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Fernando Q Cunha

Publications and source records attributed to Fernando Q Cunha.

53 records · Page 3Linked to original sources
PubMed2004

Repertaxin, a novel inhibitor of rat CXCR2 function, inhibits inflammatory responses that follow intestinal ischaemia and reperfusion injury.

1. Neutrophils are thought to play a major role in the mediation of reperfusion injury. CXC chemokines are known inducers of neutrophil recruitment. Here, we assessed the effects of Repertaxin, a novel low molecular weight inhibitor of human CXCL8 receptor activation, on the local, remote and systemic injuries following intestinal ischaemia and reperfusion (I/R) in the rat. 2. Pre-incubation of rat neutrophils with Repertaxin (10(-11)-10(-6) m) inhibited the chemotaxis of neutrophils induced by human CXCL8 or rat CINC-1, but not that induced by fMLP, PAF or LTB(4), in a concentration-dependent manner. Repertaxin also prevented CXCL8-induced calcium influx but not CXCL8 binding to purified rat neutrophils. 2. In a model of mild I/R injury (30 min of ischaemia and 30 min of reperfusion), Repertaxin dose-dependently (3-30 mg kg(-1)) inhibited the increase in vascular permeability and neutrophil influx. Maximal inhibition occurred at 30 mg kg(-1). 4. Following severe I/R injury (120 min of ischaemia and 120 min of reperfusion), Repertaxin (30 mg kg(-1)) markedly prevented neutrophil influx, the increase in vascular permeability both in the intestine and the lungs. Moreover, there was prevention of haemorrhage in the intestine of reperfused animals. 5. Repertaxin effectively suppressed the increase in tissue (intestine and lungs) and serum concentrations of TNF-alpha and the reperfusion-associated lethality. 6. For comparison, we also evaluated the effects of an anti-CINC-1 antibody in the model of severe I/R injury. Overall, the antibody effectively prevented tissue injury, systemic inflammation and lethality. However, the effects of the antibody were in general of lower magnitude than those of Repertaxin. 7. In conclusion, CINC-1 and possibly other CXC chemokines, acting on CXCR2, have an important role during I/R injury. Thus, drugs, such as Repertaxin, developed to block the function of the CXCR2 receptor may be effective at preventing reperfusion injury in relevant clinical situations.

Animals↗
PubMed2004

Tumour necrosis factor-alpha mediates neutrophil migration to the knee synovial cavity during immune inflammation.

Tumour necrosis factor (TNF)-alpha, interleukin-1beta, interleukin-8 and leukotriene B4 have an important role on neutrophil recruitment during immune-inflammation. Here we evaluated the participation of several inflammatory mediators on ovalbumin-induced neutrophil recruitment in the knee articular space of immunized rats. Ovalbumin administration in immunized, but not in control, rats induced a dose- and time-dependent neutrophil accumulation, which was inhibited by dexamethasone, pentoxifylline or thalidomide, but not by selective inhibitors of nitric oxide (nitro-L-arginine), platelet-activating factor (BN50730 or UK74505), prostaglandins (indomethacin), histamine (meclisine) or leukotriene B4 (MK 886 and CP105,696). Anti-TNF-alpha antiserum, but not anti-interleukin-1beta or anti-CINC-1 (cytokine-induced neutrophil chemoattractant 1) antisera, impaired ovalbumin-induced neutrophil accumulation. High amounts of TNF-alpha were detected in the exudates, which was inhibited by dexamethasone, pentoxifylline and thalidomide. These results suggest a specific role for TNF-alpha in this model, and the ability of pentoxifylline and thalidomide to inhibit both neutrophil influx and TNF-alpha release may have therapeutic implications in arthritis.

Animals↗
PubMed2004

Interleukin-18 induces mechanical hypernociception in rats via endothelin acting on ETB receptors in a morphine-sensitive manner.

