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J G Martin

Publications and source records attributed to J G Martin.

At least 55 records · Page 3Linked to original sources
PubMed1998

Involvement of alpha-4 integrins in allergic airway responses and mast cell degranulation in vivo.

Antibodies against integrins have been shown to inhibit allergic airway responses. The purpose of this study was to test the hypothesis that the beta1 integrin, very late antigen-4 (VLA-4), is involved in mast cell activation triggered by allergen exposure in sensitized animals. To do this we studied Brown Norway rats that were sensitized to ovalbumin (OA; 1 mg subcutaneously) using Bordetella pertussis as an adjuvant. Two weeks later rats were challenged with OA, pulmonary resistance (RL) was determined, and the concentrations of histamine and tryptase in bronchoalveolar lavage fluid and N-acetyl-leukotriene (LT)E4 in bile were measured. Pretreatment with a monoclonal antibody against VLA-4 (TA-2) attenuated the early response after OA challenge (342.9 +/- 24.4% baseline RL versus 153.3 +/- 19.4%; p < 0.01). There were significantly lower concentrations of histamine (67.11 +/- 11.90 microgram/ml versus 26.69 +/- 1.84; p < 0.01) and tryptase (0.143 +/- 0. 035 microgram/ml versus 0.053 +/- 0.022 microgram/ml; p < 0.01) in TA-2-treated animals. The increases in the concentrations of biliary N-acetyl-LTE4 after OA challenge were also significantly lower in TA-2-treated animals. These data suggest that a selective anti-VLA-4 monoclonal antibody prevents early responses through inhibition of mast cell activation.

Adjuvants, Immunologic↗
PubMed1998

CD4+ T cells can induce airway hyperresponsiveness to allergen challenge in the brown norway rat.

Airway hyperresponsiveness to inhalational challenge with methacholine (MCh) develops by 32 h after allergen challenge of actively sensitized BN rats. To test the hypothesis that CD4+ T cells mediate allergen-induced hyperresponsiveness independent of IgE-mediated mechanisms, we administered CD4+ T cells, CD8+ T cells, and a mixture of CD4+ and CD8+ T cells (total T cells) isolated from the cervical lymph nodes of rats sensitized with ovalbumin (OA) to naive BN rats that underwent aerosol challenge with either OA or bovine serum albumin (BSA) 2 d later. Responsiveness to MCh was measured 2 d before transfer of T cells and 32 h after challenge with OA or BSA. Airway responsiveness increased significantly in recipients of CD4+ T cells after OA challenge, but not in any other of the treatment groups. Analysis of bronchoalveolar lavage (BAL) cells for major basic protein expression by immunostaining showed eosinophilia in OA-challenged CD4+ and total T-cell recipients. Cells retrieved by bronchoalveolar lavage showed increased expression of IL-5 mRNA (in situ hybridization) in CD4+ T cell recipients after OA challenge compared with other groups. Interferon-gamma mRNA was expressed to the greatest extent in CD8+ recipients, but it was elevated in both OA- and BSA-challenged animals. We conclude that CD4+ T cells can induce airway hyperresponsiveness after inhalational challenge with allergen and this is associated with IL-5 production and eosinophilia. CD8+ T cells may have a negative regulatory effect on responsiveness, possibly mediated by interferon-gamma.

Aerosols↗
PubMed1998

Time-course of functional and pathological changes after a single high acute inhalation of chlorine in rats.

