-dependent way. But no significant differences were found in the serum levels of nitric oxide (NO) metabolites, tumor necrosis factor (TNF)-alpha, IL-6, IL-8 and IL-10 collected at the same time as the collection of blood for neutrophil migration experiments. In conclusion, breast cancer patients showed suppressed neutrophil migratory response upon chemotherapy, accompanied by bacterial infection episodes. Circulating factors are involved, at least partially, in the inhibitory mechanism on neutrophil migration.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2005

Nociceptive effect of subcutaneously injected interleukin-12 is mediated by endothelin (ET) acting on ETB receptors in rats.

Interleukin-12 (IL-12) is an inflammatory Th1-driving cytokine that has been clinically used as immune therapy and vaccine adjuvant. Recently, it was reported that patients receiving IL-12 presented hyperalgesia. In the present study, we investigated the mechanical hyperalgesic effect of IL-12 in rats using two tests: 1) paw constant pressure and 2) electronic pressure-meter. In both tests, intraplantar administration of IL-12 (3-30 ng paw(-1)) caused a dose- and time-dependent mechanical hyperalgesia, which peaked between 3 to 5 h, remaining significantly different from control levels until 7 h and resolved 24 h postinjection. However, the same doses of IL-12 did not induce thermal hyperalgesia, determined using the Hargreaves test. Pretreatments with effective doses of indomethacin (2.5 mg kg(-1)), atenolol (1 mg kg(-1)), 3-[1-(p-chlorobenzyl)-5-(isopropyl)-3-t-butylthioindol-2-yl]-2,2-dimethylpropanoic acid, sodium (MK886) (5-lipoxygenase activating protein inhibitor; 1 mg kg(-1)), or cyclo[(D)Trp-(D)Asp-Pro-(D)Val-Leu] (BQ123) [endothelin (ET)(A) receptor antagonist; 30 nmol paw(-1)] did not inhibit IL-12-evoked mechanical hyperalgesia (10 ng paw(-1)). However, dexamethasone (2 mg kg(-1)), morphine (3-12 microg paw(-1)), and N-cys-2,6 dimethylpiperidinocarbonyl-L-gamma-methylleucyl-D-1-methoxycarboyl-d-norleucine (BQ788) (ET(B) receptor antagonist; 3-30 nmol paw(-1)) did inhibit IL-12 hyperalgesia. Furthermore, neither pretreatment with effective doses of antiserum against rat-TNF-alpha (50 microl paw(-1)) nor against IL-18 (10 microg paw(-1)) inhibited the IL-12-induced hyperalgesia. Likewise, antiserum against IL-12 (10 ng paw(-1)) did not alter IL-18-induced hyperalgesia. In conclusion, we demonstrated for the first time that IL-12 is a prohyperalgesic cytokine that induces mechanical hyperalgesia mediated by endothelin action on the ET(B) receptor. Therefore, endothelin receptor antagonism could be beneficial in controlling IL-12 therapy-induced pain or hyperalgesia.

Analgesics↗
PubMed2005

Failure of neutrophil migration toward infectious focus in severe sepsis: a critical event for the outcome of this syndrome.

Sepsis is a systemic inflammatory response commonly caused by bacterial infection. We demonstrated that the outcome of sepsis induced by cecal ligation and puncture (CLP) correlates with the severity of the neutrophil migration failure towards infectious focus. Failure appears to be due to a decrease in the rolling and adhesion of neutrophil to endothelium cells. It seems that neutrophil migration impairment is mediated by the circulating inflammatory cytokines, such as TNF-alpha and IL-8, which induce the nitric oxide (NO) production systemically. It is supported by the fact that intravenous administration of these cytokines reduces the neutrophil migration induced by different inflammatory stimuli, and in severe sepsis the circulating concentrations of the cytokines and chemokines are significantly increased. Moreover, the neutrophil migration failure and the reduction in the rolling/adhesion were not observed in iNOS-/- mice and, aminoguanidine prevented this event. We also demonstrated that the failure of neutrophil migration is a Toll-4 receptor (TLR4) dependent mechanism, since it was not observed in TLR4 deficient mice. Furthermore, it was also observed that circulating neutrophils obtained from septic patients present failure of neutrophil chemotaxis toward fMLP, IL-8, and LTB4 and an increased in sera concentrations of NO3 and cytokines. In conclusion, we demonstrated that, in sepsis, failure of neutrophil migration is critical for the outcome and that NO is involved in the process.