Interleukin (IL)-18 has an important role in the pathogenesis of arthritis, which is accompanied by movement limitation secondary to inflammatory articular nociception. Therefore, we investigated the possible mechanical hypernociceptive effect of IL-18 in rats using the paw constant pressure and the electronic pressure-meter tests. In both tests, intraplantar administration of IL-18 (20-60 ng paw(-1)) caused a dose- and time-dependent mechanical hypernociception, which peaked 3 h and reached control levels 24 h after injection. Pretreatments with indomethacin (2.5 mg kg(-1)), atenolol (1 mg kg(-1)), or 3-[1-(p-chlorobenzyl)-5-(isopropyl)-3-t-butylthioindol-2-yl]-2;2-dimethylpropanoic acid; Na (MK886) (5-lipoxygenase-activating protein inhibitor; 1 mg kg(-1)) did not inhibit IL-18-evoked hypernociception (40 ng paw(-1)), whereas dexamethasone (2 mg kg(-1)) inhibited the process. IL-18-evoked hypernociception was not inhibited by pretreatment with antiserum to rat tumor necrosis factor-alpha (50 microl paw(-1)) or IL-1 receptor antagonist (300 pg paw(-1)). Pretreatment with N-cys-2,6 dimethylpiperidinocarbonyl-l-gamma-methylleucyl-d-1-methoxycarboyl-d-norleucine (BQ788) (ET(B) receptor antagonist; 3-30 nmol paw(-1)), but not with cyclo[(D)Trp-(D)Asp-Pro-(D)Val-Leu] (BQ123) (ET(A) receptor antagonist; 30 nmol paw(-1)), dose dependently inhibited the IL-18-induced hypernociception. Pretreatment with morphine (3-12 microg paw(-1)) also dose-dependently inhibited the IL-18-induced hypernociception. Moreover, endothelin-1-induced mechanical hypernociception also was inhibited by BQ788, but not by BQ123, indomethacin, or atenolol. In conclusion, we demonstrated for the first time that IL-18 is a prohypernociceptive cytokine that induces mechanical hypernociception mediated by endothelin, via ET(B) receptor. Therefore, inhibition of the endothelin ET(B) receptor could be beneficial on controlling inflammatory hypernociception of diseases in which IL-18 plays a role in their pathogenesis.

Animals↗
PubMed2004

Peripheral analgesic blockade of hypernociception: activation of arginine/NO/cGMP/protein kinase G/ATP-sensitive K+ channel pathway.

The final step in the direct restoration of the nociceptor threshold by peripheral administration of morphine and dipyrone was recently suggested to result from the opening of ATP-sensitive K(+) channels (K(ATP)(+)). This channel is known to be open either directly by cGMP or indirectly via protein kinase G (PKG) stimulation. In the present study, it was shown that the blockade was caused by a specific PKG inhibitor (KT5823) of the antinociceptive effect of morphine and dipyrone on acute hypernociception and of dipyrone on persistent hypernociception. It was also shown that, in both models, KT5823 prevented the peripheral antinociceptive effect of an analogue of cGMP, the nitric oxide (NO) donor (S-nitroso-n-acetyl-d,l-penicilamine). However, in acute hypernociception, KT5823 did not prevent the peripheral antinociceptive effect of diazoxide (a direct K(ATP)(+) opener). In persistent hypernociception, the sensitization plateau was induced by daily injections of prostaglandin E(2) (PGE(2), 100 ng) into the rat paw for 14 days. After cessation of PGE(2) injections, the pharmacological blockade of persistent hypernociception led to a quiescent phase in which a rather small stimulus restored the hypernociceptive plateau. In this phase, glibenclamide (which specifically closes K(ATP)(+)) fully restored persistent hypernociception, as did injection of PGE(2). Thus, the activation of the arginine/NO/cGMP pathway causes direct blockade of acute and persistent hypernociception by opening K(ATP)(+) via the stimulation of PKG. Analgesic stimulators of the neuronal arginine/NO/cGMP/PKG/K(ATP)(+) pathway constitute a previously undescribed well defined class of peripheral analgesics with a mechanism of action different from either glucocorticoids or inhibitors of cyclooxygenases.