Reactive airways dysfunction syndrome (RADS) is an asthma-like condition that follows exposure to very high concentrations of an irritant material. We assessed the time-course of pathophysiological alterations in a model of RADS. Sprague-Dawley rats were exposed to 1,500 parts per million (ppm) of chlorine for 5 min. Lung resistance (RL), responsiveness to inhaled methacholine (MCh), the airway epithelium and bronchoalveolar lavage (BAL) were assessed over a 3 month period after exposure. RL increased significantly up to 3 days after exposure, reaching a maximal change of 110+/-16% from baseline. There was a significant decrease in the concentration of MCh required to increase RL by 0.20 cmH2O x mL(-1) x s from days 1-7 after exposure. In some rats, MCh hyperresponsiveness and RL changes persisted after exposure for as long as 1 and 3 months, respectively. Histological evaluation with morphometric evaluation revealed epithelial flattening, necrosis, increase in smooth muscle mass and evidence of epithelial regeneration. BAL showed an increased number of neutrophils. The timing of maximal abnormality in the appearance of the epithelium (days 1-3) corresponded to that of the maximal functional changes. Acute high chlorine exposure results in functional and pathological abnormalities that resolve in the majority of animals after a variable period; however, these changes can persist in some animals. Functional abnormalities in the initial stages may be related to airway epithelial damage.

Administration, Inhalation↗
PubMed1998

Postprandial dyspnea and malnutrition in patients with chronic obstructive pulmonary disease.

OBJECTIVE: To compare ventilatory response, oxygen uptake and sense of dyspnea of underweight versus normal-weight patients with chronic obstructive pulmonary disease (COPD) after a standard meal, in order to investigate whether an increase in dyspnea due to diet-induced thermogenesis might lead to altered eating habits. Weight loss in patients with COPD leads to adverse health effects, but the reasons for this loss are not well understood. DESIGN: Prospective study. PARTICIPANTS: A total of 18 patients (14 men, 4 women) aged 46 to 83 with severe, stable COPD. OUTCOME MEASURES: Minute ventilation (VE), tidal volume (VT), frequency of breathing, oxygen uptake (VO2), carbon dioxide excretion (VCO2) and sense of dyspnea (using the Borg scale) were measured 15 minutes before a 2.5-MJ (600-kcal) balanced liquid meal and at four 15-minute intervals after the meal. RESULTS: Increases in VE, VT, VO2 and VCO2 were observed for all subjects. Corrected for body surface area, the maximum postprandial changes in these indicators did not differ between the underweight and the normal-weight subjects with COPD. Work of breathing (measured in 11 subjects) did not differ between the 2 groups, nor did the number of subjects reporting increased dyspnea. CONCLUSIONS: Since the increases in VE, VO2, VCO2 and perceived dyspnea did not differ between the normal-weight and underweight patients, this indicates that dyspnea at mealtimes is not likely to lead to decreased food intake.

Aged↗
PubMed1997

Structure-activity relationships of N-hydroxyurea 5-lipoxygenase inhibitors.

The discovery of second generation N-hydroxyurea 5-lipoxygenase inhibitors was accomplished through the development of a broad structure-activity relationship (SAR) study. This study identified requirements for improving potency and also extending duration by limiting metabolism. Potency could be maintained by the incorporation of heterocyclic templates substituted with selected lipophilic substituents. Duration of inhibition after oral administration was optimized by identification of structural features in the proximity of the N-hydroxyurea which correlated to low in vitro glucuronidation rates. Furthermore, the rate of in vitro glucuronidation was shown to be stereoselective for certain analogs. (R)-N-[3-[5-(4-Fluorophenoxy)-2-furyl]-1-methyl-2-propynyl]-N-hydroxyure a (17c) was identified and selected for clinical development.

Animals↗
PubMed1997

Microvascular leakage in the airway wall and lumen during allergen induced early and late responses in rats.

The potential contribution of microvascular leakage to airway narrowing during the early (ER) and late (LR) responses following allergen challenge was determined in Brown Norway (BN) rats actively sensitized with ovalbumin (OA). To study leak into the airway wall, rats (n = 46) were challenged 2 weeks later with aerosolized OA, saline, or serotonin (5-HT) to study either ER (n = 25), LR (n = 15), or 5-HT (n = 6) responses. Pulmonary resistance (RL) was used to measure airway narrowing. Microvascular leak was determined by the Evans blue (EB) technique in the airway tissues, and in another group of BN, by EB in bronchoalveolar lavage (BAL) in the airway lumen (n = 43). EB increased in the airways of 5-HT challenged rats (P < 0.05), but not during ER or LR. EB in BAL increased significantly during the ER (101 +/- 31.35 ng/ml BAL), vs saline challenge (10.82 +/- 1.66; P < 0.05) and during the LR at 3, 4, 5, and 7 h following OA challenge compared with controls (P < 0.05). These results suggest that fluid transits rapidly from the airway microvascular circulation and into the airway lumen following allergen challenge. The measurement of EB in BAL can detect microvascular leak into the airway lumen during the ER and LR. Plasma leak into the airway lumen may contribute to the increase in pulmonary resistance observed during ER and LR in BN rats.