Animals↗
PubMed2005

MIP-1alpha[CCL3] acting on the CCR1 receptor mediates neutrophil migration in immune inflammation via sequential release of TNF-alpha and LTB4.

In the present study, we investigated the involvement of macrophage-inflammatory protein-1alpha (MIP-1alpha)[CC chemokine ligand 3 (CCL3)], MIP-1beta[CCL4], regulated on activation, normal T expressed and secreted (RANTES)[CCL5], and CC chemokine receptors (CCRs) on neutrophil migration in murine immune inflammation. Previously, we showed that ovalbumin (OVA)-triggered neutrophil migration in immunized mice depends on the sequential release of tumor necrosis factor alpha (TNF-alpha) and leukotriene B(4)(LTB(4)). Herein, we show increased mRNA expression for MIP-1alpha[CCL3], MIP-1beta[CCL4], RANTES[CCL5], and CCR1 in peritoneal cells harvested from OVA-challenged, immunized mice, as well as MIP-1alpha[CCL3] and RANTES[CCL5] but not MIP-1beta[CCL4] proteins in the peritoneal exudates. OVA-induced neutrophil migration response was muted in immunized MIP-1alpha[CCL3](-/-) mice, but it was not inhibited by treatment with antibodies against RANTES[CCL5] or MIP-1beta[CCL4]. MIP-1alpha[CCL3] mediated neutrophil migration in immunized mice through induction of TNF-alpha and LTB(4) synthesis, as these mediators were detected in the exudates harvested from OVA-challenged immunized wild-type but not MIP-1alpha[CCL3](-/-) mice; administration of MIP-1alpha[CCL3] induced a dose-dependent neutrophil migration, which was inhibited by treatment with an anti-TNF-alpha antibody in TNF receptor 1 (p55(-/-))-deficient mice or by MK 886 (a 5-lipoxygenase inhibitor); and MIP-1alpha[CCL3] failed to induce LTB(4) production in p55(-/-) mice. MIP-1alpha[CCL3] used CCR1 to promote neutrophil recruitment, as OVA or MIP-1alpha[CCL3] failed to induce neutrophil migration in CCR1(-/-) mice, in contrast to CCR5(-/-) mice. In summary, we have demonstrated that neutrophil migration observed in this model of immune inflammation is mediated by MIP-1alpha[CCL3], which via CCR1, induces the sequential release of TNF-alpha and LTB(4). Therefore, whether a similar pathway mediates neutrophil migration in human immune-inflammatory diseases, the development of specific CCR1 antagonists might have a therapeutic potential.

Animals↗
PubMed2005

HPV16, HPV18, and HIV infection may influence cervical cytokine intralesional levels.

Infection with oncogenic human papillomavirus (HPV) is considered to be the major risk to cervical cancer. This study analyzed the influence of HPV infection on cytokine intralesional levels in cervical lesion in the presence or not of HIV infection. Cervical biopsies from 42 women were studied. HPV detection and typing were performed using amplified DNA hybridized with sequence-specific primers, and cytokine intralesional levels were detected using ELISA. HPV16+ biopsies exhibited increased IFN-gamma and IL-10 when compared to HPV16- (P = 0.03 and 0.04, respectively). HPV18+ biopsies exhibited decreased TNF-alpha (P = 0.009) and IFN- gamma (P = 0.01) when compared to HPV18-. In accordance to HIV status, HIV-/HPV16+ patients exhibited increased IFN-gamma when compared to those presenting HIV-/HPV16- (P = 0.007). HIV-/HPV18+ patients presented decreased IFN-gamma when compared to HIV-/HPV18- (P = 0.02). These results suggest that the presence of HPV16 infection may influence cervical lesion installation, and irrespective of HIV status, HPV18 infection may be more aggressive than HPV-16.

