Smoke-induced airway hyperresponsiveness to inhaled wood smoke in guinea pigs: tachykininergic and cholinergic mechanisms

The smoke-induced airway hyperresponsiveness (SIAHR) to inhaled wood smoke was investigated in anesthetized guinea pigs. Two smoke challenges (each 10 ml) separated by 30 min were delivered into the lungs by a respirator. In control animals, SIAHR was evidenced by an average bronchoconstrictive response (an increase in total lung resistance) to the second smoke challenge (SM2) that was approximately 4.3-fold greater than that to the first challenge (SM1). Pretreatment with CP-96,345 and SR-48,968 (neurokinin-1 and -2 receptor antagonists; each 1 mg/kg) in combination totally prevented this SIAHR, while pretreatment with CP-96,344 and SR48,965 (inactive enantiomers of CP-96,345 and SR-48,968, each 1 mg/kg) in combination failed to do so. Pretreatment with CP-96,345 (1 mg/kg), SR48,968 (1 mg/kg), or atropine (50 microg/kg) significantly alleviated this SIAHR. Pretreatment with phosphoramidon [an inhibitor of neutral endopeptidase (NEP); 2 mg/kg], which suppresses the degradation of tachykinins, induced an increase in airway reactivity that largely mimicked this SIAHR. The NEP activity measured in airway tissues excised 30 min after SM1 was significantly lower than that in air control value. These results suggest that 1) a prior wood smoke exposure induces an airway hyperresponsiveness to the subsequent wood smoke inhalation, 2) a tachykininergic mechanism involving both neurokinin-1 and -2 receptors is essential for, and a cholinergic mechanism is also involved in the development of this SIAHR, and 3) inactivation of airway NEP by wood smoke may contribute to this SIAHR.     

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.     

Participation of leukotriene D4 and tumor necrosis factor on lipopolysaccharide-induced airway hyperresponsiveness in guinea pigs

Partial failure of a free flap can create an unusual dilemma, as guidelines suggesting appropriate further intervention are not well defined. The increased complexity of a second free flap attempt is not necessarily contraindicated, but must be minimized if the same fate as the first is to be avoided. For the unique circumstance where the initial failed flap contained a vascular flow-through, the most distal patent vessels can then secondarily serve in an expeditious manner as the recipient vessels for the second or salvage free flap. The efficacy of this concept has been here validated after limited necrosis occurred in the distal portion of a radial forearm free flap. Following the requisite debridement, the residual flap still maintained a satisfactory arterial and venous flowthrough as a "bridge flap" that supported the attachment of a gracilis muscle free flap, and both flaps in turn preserved a sensate transtarsal amputation stump.     

Involvement of superoxide and nitric oxide on airway inflammation and hyperresponsiveness induced by diesel exhaust particles in mice

We previously demonstrated that chronic intratracheal instillation of diesel exhaust particles (DEP) induces airway inflammation and hyperresponsiveness in the mouse, and that these effects were partially reversed by the administration of superoxide dismutase (SOD). In the present study, we have investigated the involvement of superoxide in DEP-induced airway response by analyzing the localization and activity of two enzymes: (1) a superoxide producer, NADPH cytochrome P-450 reductase (P-450 reductase), and (2) a superoxide scavenger, SOD, in the lungs of the exposed mice and controls. P-450 reductase was detected mainly in ciliated cells and clara cells: its activity was increased by the repeated intratracheal instillation of DEP. While CuZn-SOD and Mn-SOD were also present in the airway epithelium, their activity was significantly decreased following DEP instillation. Exposure to DEP doubled the level of nitric oxide (NO) in the exhaled air. DEP exposure also increased the level of constitutive NO synthase (cNOS) in the airway epithelium and inducible NO synthase (iNOS) in the macrophages. Pretreatment with N-G-monomethyl L-arginine, a nonspecific inhibitor of NO synthase, significantly reduced the airway hyperresponsiveness induced by DEP. These results indicate that superoxide and NO may each contribute to the airway inflammation and hyperresponsiveness induced by the repeated intratracheal instillation of DEP in mice.     