Airway Resistance↗
PubMed1997

Effects of cAMP on serotonin evoked calcium transients in cultured rat airway smooth muscle cells.

Agents increasing intracellular adenosine 3',5'-cyclic monophosphate (cAMP) cause relaxation of airway smooth muscle. However, the mechanisms of their action are not fully understood. We investigated the role of cAMP in the modulation of intracellular Ca2+ concentration ([Ca2+]i) transients evoked by serotonin (5-HT) in cultured rat tracheal smooth muscle (TSM) cells. Forskolin (10(-7) M) caused a significant elevation of intracellular cAMP and a 60% relaxation of tracheal rings contracted with 5-HT but did not affect [Ca2+]i in TSM cells. Forskolin (10(-5) M) completely relaxed tracheal rings and significantly decreased [Ca2+]i during the sustained phase of the 5-HT response. Forskolin-induced relaxation was attenuated by the cAMP-dependent protein kinase A (PKA) inhibitor Rp diastereomer of cAMP (Rp-cAMPS; 10(-4) M) and by the guanosine 3',5'-cyclic monophosphate (cGMP)-dependent protein kinase (PKG) inhibitor [Rp isomer of 8-(4-chlorophenylthio)-guanosine 3',5'-cyclic monophosphorothioate, 10(-4) M]. The effects of forskolin on [Ca2+]i were not altered by the PKA inhibitor but were abolished by the PKG inhibitor and thapsigargin. These results indicate that, in rat TSM, the relaxant effects of high concentrations of cAMP may be mediated, at least in part, by facilitating the sequestration of Ca2+ into intracellular stores by a mechanism involving PKG.

Animals↗
PubMed1997

Hyperpnea-induced bronchoconstriction is dependent on tachykinin-induced cysteinyl leukotriene synthesis.

The purpose of the study was to test the hypothesis that tachykinins mediate hyperpnea-induced induced bronchoconstriction indirectly by triggering cysteinyl leukotriene (LT) synthesis in the airways. Guinea pigs (350-600 g) were anesthetized with xylazine and pentobarbital sodium and received hyperpnea challenge (tidal volume 3.5-4.0 ml, frequency 150 breaths/min) with either humidified isocapnic gas (n = 6) or dry gas (n = 7). Dry gas challenge was performed on animals that received MK-571 (LTD4 antagonist; 2 mg/kg i.v.; n = 5), capsaicin (n = 4), neurokinin (NK) antagonists [NK1 (CP-99994) + NK2 (SR-48968) (1 mg/kg i.v.); n = 6], or the H1 antihistamine pyrilamine (2 mg/kg i.v.; n = 5). We measured the tracheal pressure and collected bile for 1 h before and 2 h after hyperpnea challenge. We examined the biliary excretion of cysteinyl LTs; the recovery of radioactivity in bile after instillation of 1 microCi [3H]LTC4 intratracheally averaged 24% within 4 h (n = 2). The major cysteinyl LT identified was LTD4 (32% recovery of radioactivity). Cysteinyl LTs were purified from bile of animals undergoing hyperpnea challenge by using reverse-phase high-pressure liquid chromatography and quantified by radioimmunoassay. There was a significant increase in the peak value of tracheal pressure after challenge, indicating bronchoconstriction in dry gas-challenged animals but not after humidified gas challenge. MK-571, capsaicin, and NK antagonists prevented the bronchoconstriction; pyrilamine did not. Cysteinyl LT levels in the bile after challenge were significantly increased from baseline in dry gas-challenged animals (P < 0.05) and were higher than in the animals challenged with humidified gas or dry gas-challenged animals treated with capsaicin or NK antagonists (P < 0.01). The results indicate that isocapnic dry gas hyperpnea-induced bronchoconstriction is LT mediated and the role of tachykinins in the response is indirect through release of LTs. Endogenous histamine does not contribute to the response.

