Effect of heparin on airway goblet cell secretion in sensitized guinea pigs

Heparin and related proteoglycans are released from mast cells and possess anti-inflammatory and anti-complement activities. To elucidate whether heparin affects goblet cell secretion in asthmatic airways and, if so, what the mechanism of action is, we studied guinea pigs sensitized with ovalbumin (OVA) by determining the mucus score (MS) of tracheal goblet cells stained with Alcian blue and PAS. Inhalation of OVA caused a rapid decrease in MS in a dose-dependent manner, with the maximal decrease being from 545 +/- 26 to 192 +/- 35 (p < 0.001), indicating an increase in goblet cell mucus discharge. This effect was selectively inhibited by the histamine H2 receptor blockade with cimetidine. Prior inhalation of heparin inhibited OVA-induced goblet cell secretion in a dose-dependent fashion, but had no effect on histamine-induced goblet cell secretion. The OVA-induced histamine release from the tracheal tissue was likewise inhibited by heparin. These results suggest that allergic challenge stimulates airway goblet cell secretion mainly through the release of histamine and the concomitant activation of histamine H2 receptors on goblet cells, and that heparin protects against this effect by inhibiting the histamine release from mast cells.     

Effects of uroguanylin and guanylin against antigen-induced bronchoconstriction and airway microvascular leakage in sensitized guinea-pigs

Uroguanylin and guanylin are isolated mainly from the gastrointestinal tract and are activators of guanylyl cyclase C receptor (GC-C), which mediates the production of intracellular cyclic guanosine 3',5'-monophosphate (cyclic GMP). The bronchodilator effects of agents that raise cyclic GMP levels, such as atrial natriuretic peptide, have been reported, and uroguanylin mRNA has recently been detected in extra-gastrointestinal tissues, including the lung, suggesting their role in pulmonary activity. In the first step of this study, we examined the relaxant effects of uroguanylin and guanylin on isolated tracheal smooth muscle of guinea-pigs, and measured tissue cyclic GMP levels by means of enzymeimmunoassay. Uroguanylin produced concentration-dependent relaxant effects on resting tone and significant elevated cyclic GMP levels. Guanylin produced the same, but less potent, effects. In this study, we first investigated the effects of uroguanylin and guanylin on antigen-induced bronchoconstriction and airway microvascular leakage in actively sensitized guinea-pigs. Anesthetized male guinea-pigs, ventilated via a tracheal cannula, were placed in a plethysmograph to measure pulmonary mechanics for 10 min after challenging with 1 mg/kg of ovalbumin. Evans blue dye was then extravasated into their airway tissues to measure microvascular leakage. Intravenous pretreatment with uroguanylin significantly inhibited ovalbumin-induced bronchoconstriction and microvascular leakage in a dose-dependent manner. These inhibitory effects were mimicked by 8-bromoguanosine 3', 5'-cyclic monophosphate. This study is the first to show that uroguanylin not only had a potent bronchodilatory effect but also inhibited microvascular leakage. These results encouraged us to continue the above experimental and clinical studies in bronchial asthma.     

Involvement of tachykinin NK1 receptor in the development of allergen-induced airway hyperreactivity and airway inflammation in conscious, unrestrained guinea pigs