Effect of exposure of guinea pigs to cigarette smoke on elastolytic activity of pulmonary macrophages

STUDY OBJECTIVE: To determine the effect of exposure to cigarette smoke on the elastolytic activity of guinea pigs' alveolar macrophages (AMs), and to compare elastolytic activity of AMs obtained by BAL with that of lung macrophages (LMs) obtained from minced lung tissue. METHODS: AMs were obtained by BAL from seven adult guinea pigs exposed to cigarette smoke for 5 d/wk during 6 weeks, as well as from age-matched control guinea pigs. From each animal, one lung was used to obtain LMs by mincing and teasing the lung, followed by enzymatic digestion and isolation of mononuclear cells by Hypaque-Ficoll separation. The other lung was inflated and fixed to quantitate emphysema by the destructive index (DI). Elastolytic activity (microgram of elastin degraded by 10(6) macrophages) was determined at 24, 48, and 72 h, by culturing AMs and LMs (1 x 10(6) cells in 1 mL of medium) in 3H-elastin-coated wells. RESULTS: In animals exposed to cigarette smoke, the total number of BAL cells (8.6+/-2.1 x 10(6)) and DI (21.8+/-8.1) were significantly higher than in nonexposed animals (6.4+/-1.8 x 10(6), p<0.05 for cells, and 12.1+/-4.1, p<0.01 for DI). Elastolytic activity of AMs from smoke-exposed guinea pigs was significantly higher at 24, 48, and 72 h than elastolytic activity of AMs from control animals (19.0+/-9.4 vs 10.0+/-5.3, p<0.05 at 72 h). Likewise, elastolytic activity of LMs was significantly higher in exposed than nonexposed guinea pigs (11.8+/-7.7 vs 7.4+/-5.0 at 72 h, p<0.05). Elastolytic activity of LMs was not significantly different from elastolytic activity of AMs, both in exposed guinea pigs (11.8+/-7.7 vs 19.0+/-9.4 at 72 h) and nonexposed animals (7.4+/-5.0 vs 10.0+/-5.3 at 72 h). CONCLUSIONS: These results indicate that elastolytic activity of both AMs and LMs of guinea pigs increases significantly after exposure to cigarette smoke and that AMs and LMs have similar elastolytic activities.     

Inhalation of platelet-activating factor induced guinea pig airway hyperresponsiveness: role of eosinophils activation

Exposure of guinea pigs to aerosols of 200 micrograms/ml platelet-activating factor 24 h later, airway hyperresponsiveness to histamine induced and number of eosinophils and hypodense eosinophils in bronchoalveolar lavage fluid (BALF) increased, comparing with the control group. The number of eosinophils in BALF was corelated with PC20 value in PAF-treated group (r = -0.62, P < 0.05). However, the percentage of hypodense eosinophil in BALF had closer relation to airway responsiveness (r = -0.84, P < 0.01). The content of peroxidase in hypodense eosinophils in BALF for guinea pigs treated by inhalation of PAF was lowered markedly than that in normodense eosinophil (P < 0.05). The result suggested that chemotaxis and activation of eosinophils by PAF might play an important role in airway hyperresponsiveness.     

Role of neutrophil elastase in allergen-induced airway microvascular leakage in sensitized guinea pigs

To determine the role of neutrophil elastase in allergen-induced airway microvascular leakage, we assessed vascular permeability of guinea pig trachea by measuring the extravasation of Evans blue dye in the circulating blood. Inhalation of ovalbumin (OA) to guinea pigs sensitized with OA caused Evans blue extravasation, indicating an increased microvascular permeability. Pretreatment with ONO-5046 a specific inhibitor of neutrophil elastase, inhibited OA-induced vascular leakage in a dose-dependent manner. Tracheal instillation of human neutrophil elastase likewise increased microvascular permeability, and this effect was almost completely abolished by ONO-5046. Challenge with OA increased the number of neutrophils and neutrophil elastase activity in the bronchoalveolar lavage fluid, and these effects were inhibited by ONO-5046. These results suggest that neutrophil accumulation into the airway and the subsequent release of neutrophil elastase may play a role in the airway microvascular leakage produced by antigen challenge.     

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.     