Adenosine Triphosphate↗
PubMed2004

Interferon-gamma-induced nitric oxide causes intrinsic intestinal denervation in Trypanosoma cruzi-infected mice.

In this study, the role of nitric oxide (NO) in neuronal destruction during acute-phase Trypanosoma cruzi infection was evaluated in male C57BL/6 (WT, wild-type) mice and knockout mice [inducible nitric oxide synthase (iNOS)(-/-) and interferon (IFN)(-/-)]. Selected animals were infected by intraperitoneal injection of 100 trypomastigote forms of the Y strain of T. cruzi. Others were injected intraperitoneally with an equal volume of saline solution and served as controls. Our findings support those of previous studies regarding myenteric denervation in acute-phase T. cruzi infection. In addition, we clearly demonstrate that, despite the fact that parasite nests and similar inflammatory infiltrate in the intestinal wall were more pronounced in infected iNOS(-/-) mice than in infected WT mice, the former presented no reduction in myenteric plexus neuron numbers. Neuronal nerve profile expression, as revealed by the general nerve marker PGP 9.5, was preserved in all knockout animals. Infected IFN(-/-) mice suffered no significant neuronal loss and there was no inflammatory infiltrate in the intestinal wall. On days 5 and 10 after infection, iNOS activity was greater in infected WT mice than in controls, whereas iNOS activity in infected knockout mice remained unchanged. These findings clearly demonstrate that neuronal damage does not occur in NO-impaired infected knockout mice, regardless of whether inflammatory infiltrate is present (iNOS(-/-)) or absent (IFN(-/-)). In conclusion, our observations strongly indicate that myenteric denervation in acute-phase T. cruzi infection is because of IFN-gamma-elicited NO production resulting from iNOS activation in the inflammatory foci along the intestinal wall.

Animals↗
PubMed2003

Bacterial lipopolysaccharide signaling through Toll-like receptor 4 suppresses asthma-like responses via nitric oxide synthase 2 activity.

Asthma results from an intrapulmonary allergen-driven Th2 response and is characterized by intermittent airway obstruction, airway hyperreactivity, and airway inflammation. An inverse association between allergic asthma and microbial infections has been observed. Microbial infections could prevent allergic responses by inducing the secretion of the type 1 cytokines, IL-12 and IFN-gamma. In this study, we examined whether administration of bacterial LPS, a prototypic bacterial product that activates innate immune cells via the Toll-like receptor 4 (TLR4) could suppress early and late allergic responses in a murine model of asthma. We report that LPS administration suppresses the IgE-mediated and mast cell-dependent passive cutaneous anaphylaxis, pulmonary inflammation, airway eosinophilia, mucus production, and airway hyperactivity. The suppression of asthma-like responses was not due to Th1 shift as it persisted in IL-12(-/-) or IFN-gamma(-/-) mice. However, the suppressive effect of LPS was not observed in TLR4- or NO synthase 2-deficient mice. Our findings demonstrate, for the first time, that LPS suppresses Th2 responses in vivo via the TLR4-dependent pathway that triggers NO synthase 2 activity.

Administration, Inhalation↗
PubMed2003

IL-18 enhances collagen-induced arthritis by recruiting neutrophils via TNF-alpha and leukotriene B4.