It has been suggested that tachykinin NK1 receptor-mediated neurogenic inflammation, characterized by microvascular leakage, mucus secretion, and infiltration and activation of inflammatory cells in the airways, may be involved in allergic asthma. Therefore, in a guinea pig model of allergic asthma, we investigated the involvement of the NK1 receptor in allergen-induced early (EAR) and late (LAR) asthmatic reactions, airway hyperreactivity (AHR) after these reactions and airway inflammation, using the selective nonpeptide NK1 receptor antagonist SR140333. On two different occasions, separated by 1 wk interval, OA-sensitized guinea pigs inhaled either saline (3 min) or SR140333 (100 nM, 3 min) at 30 min before as well as at 5.5 h after OA provocation (between the EAR and LAR) in a random crossover design. A control group, receiving saline inhalations before and at 5.5 h after the two OA provocations, was included as well. SR140333 had no significant effect on either the EAR or the LAR compared with saline control inhalations. However, the NK1 receptor antagonist significantly reduced the OA-induced AHR to histamine, both after the EAR at 5 h after OA challenge (1.77 +/- 0.13-fold increase in histamine reactivity versus 2.50 +/- 0.25-fold increase in the control animals, p < 0.01) and after the LAR at 23 h after OA challenge (1.15 +/- 0.12-fold increase versus 1.98 +/- 0. 34-fold increase, respectively, p < 0.05). Moreover, bronchoalveolar lavage studies performed at 25 h after the second OA provocation indicated that SR140333 significantly inhibited the allergen-induced infiltration of eosinophils, neutrophils, and lymphocytes in the airways (p < 0.05 for all observations), whereas a tendency to reduced accumulation of ciliated epithelial cells in the airway lumen was observed (p = 0.10). These results indicate that the NK1 receptor is involved in the development of allergen-induced AHR to histamine, and that NK1 receptor-mediated infiltration of inflammatory cells in the airways may contribute to this AHR.     

Role of Leukotriene-degrading enzymes in pulmonary response to antigen infusion in sensitized guinea pigs in vivo

Although the expression of nerve growth factor (NGF) in the rat striatum is the highest at 2 postnatal weeks (P2w), the action of NGF at that age has not been studied in detail. We examined the effects of several neurotrophic factors, including NGF, on striatal cholinergic neurons cultured from P2w rats. We also examined the effects of a cyclic AMP (cAMP) analog and high K(+)-evoked depolarization. NGF specifically promoted the survival of choline acetyltransferase (ChAT)-positive neurons, and consequently increased the ChAT activity per well, whereas it did not induce the ChAT activity per cholinergic neuron. NGF-responsiveness was the highest in striatal cultures from P2w rats, but it was almost lost in cultures from P4w rats. Brain-derived neurotrophic factor (BDNF), neurotrophin-4/5 (NT-4/5), and a cAMP analog had survival-promoting effects on striatal total neurons including cholinergic neurons. On the other hand, high K+ hardly promoted the survival of striatal cholinergic neurons in cultures from P2w rats, although it increased the viable number of total striatal neurons. High K+ did not increase the ChAT activity in any tested cultures from postnatal 3- to 28-day-old rats. These results demonstrated that NGF prevented the death of striatal cholinergic neurons in cultures from P2w rats, but not from P4w rats, and that high K+ could not rescue these deaths. We propose that cholinergic neurons in the striatum are programmed to die at P2w, and that this programmed cell death can be restored by neurotrophins, but not by depolarization.     

Role of superoxide anions in airway hyperresponsiveness induced by cigarette smoke in conscious guinea pigs

To investigate the involvement of superoxide in airway hyperresponsiveness and bronchoconstriction induced by cigarette smoke (CS), we evaluated the effects of superoxide dismutase (SOD), a scavenger of superoxide anion, and apocynin, an inhibitor of superoxide anion-generating NADPH oxidase in phagocytes, on the airway responses induced by CS in conscious guinea pigs. Airway responsiveness was assessed by PC200Mch, the concentration required to produce a doubling in the baseline specific airway resistance (sRaw) to an inhaled methacholine aerosol, in nonanesthetized spontaneously breathing animals. Before being exposed to ten puffs of CS, animals inhaled either SOD (5,000 units/ml or 25,000 units/ml) or vehicle. Although SOD did not affect PC200Mch in the air control group, this agent significantly reduced the CS-induced airway hyperresponsiveness. Repeated administration of apocynin (12 mg/kg for 4 days) did not affect PC200Mch after exposure to CS. These data suggest that the superoxide from CS was involved in the airway hyperresponsiveness induced by CS, whereas phagocytic reactive oxygen species were not. The data also suggest a potential therapeutic role for antioxidants in airway hyperresponsiveness.     