Adolescent↗
PubMed2005

Opposing and hierarchical roles of leukotrienes in local innate immune versus vascular responses in a model of sepsis.

The 5-lipoxygenase (5-LO)-derived leukotrienes (LTs) influence both local innate immunity and vascular responses, but the relative importance of effects on these two processes in sepsis is unknown. In a cecal ligation and puncture model of peritonitis with severe sepsis, 5-LO(-/-) mice showed a reduction in peritoneal neutrophil accumulation and an increase in the number of bacteria in the peritoneal cavity. Despite this impairment of local innate immunity, the null mice exhibited a marked improvement in survival, and this protection was also seen in wild-type animals treated with the LT synthesis inhibitor MK 886. A survival advantage in severe sepsis was also observed in mice treated with the cysteinyl-LT receptor antagonist MK 571, but not with the LTB(4) receptor antagonist CP 105, 696. Protection in the 5-LO(-/-) mice was associated with reduced vascular leak and serum lactate levels. Moreover, wild-type mice treated with MK 571 exhibited less sepsis-induced hypotension. These data demonstrate opposing effects of cysteinyl-LTs on innate immune vs hemodynamic responses, demonstrating protective effects on local immunity and deleterious effects on the vasculature. They also suggest the possible therapeutic utility of targeting vascular events in sepsis with cysteinyl-LT blockade.

Acidosis, Lactic↗
PubMed2005

Effect of salivary gland extract of Leishmania vector, Lutzomyia longipalpis, on leukocyte migration in OVA-induced immune peritonitis.

Salivary gland extracts (SGE) from Lutzomyia longipalpis potentate L. major infection by inducing a Th2 immune response. However, the effect of SGE on the effector phase of immune response is not known. Herein, we demonstrate that SGE inhibited neutrophil migration in ovalbumin (OVA)-induced peritonitis in immunized mice. SGE pretreatment of mice inhibited OVA-induced CD4+ and CD8+ T lymphocyte migration. The OVA-induced production of TNF-alpha, IL-1beta and leukotriene B4 (LTB4), neutrophil chemotactic mediators in this model, were inhibited by SGE. On the other hand, SGE enhanced production of IL-10 and IL-4. In naive mice, SGE also blocked LTB4-induced neutrophil migration, but not that induced fMLP. Moreover, co-incubation of LTB4 (but not fMLP, TNF-alpha and MIP-1alpha) with SGE inhibited the ability of LTB4 to induce neutrophil migration in vivo and in vitro. Altogether, the results suggest that SGE has anti-inflammatory properties that are associated with inhibition of TNF-alpha and LTB4 production and/or with the neutrophil chemotactic activity of LTB4. The effectiveness of SGE in inhibiting neutrophil migration and inflammatory mediators release in a Th1 immune inflammatory response model reinforces the need for isolation of the compounds responsible for these activities, which could be used as prototypes for the development new anti-inflammatory drugs.

Animals↗
PubMed2005

Sildenafil prevents indomethacin-induced gastropathy in rats: role of leukocyte adherence and gastric blood flow.