IL-18 expression and functional activity have been associated with a range of autoimmune diseases. However, the precise mechanism by which IL-18 induces such pathology remains unclear. In this study we provide direct evidence that IL-18 activates neutrophils via TNF-alpha induction, which drives the production of leukotriene B(4) (LTB(4)), which in turn leads to neutrophil accumulation and subsequent local inflammation. rIL-18 administered i.p. resulted in the local synthesis of LTB(4) and a rapid influx of neutrophils into the peritoneal cavity, which could be effectively blocked by the LTB(4) synthesis inhibitor MK-886 (MK) or its receptor antagonist CP-105,696. IL-18-induced neutrophils recruitment and LTB(4) production could also be blocked by a neutralizing anti-TNF-alpha Ab. In addition, IL-18 failed to induce neutrophil accumulation in vivo in TNFRp55(-/-) mice. In an IL-18-dependent murine collagen-induced arthritis model, administration of MK significantly inhibited disease severity and reduced articular inflammation and joint destruction. Furthermore, MK-886-treated mice also displayed suppressed proinflammatory cytokine production in response to type II collagen in vitro. Finally, we showed that IL-18-activated human peripheral blood neutrophils produced significant amounts of LTB(4) that were effectively blocked by the MK. Together, these findings provide a novel mechanism whereby IL-18 can promote inflammatory diseases.

Adjuvants, Immunologic↗
PubMed2003

TNF-alpha mediates the induction of nitric oxide synthase in macrophages but not in neutrophils in experimental cutaneous leishmaniasis.

Leishmania major infection in C57BL/6 mice is controlled by the activation of a Th1 response and nitric oxide (NO) production by macrophages. TNF-alpha is considered one of the most important cytokines involved in this response. In the present study, we investigated the expression of nitric oxide synthase (iNOS) in the inflammatory cells present in the lesion and draining lymph nodes, and the cytokine production by lymph node cells in animals treated with anti-TNF-alpha. Our results demonstrated that mice treated with anti-TNF-alpha presented an increase in the number of parasites and the size of lesion, but they were able to control the infection. The increase in the lesion size correlated to the reduction of iNOS activity in the draining lymph nodes. Furthermore, the anti-TNF-alpha treatment also reduced the expression of iNOS in the macrophages, but did not affect the iNOS expression in the neutrophils. The anti-TNF-alpha mAb did not reduce the iNOS expression in IFN-gamma-stimulated L. major infected neutrophils in vitro. Anti-TNF-alpha mAb treatment caused an increase in the production of IFN-gamma and IL-10 by the lymph node cells from infected mice. Consequently, these results suggest that neutrophils do not respond to anti-TNF-alpha treatment and might be a source of NO to control L. major infection under these experimental conditions.

Animals↗
PubMed2003

Interleukin 6 concentration in ascitic fluid of cirrhotic patients: relationship with previous episodes of spontaneous bacterial peritonitis.

BACKGROUND: We aimed to determine whether inter-leukin (IL)-6 concentrations in plasma and ascitic fluid from cirrhotic patients with previous episodes of spontaneous bacterial peritonitis (SBP) differred from those with no previous episodes of SBP. METHODS: Cirrhotic patients with ascites were divided into two groups: G1, without previous episodes of SBP (n = 6), and G2, with previous episodes of SBP (n = 6). Patients with chronic heart failure (n = 5) with ascites, without hepatic diseases, were included as controls (G3). IL-6 concentration was determined in ascitic fluid and plasma by enzyme-linked immunosorbent assay (ELISA). A group of healthy subjects (n = 8) was used as a control for the blood IL-6 assay. RESULTS: IL-6 concentration in ascitic fluid was significantly higher in G1 (P < 0.05) than in G2 or G3. No significant difference in plasma IL-6 concentrations was observed between the groups or between each group and the healthy subjects. A significant positive linear correlation (P < 0.002) was observed between IL-6 concentration and total protein in ascitic fluid. CONCLUSIONS: A low concentration of IL-6 in ascitic fluid could predispose cirrhotic patients to SBP.

Ascitic Fluid↗
PubMed2003

The galactose-binding lectin from Vatairea macrocarpa seeds induces in vivo neutrophil migration by indirect mechanism.