Role of endogenous nitric oxide in allergen-induced airway responses in guinea-pigs

1. Endogenous nitric oxide (NO) can be detected in exhaled air and accumulates in inflamed airways. However its physiological role has not been fully elucidated. In this study, we investigated a role for endogenous NO in allergen-induced airway responses. Sensitised guinea-pigs were treated with NG-nitro-L-arginine methyl ester L-NAME (2.0 mM) or aminoguanidine (AG) (2.0 mM) 30 min before the allergen challenge, and 3 and 4 h after the challenge. Alternatively, L-arginine (2.4 mM) treatment was performed 30 min before, and 2 and 3 h after the challenge. In all groups, ovalbumin (OVA) challenge (2 mg ml(-1) for 2 min) was performed, and airway responses, NO production, infiltration of inflammatory cells, plasma exudation and histological details were examined. 2. Allergen-challenged animals showed an immediate airway response (IAR) and a late airway response (LAR), which synchronised with an increase in exhaled NO. Treatment with L-NAME and AG did not affect IAR while they significantly blocked LAR (72% and 80% inhibition compared to vehicle) and production of NO (35% and 40% inhibition). On the other hand, treatment with L-arginine did not affect IAR but potentiated LAR (74% augmentation). 3. In bronchoalveolar lavage (BAL) fluid, allergen-induced increases in eosinophils were reduced by 48% for L-NAME treatment compared to vehicle, and increased by 56% for L-arginine treatment. 4. Treatment with L-NAME significantly decreased airway microvascular permeability to both Monastral blue (MB) and Evans blue (EB) dye (50.6% and 44% inhibition). 5. We conclude that allergen-induced LAR is closely associated with NO production, and that NO plays a critical role in inflammatory cell infiltration and plasma exudation in the allergic condition.     

Relationships among allergen-induced early and late phase airway obstructions, bronchial hyperreactivity, and inflammation in conscious, unrestrained guinea pigs

The relationship among allergen-induced early asthmatic reactions (EARs) and late asthmatic reactions (LARs), early (between EAR and LAR) and late (after LAR) changes in bronchial reactivity to histamine and infiltration of inflammatory cells into the airways were investigated with a new model of chronically instrumented, unrestrained, and ovalbumin-sensitized guinea pigs. Two different provocation strategies were examined. With the use of stepwise increasing allergen concentrations, all 21 animals responded with an EAR, which in 15 animals (71%) was followed by an LAR. By inhalation of a single allergen concentration for up to 15 minutes, 11 of 14 animals showed an EAR, which in 10 animals (71%) was followed by an LAR. One animal did not respond, whereas the remaining two showed only an LAR. At 6 hours (after the EAR) and 24 hours (after the LAR) after allergen provocation, a significant bronchial hyperreactivity (BHR) toward histamine aerosol was observed in the dual responding animals (both protocols), but not significant changes were observed in animals with a single EAR or a single LAR. Significant correlations were found between the initial increase in airway obstruction after allergen provocation and the severity of the EAR and LAR, as well as the early and late BHR; in addition, a significant correlation was found between the early and late BHR. In contrast, the severity of the LAR did not correlate with the BHR at 6 hours and 24 hours. At 6 hours, there was a marked tendency to an increase in the number of eosinophils and a significant increase in the number of neutrophils in the bronchoalveolar lavage. At 24 hours after provocation, the number of eosinophils and neutrophils was significantly enhanced. These data suggest that early activation of mast cells and/or inflammatory leukocytes may determine the development of the LAR, as well as the early and late BHR, although there appears to be no causal relationship between the BHR at both time points and the severity of the LAR. The relationships among allergen-induced EAR and LAR, early and late BHR, and airway inflammation observed in this new guinea pig model are strikingly similar to those observed in patients with asthma.     