Pathology of interstitial nephritis induced in guinea pigs by exoantigens

Histological and immunofluorescent assessment of the kidney, renal core cultures, and determination of circulating antibodies were carried out in Hartley guinea pigs with a selective delayed-type hypersensitivity state (DTH) and acute interstitial nephritis induced and elicited by exoantigens. The results show that the normal tubule-vascular structure of the kidney, the simplicity of the molecular structure of the exoantigens and the modification of the native form of the exoantigens, when it is presented to the kidney in the elicitation phase of the DTH reaction, are factors which may reduce the cellular response in the normal renal parenchyma. The cytological events over a 48-hour period are not different to those which have been described in DTH reactions in extrarenal tissues. Exoantigens can induce renal lesions evoking an acute interstitial nephritis picture in animals with selective DTH at a time when there are neither circulating antibodies nor deposition of immunoglobulins or infection in the renal parenchyma.     

Effect of indomethacin and atropine in experimental asthma in conscious guinea pigs

Pulmonary mechanics were measured in unanesthetized guinea pigs sensitized to horseradish peroxidase (HRP) before and during two aerosolized challenges of this antigen. During the first challenge the pulmonary resistance increased in all animals. Prior to second challenge the animals received either atropine (0.2 mg/kg) or indomethacin (10 mg/kg) intraperitoneally. We found that during the second challenge the indomethacin group had an increase in pulmonary resistance slightly greater or similar to that during the first exposure to the antigen, while the animals treated with atropine had a significantly diminished response (P less than 0.05). In five guinea pigs sensitized to HRP but challenged with a nonspecific aerosal made up of rabbit albumin, we found that pulmonary resistance increased in some animals and that this increase could be partially blocked by atropine. These results show that indomethacin has no effect on this model of allergic airways disease. They also confirm the importance of the vagus nerves in allergic bronchoconstriction and in addition show that nonspecific hyperirritability can be induced in some animals by immunization.     

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.     

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.     

Role of superoxide anions in changes of endothelial vasoactive response during acute hyperglycemia

The effects of acute hyperglycemia on endothelial Ca2+ signaling, formation of endothelium-derived relaxing factor (EDRF) and bioactivity of EDRF were investigated. Hyperglycemia increased 2,5-tert-butyl-1,4-hydrochinone (BHQ)-initiated Ca2+ signaling and EDRF formation in a concentration-dependent manner. The effect of elevated D-glucose on Ca2+/EDRF response could be diminished by co-incubation with the antioxidants vitamin E, probucol, GSH, vitamin C and superoxide dismutase. Convincingly, hyperglycemic conditions yielded an increase in superoxide anion release from endothelial cells and the superoxide anion-generating mixture xanthine oxidase/hypoxanthine mimicked the effect of hyperglycemia on Ca2+/EDRF signaling. Besides an enhanced formation of the vasodilatatory NO compound EDRF, hyperglycemia enhanced NO degradation by endothelial cells and, thus, reduced bioactivity of EDRF. We suggest that vasoactivity during acute hyperglycemia depends on the superoxide anion scavenging properties of the vascular wall. In acute hyperglycemia and early stages of diabetes, radical scavenging capacity may be suitable to protect NO degradation, resulting in an enhanced vasodilation. In contrast, decreased free radical scavenging properties of the vasculature in prolonged hyperglycemia and in later stages of diabetes might promote NO degradation by an overshoot of superoxide anions, resulting in an attenuation of endothelium-dependent vasodilation.     

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.     

Time course study for airway inflammation and responsiveness by repeated provocation of aeroantigen in guinea pigs

To investigate the mechanisms of airway hyperresponsiveness (AHR), we examined the time course for asthmatic responses (including immediate asthmatic response (IAR), late asthmatic response (LAR), and AHR), airway inflammation (including edema in the airway, accumulation of inflammatory cells in bronchoalveolar lavage fluid (BALF), and mediator release including histamine and thromboxane A2 (TXA2) in BALF after the repeated provocation of aeroantigen in sensitized guinea pigs. Furthermore, we examined the effect of S-1452, a TXA2 receptor antagonist, on the antigen-induced airway obstruction and AHR in guinea pigs. We found that IAR occurred 1 min after every antigen inhalations. LAR was observed every 4 h after the inhalation of antigen without 1st or 2nd challenge. AHR was initially observed 4 h after the 5th inhalation of antigen, and then AHR was observed at every time measured even after the 6th provocation. The water content of the airway increased after the 2nd antigen inhalation. A number of leukocytes, especially eosinophils in BALF, was observed 30 min after the 2nd antigen inhalation. Desquamation of epithelia was observed 30 min after the 5th antigen inhalation. TXB2 and histamine in BALF were detected after the first antigen inhalation. These results suggest that LAR is caused by repeated airway inflammation such as eosinophilia and mediator release including TXA2. AHR may appear with the damages of lung tissue such as desquamation of epithelia. Oral administration of S-1452 (1 and 10 mg/kg) significantly inhibited LAR and AHR, assessed after the 6th antigen challenge. The present findings suggest that repeated antigen challenge causes airway inflammation and leads to the onset of LAR and AHR when became chronic. Furthermore, persistent generated TXA2 plays an important role in the pathogenesis of antigen-induced late-phase obstruction and AHR.     