To explore the pathways by which lectins induce an inflammatory response, the lectin from Vatairea macrocarpa (VML) seeds was used to induce neutrophil migration in rats. The lectin was shown to cause cell migration, with the effect partially blocked when galactose was added to inhibit lectin activity. Neutrophil migration was also reduced when peritoneal cavity of the animals was depleted of their resident cells beforehand, suggesting that neutrophil migration was mediated by an indirect mechanism. Pre-treatment of rats with thioglycollate increased recruitment of neutrophils while depletion of mast cells by the addition of compound 48/80 had little effect on neutrophil infiltration, suggesting the involvement of macrophages in the inflammatory process induced by the lectin. Inhibition of the cyclooxigenase, leukotriene and PAF activities by indomethacin, MK886 and BN50730, respectively, did not modify the pro-inflammatory effect previously observed. However, dexamethasone and thalidomide significantly reduced the population of neutrophils in the peritoneal cavity after lectin injection. The present study suggests that the effects produced by a galactose-binding lectin do not involve lipoxygenase, cyclooxygenase or PAF mediators that are well known to be involved in the inflammatory process. The blocking actions of dexamethasone and thalidimide suggest that as yet unidentified pro-inflammatory mediators are involved.

Animals↗
PubMed2003

Antinociceptive effects of interleukin-4, -10, and -13 on the writhing response in mice and zymosan-induced knee joint incapacitation in rats.

The antinociceptive effects of interleukin (IL)-4, -10, and -13 were investigated in two different experimental pain models. Our results showed that pretreatment (30 min) with IL-4 (1-5 ng/animal), IL-10 (0.4-10 ng/animal), or IL-13 (0.4-2.5 ng/animal) inhibited the writhing response induced by the i.p. administration of acetic acid (53-89%) or zymosan (63-74%) in mice, and the knee joint incapacitation induced by i.a. injection of zymosan (49-66%) in rats. Neither of the cytokines affected the pain elicited in mice using the hot-plate test. This analgesic effect of IL-4, -10, and -13 was not reversed by the combined pretreatment with the opioid receptor antagonist naloxone. IL-4, -10, or -13 significantly inhibited the release of both tumor necrosis factor (TNF)-alpha (60, 53, and 100%, respectively) and IL-1beta (80, 100, and 100%, respectively) by mice peritoneal macrophages obtained after local (i.p.) injection of zymosan. Antisera against IL-4, -10, and -13 potentiated both the zymosan-induced writhing response and the articular incapacitation. Our results demonstrate that IL-4, -10, and -13 display analgesic activity that is probably not due to endogenous opioid release. This analgesic effect could be related to a peripheral mechanism, probably via the inhibition of the release of the pro-inflammatory cytokines TNF-alpha and IL-1beta by resident peritoneal macrophages.

Acetic Acid↗
PubMed2002

Porcine spermadhesin PSP-I/PSP-II stimulates macrophages to release a neutrophil chemotactic substance: modulation by mast cells.