Role of neutrophil elastase in stress-induced gastric mucosal injury in rats

To evaluate the growth of a pulmonary trunk reconstructed without an extracardiac conduit, the hemodynamics and diameter of a new pulmonary trunk were measured in 5 patients from the right ventriculogram and MRI at postoperative follow-up periods. There were tetralogy of Fallot with pulmonary atresia in two patients, tetralogy of Fallot with single coronary in one, truncus arteriosus type I in one and transposition of the great arteries with ventricular septal defect and pulmonary stenosis in one. The age at operation ranged from 26 days to 4.5 years. The posterior wall continuity of the right ventricle and pulmonary artery was established by the direct pulmonary-right ventricular anastomosis in three patients and by the interposition of the left atrial appendage in two. Postoperative follow-up periods ranged from 2 years and 6 months to 3 years and 10 months (median: 2 years and 11 months). In four of them, the postoperative right ventricular to aortic or left ventricular systolic pressure ratios were less than 0.4 without any significant systolic pressure gradients between pulmonary artery and right ventricle. In these four patients, the diameters of the reconstructed pulmonary trunks grew from 10-18 mm to 18-21 mm postoperatively. These diameters were more than 100% of normal values. In the remaining patient with tetralogy of Fallot and single coronary artery, the obstruction of the new pulmonary trunk by a bulged left atrial appendage, which was used as the posterior wall, was observed on the right ventricular outflow tract reconstruction without an extracardiac conduit has growth potential in the future.     

Role of neutrophil elastase in compression-induced spinal cord injury in rats

Myeloperoxidase (MPO) is an essential component of the oxygen-dependent microbicidal system of neutrophils and monocytes. Hereditary deficiency of MPO occurs in 1 in 2,000 to 4,000 individuals in the general population and has been generally considered an autosomal recessive trait. Previous studies have used the peroxidase activity of blood leukocytes to assess the phenotype of affected family members. Eosinophil peroxidase (EPO) also contributes to the peroxidase activity of blood leukocytes. Because EPO expression is normal in MPO-deficient subjects, eosinophil contamination can significantly contribute to peroxidase activity in leukocytes from family members of an MPO-deficient subject and thereby undermine correct interpretation of the inheritance pattern. To avoid this potential problem, we used cytochemical, immunochemical, and genetic techniques to assess the inheritance pattern of MPO deficiency in sixteen individuals from five unrelated kindreds. Each kindred had an index case with MPO deficiency and the R569W missense mutation, a genotype that causes MPO deficiency. Our analysis demonstrated that MPO deficiency was not inherited as a simple autosomal recessive trait. Most subjects were compound heterozygotes with respect to the R569W mutation and demonstrated a spectrum of phenotypes. Our data demonstrate the broad phenotypic impact of compound heterozygosity on the expression and function of a multimeric protein such as MPO.     

Effect of cetirizine on antigen-induced tracheal contraction of passively sensitized guinea pigs

BACKGROUND: Cetirizine dihydrochloride (cetirizine), a potent histamine H1-receptor antagonist, has been developed as an anti-allergy drug. OBJECT: The anti-allergic effects and mechanism of cetirizine were studied using in vitro assay systems. METHODS: We investigated the effect of cetirizine on antigen-induced contractions of isolated tracheal strips and on chemical mediator release from antigen-stimulated lung chips taken from passively sensitized guinea pigs. We examined the antigen-induced mobilization of Ca2+ in MC/9 mast cells sensitized with IgE. RESULTS: Cetirizine inhibited the antigen-induced contraction of isolated guinea-pig trachea concentration dependently. Pyrilamine, another histamine H1-receptor antagonist, delayed the response but did not change the maximum amplitude. Cetirizine at the concentration of 3 microM also inhibited the antigen-induced release of histamine, leukotriene D4, and leukotriene E4 from guinea pig lung chips. Furthermore, it inhibited the antigen-induced Ca2+ increase in MC/9 mast cells, whereas pyrilamine did not. CONCLUSION: These findings suggest that one anti-allergic mechanism of cetirizine may inhibit mediator release which is, at least partially, mediated by a decrease in the transient Ca2+ influx in mast cells.     