Liver fibrosis in guinea pigs experimentally induced by combined copper and aflatoxin application

Aflatoxin B1 alone (0.05 mg resp. 0.037 mg/kg/d), copper alone (6.6 mg/kg/d or 200 mg/l drinking water) or a combination of both was administrated orally for 6 months to young guinea pigs from the first/second day of life. In the copper group there were no pathomorphological changes. For the aflatoxin B1 group liver damage was established. In the combined group liver injury was more frequent and more severe compared to the aflatoxin B1 group. Compared with the copper group biliary copper excretion was diminished and the kidney copper content was elevated in the Afl. B1 + Cu group. While copper concentrations in bile and kidney correlated with other parameters, notably the pathological lesions of the liver, no such correlation was found for liver copper. Therefore in this experiment the degree of Cu accumulation was not decisive for the liver lesions. The livers' capacity for excreting Cu by bile seems to be a much more important factor. Histologically only the livers of the combined group exhibited degeneration, atrophy and steatosis of liver cells, and a fibrosis more or less pronounced. For childhood cirrhosis (ICC and ICT), a combined etiology--a liver damaging agent plus elevated alimentary copper--is a plausible hypothesis.     

A role for cellular immunity in the induction of airway hyperresponsiveness induced by small molecular weight compounds

In a murine model it was shown that during a T help-1 cell dependent immune reaction, i.e. delayed type hypersensitivity (DTH), directed against the small molecular weight compound picryl chloride (PCI), altered lung functions are induced. Skin sensitization with PCI followed by intranasal hapten challenge resulted in an increment of pulmonary resistance and airway hyperresponsiveness which are general features of asthma. Whether this is also true for low molecular weight compounds, such as toluene diisocyanate, that can induce asthmatic complaints in humans, in addition to T help-2 cell dependent immune responses, remains to be clarified in future studies.     

Induction of endothelial cell injury by cigarette smoke

Cigarette smoke contains different populations of free radicals which may be responsible for endothelial cell (EC) injury of smokers. The purpose of this study was to examine the effects of gas-phase cigarette smoke on EC endothelium-derived relaxing factor (EDRF)/NO-guanylate cyclase (GC)-cGMP pathway and on EC detachment-type injury after incubation with smoke. Furthermore, we examined whether different kind of antioxidants can prevent smoke-caused EC injury. We measured cGMP pathway using direct (sodium nitroprusside, SNP) and indirect (A23187, the calcium ionophore and bradykinin, BK) activators of GC. Directly and indirectly stimulated EC cGMP production dose-dependently decreased and EC detachment increased after incubation with smoke. Externally added thiols (glutathione, GSH; D-Penicillamine, DP; N-acetylcysteine, NAC) protected EC from damage of cGMP production and cell detachment. Other antioxidants (catalase, deferoxamine and superoxide dismutase) were ineffective. These results suggest that the thiol containing GC in EC is destroyed or inactivated or thiol like species responsible for activation of GC is incomplete in EC after incubation with smoke. It is also possible that externally added thiols bind an unknown component of smoke and this way, EC is protected. EC injury may contribute to vascular diseases associated with cigarette smoking.     

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.     

A possible involvement of oxidative lung injury in endotoxin-induced bronchial hyperresponsiveness to substance P in guinea pigs

Fragile-X syndrome and myotonic dystrophy are caused by triplet repeat expansions embedded in CpG islands in the transcribed non-coding regions of the FMR1 and the DMPK genes, respectively. Although initial reports emphasized differences in the mechanisms by which the expanded triplet repeats caused these diseases, results published in the past year highlight remarkable parallels in the likely molecular etiologies. At both loci, expansion is associated with altered chromatin, aberrant methylation, and suppressed expression of the adjacent FMR1 and DMAHP genes, implicating epigenetic mediation of these genetic diseases.