Nitric oxide (NO) is an important mediator of gastric mucosal defense. Sildenafil (SILD), a cyclic GMP-specific phosphodiesterase inhibitor, promotes an increase in cGMP concentrations in the gastrointestinal tract. cGMP mediates many of the biological actions of NO. We tested the hypothesis that SILD could increase mucosal defense against indomethacin-induced gastropathy in rats. SILD (1, 4 or 10 mg kg(-1), p.o.) pretreatment significantly reduced (P < 0.01) the gastric damage and the increase in gastric myeloperoxidase (MPO) activity elicited by indomethacin (20 mg kg(-1) p.o.), with the maximal effect at the dose of 10 mg kg(-1). L-NAME (3, 10 or 20 mg kg(-1), i.p.) dose dependently reversed the protective effects of SILD, an effect not seen when L-arginine (L-ARG) (200 mg kg(-1), i.p.) was co-administered with L-NAME. Indomethacin-induced leukocyte adhesion, assessed by intravital microscopy, was decreased (P < 0.01) by SILD, and this effect was reversed by L-NAME cotreatment. Indomethacin elicited a decrease in gastric blood flow and in gastric PGE2 levels. SILD was able to prevent the decrease in gastric blood flow (P < 0.01), without diminishing the inhibitory effect of indomethacin on prostaglandin synthesis. These results indicate that SILD, acting via NO-dependent mechanisms, prevents indomethacin-induced gastropathy, possibly through a reduction of leukocyte adhesion and maintenance of gastric blood flow.

Animals↗
PubMed2005

Glutamine depletion potentiates leucocyte-dependent inflammatory events induced by carrageenan or Clostridium difficile toxin A in rats.

This research investigated the effect of glutamine (Gln) depletion on leucocyte-dependent inflammatory events. Rats were treated intraperitoneally, 16 hr prior to the peak of every parameter evaluated, with either 0.9% NaCl, methionine-sulphoximine (MSO, an inhibitor of endogenous Gln synthesis, 25 mg/kg) or with MSO + Gln (MSO as above plus Gln 3 g/kg in three doses). MSO-induced Gln depletion increased paw oedema induced both by carrageenan (Cg) and by Clostridium difficile toxin A (TxA) (66.2% and 45.5%, respectively; P < 0.05). In dextran-injected animals, oedema and myeloperoxidase (MPO) activity were not modified by Gln depletion. In Cg-treated paws, Gln depletion increased MPO activity by 44% (P < 0.05), interleukin-1beta (IL-1beta) and tumour necrosis factor-alpha (TNF-alpha) concentrations by 47% and 52%, respectively (P < 0.05), and immunostaining for TNF-alpha in paw tissue. In TxA-injected paws, Gln depletion increased MPO activity (46%; P < 0.05). Gln depletion increased Cg- and TxA-induced neutrophil migration to subcutaneous air pouches by 56% and 77% (P < 0.05), respectively, but did not affect migration induced by N-formyl-methionyl-leucyl-phenylalanine (fMLP). Gln infusions reversed all the effects of MSO. Leucocyte counts did not differ between groups. Gln depletion potentiates acute inflammation, possibly by increasing neutrophil migration through resident cell activation and production of IL-1beta and TNF-alpha. Gln supplementation reverses these effects and may be useful during inflammatory catabolic stress.

Animals↗
PubMed2005

The ATP-sensitive potassium channel blocker glibenclamide prevents renal ischemia/reperfusion injury in rats.

BACKGROUND: Renal ischemia/reperfusion (I/R) is a complex neutrophil-mediated syndrome. Adenosine-triphosphate (ATP)-sensitive potassium (K(ATP)) channels are involved in neutrophil migration in vivo. In the present study, we have investigated the effects of glibenclamide, a K(ATP) channel blocker, in renal I/R injury in rats. METHODS: The left kidney of the rats was excised through a flank incision and ischemia was performed in the contralateral kidney by total interruption of renal artery flow for 45 minutes. Renal perfusion was reestablished, and the kidney and lungs were removed for analysis of vascular permeability, neutrophil accumulation, and content of cytokines [tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, and IL-10] 4 and 24 hours later. Renal function was assessed by measuring creatinine, Na(+), and K(+) levels in the plasma and by determination of creatinine clearance. Drugs were administered subcutaneously after the onset of ischemia. RESULTS: Reperfusion of the ischemic kidney induced local (kidney) and remote (lung) inflammatory injury and marked renal dysfunction. Glibenclamide (20 mg/kg) significantly inhibited the reperfusion-associated increase in vascular permeability, neutrophil accumulation, increase in TNF-alpha levels and nuclear factor-kappaB (NF-kappaB) translocation. These inhibitory effects were noticed in the kidney and lungs. Moreover, glibenclamide markedly ameliorated the renal dysfunction at 4 and 24 hours. CONCLUSION: Treatment with glibenclamide is associated with inhibition of neutrophil recruitment and amelioration of renal dysfunction following renal I/R. Glibenclamide may have a therapeutic role in the treatment of renal I/R injury, such as after renal transplantation.