Role of vagus nerves in resiniferatoxin-induced bronchoconstriction of guinea pigs

To study the role of vagal afferent C-fibers in resiniferatoxin (RTX)-induced bronchoconstriction in vivo, 30 guinea pigs weighing 347 +/- 28 g were evenly and randomly divided into five groups: Group 1, control; 2, chronic vagotomy; 3, local capsaicin (acute); 4, local capsaicin (chronic); and 5, systemic capsaicin. Each animal was anesthetized with pentobarbital sodium, cannulated with a tracheal cannula and venous catheter, paralyzed with gallamine triethiodide, and artificially ventilated. All animals were pretreated with atropine and phenoxybenzamine. Immediately after RTX was intravenously injected, each animal in the control group exhibited profound decreases in maximal expiratory flow, dynamic respiratory compliance, and total lung capacity, as well as an increase in functional residual capacity, indicating severe airway constriction. Animals in Groups 2-4 exhibited partial abolishment, while those in Group 5 showed complete abolishment of the RTX-induced bronchoconstriction. In 12 additional animals (6 animals each in control and chronic vagotomy groups), chronic vagotomy caused also suppressive effects on capsaicin-induced airway constriction. At one min, our data demonstrate that 36-51% of noncholinergic bronchoconstriction is due to the vagal component while the remaining constriction is due to the nonvagal component. Thus, the nonvagal component plays a significant role in this type of tachykinin-mediated airway constriction.     

Involvement of neutrophil elastase in crescentic glomerulonephritis

To elucidate the role of neutrophils in the tissue damage of crescentic glomerulonephritis (GN), we examined neutrophils infiltrated in renal tissues and the localization of neutrophil elastase (NE), as a neutrophil-derived tissue destructive mediator, using an immunohistochemical technique with antibodies specific for neutrophils and neutrophil elastase; the enzyme histochemical technique (chloroesterase staining) also was used to detect neutrophils. In normal controls, neutrophil infiltration was scarce, and NE was localized in neutrophil cytoplasm. Neutrophils were abundant in crescentic GN and infiltrated in the glomerulus and interstitium; the infiltrating neutrophils were often aggregated. NE was localized in the cytoplasm of neutrophils and also appeared extracellularly (in granular or diffuse patterns) in glomerular necrotizing lesions, crescents, ruptured portions of Bowman's capsules, and in periglomerular and perivascular sites of the interstitium. Moreover, urinary concentration of NE measured by enzyme-linked immunosorbent assay (ELISA) in crescentic GN patients was significantly higher than in normals (93.6 +/- 13.3 v 1.4 +/- 0.5 microg/g x Cr, respectively; P < .001). These data suggest that NE plays a significant role in renal tissue damage, especially in the formation of glomerular necrotizing and crescentic lesions and in periglomerular interstitial lesions of crescentic GN.     

Effect of a leukotriene antagonist, ONO-1078, on electric stimulation of vagus (ESV)-induced bronchoconstriction and microvascular leakage in guinea pigs

In atropine-pretreated guinea pigs, electric stimulation of vagus (ESV, 10 Hz, 5 ms, 2 V or 10 V, for 90 s) increased intrapulmonary pressure (IPP), and Evans blue extravasation in trachea, main bronchi, peripheral and distal intrapulmonary airways in a voltage-dependent manner. ONO-1078, a noval leukotriene antagonist, (0.03 and 0.1 mg.kg-1, iv) showed no remarkable inhibiting effect on ESV-induced increase of IPP. However, the agent significantly inhibited ESV-induced increase of Evans blue extravasation in the airways, especially in lower potency of stimulation (2 V). The results suggest that leukotrienes may be involved in airway microvascular leakage in response to neurogenic inflammation.     