The complex of porcine seminal plasma heterodimers I and II (PSP-I/PSP-II), which are heterodimers of glycosylated spermadhesins, is the major component of porcine seminal fluid. The proinflammatory and immunostimulatory activities of this spermadhesin complex suggest its participation in modulation of the uterine immune activity that may ensure reproductive success. Spermadhesin PSP-I/PSP-II induced the migration of neutrophils into the peritoneal cavity of rats via activation of resident cells. In the present study, we have investigated the involvement of macrophages and mast cells in the neutrophil chemotactic activity of PSP-I/PSP-II and the underlying mechanism. Macrophages and mast cells were isolated, cultured, and stimulated with purified PSP-I/PSP-II. Pharmacological modulation was performed using the glucocorticoid dexamethasone, indomethacin (cyclooxygenase inhibitor), MK886 (leukotriene inhibitor), and the supernatant of spermadhesin-stimulated mast cells. Macrophages stimulated with PSP-I/PSP-II released into the culture supernatant a neutrophil chemotactic substance. This activity was partly inhibited by both dexamethasone (85%) and the supernatant of spermadhesin-stimulated mast cells (74%) but not by indomethacin and MK886. An anti-tumor necrosis factor (TNF) alpha antibody neutralized (by 68%) the neutrophil chemotactic activity of PSP-I/PSP-II-stimulated macrophages. An anti-interleukin (IL)-4 antibody blocked the inhibitory activity of spermadhesin-stimulated mast cells on release of a neutrophil chemotactic substance by PSP-I/PSP-II-stimulated macrophages. As a whole, these data indicate that the neutrophil migration-inducing ability of spermadhesin PSP-I/PSP-II involves the release of the inflammatory cytokine TNFalpha by stimulated macrophages and that this activity is modulated by the lymphokine IL-4 liberated by mast cells. The balance between these two cytokines may control onset of the local inflammatory reaction, avoiding excessive neutrophil recruitment that would lead to tissue damage.

Animals↗
PubMed2002

Dual effect of local application of nitric oxide donors in a model of incision pain in rats.

The effects of local application of a cream containing nitric oxide (NO) donors, S-nitroso-N-acetylpenicillamine (SNAP) or isosorbide dinitrate were studied in a rat model of incision pain. An incision was made in the plantar aspect of a hind paw and the cream was applied inside the surgical wound. SNAP (1-10%) or isosorbide (2.5-5%) reduced the incision allodynia as measured with von Frey filaments. Higher concentrations produced a smaller or no effect, but SNAP (30%) intensified the allodynia. Allodynia was also intensified by SNAP (5% or 30%) in rats pretreated with intraplantar 1H-[1,2,4]oxadiazolo[4,3-alpha]quinoxalin-1-one (ODQ, 4 microg), a guanylate cyclase inhibitor. The effect of isosorbide (5%) was prevented by ODQ. The cream containing SNAP released 10- to 20-fold more nitrite than did isosorbide from a macrophage culture. We conclude that local application of drugs generating a low NO concentration reduces incision pain through activation of guanylate cyclase. Drugs generating high NO concentrations, however, intensify pain via a guanylate cyclase-independent mechanism.

Animals↗
PubMed2002

Spermadhesin PSP-I/PSP-II heterodimer and its isolated subunits induced neutrophil migration into the peritoneal cavity of rats.

Spermadhesins are a group of (glyco)proteins from seminal fluid involved in various aspects of porcine fertilization. PSP-I/PSP-II, a heterodimer of glycosylated spermadhesins, is the major component of porcine seminal fluid. Its biological function remains, however, enigmatic. Using an in vitro chemotaxis assay, we showed that PSP-I/PSP-II and its isolated subunits induced migration of purified neutrophils. A possible proinflammatory activity of PSP-I/PSP-II induced upon injection of the spermadhesin heterodimer and its isolated subunits into the peritoneal cavity of rats was investigated. Lavage of peritoneal cavities, thioglycolate treatment, and mast cell depletion were done before spermadhesin administration, and neutrophil migration was evaluated 4 h after injections. Pharmacological modulation was also investigated. Resident cell depletion by lavage reduced the neutrophil migration induced by PSP-I/PSP-II and the PSP-II subunit but had no effect on that induced by isolated PSP-I. Both an increase of macrophage population by thioglycolate treatment and mast cell depletion potentiated the neutrophil migration induced by PSP-I/PSP-II and by PSP-II. The glucocorticoid dexamethasone but not indomethacin (cyclooxygenase inhibitor), MK886 (leukotriene inhibitor), and BN50739 (platelet activation factor [PAF] antagonist) inhibited neutrophil migration induced by PSP-I/PSP-II. Coincubation with mannose-6-phosphate (a PSP-II-specific ligand) inhibited neutrophil recruitment induced by PSP-II but did not alter the PSP-I activity. As a whole, the data suggested that enhancement of the neutrophil migration-inducing activity of PSP-I/PSP-II and PSP-II involved an indirect mechanism, i.e., via activation of resident cells, probably macrophages. On the other hand, PSP-I appeared to act directly on neutrophils. We hypothesize that the neutrophil migration-inducing effect displayed by PSP-II might be due to interaction of its lectin domain with cellular receptors and that neutrophil recruitment induced by PSP-I may involve protein-protein interactions.