Adenosine Triphosphate↗
PubMed2004

Antihyperalgesic effect of pentoxifylline on experimental inflammatory pain.

The antihyperalgesic effect of pentoxifylline was investigated in three experimental pain models. Pentoxifylline (0.5-1.6 mg kg(-1)) given 30 min before the stimulus significantly inhibited the writhing response induced by the intraperitoneal (i.p.) administration of either acetic acid (-90%) or zymosan (-83%), but not that of iloprost, in mice, as well as the zymosan-induced articular hyperalgesia in the zymosan arthritis in rats (-50%). Pentoxifylline also inhibited the mechanical hypernociception in rats induced by the intraplantar injection of either carrageenin (-81%), bradykinin (-56%) or tumor necrosis factor alpha (TNF-alpha; -46%), but not that induced by interleukin-1beta (IL-1beta) or prostaglandin E(2) (PGE(2)). Pentoxifylline did not inhibit the nociceptive response in the hot plate test in mice. Further, the antinociceptive effect of pentoxifylline in the writhing test in mice and the zymosan-induced articular hyperalgesia were not reversed by the coadministration of the opioid receptor antagonist naloxone. Thus, pentoxifylline antinociceptive effect is probably not mediated at a central level. Pentoxifylline significantly reduced TNF-alpha (-43%) and IL-1beta (-42%) concentrations in the joint exudates of rats stimulated by intra-articular injection of zymosan and the production of both cytokines (-66 and -86%, respectively) by mouse peritoneal macrophages stimulated in vivo with zymosan as well as the expression of TNF-alpha at the tissue level in carrageenin-injected rat paws. In conclusion, the antinociceptive activity of pentoxifylline is associated with the inhibition of the release of both TNF-alpha and IL-1beta.

Acetic Acid↗
PubMed2004

Induction of bone-marrow eosinophilia in mice submitted to surgery is dependent on stress-induced secretion of glucocorticoids.

1 We examined bone-marrow in mice receiving subcutaneous implants of heat-coagulated egg white, which are known to present chronic eosinophilic inflammation at the implant site. Egg white implants (EWIs) induced marked bone-marrow eosinophilia, and increased bone-marrow cell responses to granulocyte-macrophage colony-stimulating factor and interleukin-5 in culture. These effects were observed as early as 24 h and lasted for, at least, 30 days in implant recipients. 2 We found, however, that increased eosinophil production was also observed in control mice which underwent surgery but received no EWI (sham-implanted mice), up to 15 days post-surgery. As this suggests an important contribution of nonspecific stress mechanisms to eosinopoiesis, we further evaluated the role of stress hormones produced by the adrenal glands in the bone-marrow eosinophilia of sham-implanted mice. 3 Bone-marrow eosinophilia in mice undergoing surgery was dissociated from increases in other haemopoietic lineages. Surgery by itself increased circulating corticosterone levels by 24 h, and the increase was prevented by inhibition of adrenal glucocorticoid production by metyrapone. The effect of surgery on bone-marrow eosinophilia was prevented by pretreatment with both the glucocorticoid receptor antagonist, mifepristone, and metyrapone, and by surgical adrenalectomy. 4 By contrast, cathecolamine receptor antagonists (propranolol, prazosin and yohimbine) were ineffective, indicating that cathecolamine release from the adrenal glands was not responsible for the effects on bone-marrow. 5 These results highlight a critical role for stress-induced glucocorticoid hormones in selectively upregulating bone-marrow eosinopoiesis in mice submitted to surgery.

Adrenal Glands↗