Role of tachykinins in ozone-induced acute lung injury in guinea pigs

To examine the hypothesis that the acute reversible changes caused by ozone (O3) exposure are mediated by tachykinin release, guinea pigs were depleted of tachykinins by use of repeated capsaicin (CAP) injections before O3 exposure in an attempt to prevent O3-induced functional changes. Unexpectedly, CAP pretreatment caused divergent results in the functional responses to O3. Ventilatory measurements obtained from CAP-pretreated O3-exposed (CAP-O3) animals were exacerbated rather than diminished compared with the effects of O3 alone. Similarly, lavage fluid protein accumulation was enhanced in the CAP-O3 group compared with the O3-exposed group. In better agreement with our initial hypothesis, the CAP-O3 group was less responsive than the O3-exposed animals to histamine aerosol challenge. Additionally, Evans blue dye accumulation, a hallmark of tachykinin release, was increased in O3-exposed animals and was partially blocked in the CAP-O3 group. These data suggest that tachykinin-containing sensory fibers are unlikely to mediate the acute effects of O3 exposure on tidal breathing and lavage fluid protein accumulation but may play a role in causing post-O3 airway hyperreactivity and protein extravasation into the trachea.     

Effects of iodinated contrast media on pulmonary airway resistance in anesthetized guinea pigs

RATIONALE AND OBJECTIVES: Bronchospasm is occasionally observed following iodinated X-ray contrast medium administration. We performed an in vivo study in guinea pigs to investigate the effects of a number of iodinated contrast media on pulmonary airway resistance and the mechanisms underlying the potential bronchoconstrictor effect. METHODS: The contrast media studied were the pharmaceutical formulations of iomeprol (400 mg I/ml), iopamidol (370 mg I/ml), and iohexol (350 mg I/ml), which are nonionic, triiodinated contrast media; diatrizoate (370 mg I/ml), an ionic, triiodinated contrast medium; iotrolan (300 mg I/ml), a nonionic, hexaiodinated contrast medium; and iocarmate (280 mg I/ml) and ioxaglate (320 mg I/ml), which are both hexaiodinated and ionic contrast media. Each contrast medium was administered intravenously at 2 g I/kg. Changes in pulmonary airway resistance were evaluated by measuring intratracheal pressure at the moment of maximum insufflation, or maximal insufflation pressure (MIP), in anesthetized guinea pigs submitted to forced ventilation. RESULTS: All contrast media except ioxaglate caused mean increases of MIP of no more than 20%. By contrast, ioxaglate caused a marked bronchoconstrictor effect, increasing MIP by 242% +/- 46%. Of the drugs tested for antagonistic action on this increase in MIP, salbutamol inhibited almost completely the increase in MIP for the first 40 min posttreatment. Similarly, lysine acetylsalicylate and indomethacin consistently reduced MIP after contrast media administration to levels only 30% and 14% above those of baseline precontrast media, respectively. Promethazine had only a minor inhibitory effect, and the response to prednisolone varied. CONCLUSION: There was no apparent relationship between the size of the increase in airway resistance and the charge or molecular weight of the contrast agent molecule or the pharmaceutical formulation. The increase induced by ioxaglate must be attributed to inherent molecular toxicity mediated through a direct action on the production of bradykinin and/or the prostanoid products of the cyclooxygenase pathway, rather than through a direct action on the release of histamine.     

Nitric oxide derived from sympathetic nerves regulates airway responsiveness to histamine in guinea pigs

Nitric oxide (NO), which can be derived from the nervous system or the epithelium of the airway, may modulate airway responsiveness. We investigated how NO derived from the airway nervous system would affect the airway responsiveness to histamine and acetylcholine in mechanically ventilated guinea pigs. An NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) (1 mmol/kg i.p.) significantly enhanced airway responsiveness to histamine but not to acetylcholine. Its enantiomer D-NAME (1 mmol/kg i.p.), in contrast, had no effect. The L-NAME-induced airway hyperresponsiveness was still observed in animals pretreated with propranolol (1 mg/kg i.v.) and atropine (1 mg/kg i.v.). Pretreatment with the ganglionic blocker hexamethonium (2 mg/kg i.v.) completely abolished enhancing effect of L-NAME on airway responsiveness. Bilateral cervical vagotomy did not alter the L-NAME-induced airway hyperresponsiveness, whereas sympathetic stellatectomy completely abolished it. Results suggest that NO that was presumably derived from the sympathetic nervous system regulates airway responsiveness to histamine in guinea pigs.     