Animals↗
PubMed2002

Failure of neutrophil chemotactic function in septic patients.

OBJECTIVE: To investigate the in vitro chemotactic function of neutrophils obtained from patients with sepsis. DESIGN: Prospective study in which purified neutrophils obtained from septic patients and nonseptic control volunteers were assayed for chemotactic function induced by N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP) and leukotriene B4. The sera nitrate concentrations also were quantified. SETTING: University hospital. PATIENTS: Twenty patients with sepsis caused by different infectious foci. INTERVENTIONS: Routine blood tests, blood or other site cultures, blood collection for neutrophil purification sera collection for nitrate assay. MEASUREMENTS AND MAIN RESULTS: Neutrophils from septic patients exhibited significantly less chemotactic activity than neutrophils obtained from healthy volunteers, in response to FMLP (93.4 +/- 6.6 vs. 51 +/- 8.3 migrated neutrophils) and leukotriene B4 (90.2 +/- 10 vs. 42.4 +/- 11.6 migrated neutrophils) stimuli, in a microchemotaxis chamber assay. The impaired chemotaxis occurred mainly in neutrophils from nonsurvivor patients. The extent of neutrophil chemotaxis inhibition (survivor/nonsurvivor) was 33.43%/61.67% and 43.4%/86.98%, in response to FMLP and leukotriene B4, respectively. Increased serum nitrate (micromoles of NO2 + NO3) concentrations were detected in septic patients, compared with controls, but no differences were found between survivor (91.84 +/- 14.12) and nonsurvivor (102.6 +/- 17.36) groups. CONCLUSIONS: Septic patients present suppressed neutrophil chemotactic responses to FMLP and leukotriene B4 stimuli compared with healthy controls. This is accompanied by increased serum concentrations of nitrate. The impairment of neutrophil chemotaxis was observed mainly in the cells obtained from nonsurvivor patients and may thus be an additional factor contributing to disease outcome.

Adolescent↗
PubMedDate not supplied

Cytokine-induced neutrophil chemoattractant 1 (CINC-1) mediates the sympathetic component of inflammatory mechanical hypersensitivitiy in rats.

The hyperalgesic effect of cytokine-induced neutrophil chemoattractant 1 (CINC-1/CXCL1) was measured in a model of mechanical hyperalgesia in rats. CINC-1 evoked a dose-dependent mechanical hypersensitivity, which was already significant 2 h after the cytokine injection, peaked 4 h after and decreased thereafter. The local pre-treatment of the rats with the beta-adrenoceptor antagonist, atenolol (25 microg paw-1), but not with the cyclooxygenase inhibitor indomethacin (100 microg paw-1), inhibited (86%) the CINC-1-induced hypersensitivity. Conversely, IL-1beta-evoked hypersensitivity was inhibited (76%) by local pre-treatment of the animals with indomethacin, but not by atenolol. Carrageenin- and TNF-alpha-evoked hypersensitivity were attenuated to about the same extent (50%) by antisera neutralising CINC-1 or IL-1beta. The association of both antisera abolished the hypersensitivity effect of carrageenin and TNF-alpha. In addition, carrageenin, LPS and TNF-alpha were shown to stimulate the production of immunoreactive CINC-1 in the skin of injected paws. These data suggest that CINC-1, released at sites of inflammation, mediates inflammatory hyperalgesia in rats via release of sympathomimetic amines.

Animals↗