Viral respiratory infection causes airway hyperresponsiveness and decreases histamine N-methyltransferase activity in guinea pigs

We investigated the effects of viral respiratory infection by Sendai virus on bronchial responses to aerosolized histamine in anesthetized guinea pigs and on the activity of histamine N-methyltransferase (HMT). We measured the change in total pulmonary resistance induced by histamine in the presence or absence of a specific HMT inhibitor, SKF 91488, in noninfected and infected animals. In the absence of SKF 91488, the bronchoconstrictor response to histamine was greater in infected than in noninfected animals. SKF 91488 (10(-2) M, 90 breaths) potentiated the responses to histamine in noninfected animals, and the magnitude of augmented responses to histamine by SKF 91488 was similar to that by viral infection. Furthermore, SKF 91488 did not further potentiate the responses to histamine in infected animals. However, responses to aerosolized acetylcholine were unaffected by viral infection and SKF 91488. The HMT activity decreased by 56% in the trachea, 86% in the bronchi, and 52% in the parenchymal tissue in the infected animals. In contrast to HMT activity, acetylcholinesterase activity was unaffected by viral infection. These results suggest that respiratory infection by Sendai virus causes enhanced bronchial responsiveness to histamine by decreasing HMT activity in airways.     

Myopathy in guinea pigs

Myopathy resembling nutritional muscular dystrophy occurred in a colony of 150 guinea pigs. Of 54 animals affected, 27 died. Major clinical signs were depression, conjunctivitis, and reluctance to move. Lesions were widespread throughout skeletal and cardiac musculature. Clinical signs and deaths ceased when the diet was changed to a different commercial ration. A single intramuscular injection of sodium selenite and alphatocopherol brought prompt remission of clinical signs in one group of 20 so treated.     

Role of cytokine-induced neutrophil chemoattractant (CINC) in ozone-induced airway inflammation and hyperresponsiveness

Cytokine-induced neutrophil chemoattractant (CINC) is a rat chemokine with potent chemoattractant effects on neutrophils. We determined the involvement of CINC in ozone-induced airway neutrophilia and bronchial hyperresponsiveness (BHR) in the rat. We found a marked increase in lung CINC messenger RNA (mRNA) within 2 h after cessation of ozone exposure (1 ppm for 3 h), as measured by Northern blot analysis, whereas rats exposed to room air had no detectable CINC mRNA. Ozone exposure induced a significant neutrophilia in bronchoalveolar lavage fluid (BALF) at 24 h after exposure (air-exposed rats: 4.2 +/- 2.0 x 10(4), versus ozone-exposed rats: 16.1 +/- 3.7 x 10(4)); prior treatment with a goat anti-CINC antibody (1 mg, intravenously) suppressed the neutrophilia (3.1 +/- 0.9 x 10(4)). When administered intratracheally, the antibody (230 micrograms) partially inhibited the influx of neutrophils. The increase in bronchial responsiveness to acetylcholine observed after ozone exposure was not inhibited by the anti-CINC antibody. The anti-CINC antibody (1 mg, intravenously) also inhibited BALF neutrophilia induced by exposure to a higher concentration of ozone (3 ppm, 3 h), without an effect on BHR. CINC is an important chemokine causing ozone-induced neutrophil chemoattraction, but is not involved in the induction of ozone-induced BHR. The neutrophil is unlikely to contribute to BHR in this model.