Animals↗
PubMed1997

Airway hyperresponsiveness in a rat model of chronic bronchitis: role of C fibers.

We evaluated the role of C fibers in the development of airway hyperresponsiveness in a rat model of chronic bronchitis. Neonatal rats were treated with capsaicin (50 mg/kg, subcutaneously), a procedure which results in permanent depletion of tachykinins from the lungs and airways as well as degeneration of C fibers. Control rats were treated with the vehicle used to dissolve capsaicin. Three months later, rats from both groups were exposed either to SO2 gas (250 ppm, 5 h/d, 5 d/wk for 4 wk) or to filtered air for the same period of time. One day after the last exposure, rats were anesthetized and instrumented for the measurement of pulmonary resistance (R(L)), dynamic compliance (Cdyn), and airway responsiveness to inhaled aerosolized methacholine. There was a small (30%) but significant increase in R(L) in neonatal capsaicin- but not vehicle-treated rats exposed to SO2. Chronic exposure to SO2 resulted in increased airway responsiveness in both groups of rats, but the effect was more pronounced in the neonatal capsaicin-treated animals in which the doses of methacholine required to double R(L) or decrease Cdyn by 50% decreased 6.3-fold and 4.6-fold, respectively, compared with only 2.2- and 1.3-fold decreases in vehicle-treated rats. Morphometric analysis of histologic sections of airways demonstrated that the average area of smooth muscle in the airway wall, normalized by the length of basement membrane, was significantly greater in SO2 compared with air-exposed capsaicin-treated rats, but not in vehicle-treated control rats (p < 0.012). The maximal tension generated by tracheal rings in response to cholinergic agonists was also significantly increased by SO2 exposure in neonatal capsaicin-treated, but not vehicle-treated rats (p < 0.002). These results support the hypothesis that rather than contributing to the pathophysiologic manifestations of bronchitis, C fibers limit the development of airway obstruction and airway hyperresponsiveness during induction of chronic bronchitis by SO2 exposure. The enhanced contractile responses of airways from the SO2-exposed neonatal capsaicin-treated rats may result from increased airway smooth muscle mass and contribute to the increased airway responsiveness observed in these animals.

Animals↗
PubMed1997

Impact of nutritional support on functional status during an acute exacerbation of chronic obstructive pulmonary disease.

The impact of oral nutritional supplementation during an acute exacerbation of COPD on functional status was assessed through measuring change in lung function, strength testing, and general well-being. Subjects hospitalized for an acute exacerbation of COPD (n = 33) were randomized to extra nutritional support or the regular hospital care. They consumed an additional 10 kcal/kg/d. Outcome measures were measured at 2 wk as change scores. Forced vital capacity (% predicted) improved in the treatment group as compared with the control group (+8.7% versus -3.5%, p = 0.015), and change in FEV1 was in the same direction but not significantly different (p = 0.099). There were no changes in handgrip strength or respiratory muscle strength, but there was a trend towards more improvement in the general well-being score (+11.96 versus -10.25, p = 0.066). Almost all subjects were in negative nitrogen balance, indicating muscle wasting. The degree of muscle wasting was strongly correlated with the dose of corticosteroids (r = 0.73, p < 0.005). In conclusion, it is difficult to prevent important muscle wasting in patients with COPD treated with corticosteroids, but some small gains were observed with increased dietary intake.

Activities of Daily Living↗
PubMed1997

Adoptively transferred late allergic airway responses are associated with Th2-type cytokines in the rat.

Late allergic airway responses can be transferred by CD4+ T cells in the rat. To investigate the role of T-cell cytokines in these responses, we examined the expression of mRNA for Th2 (interleukin [IL]-4 and IL-5) and Th1 (IL-2 and interferon gamma [INF-gamma])-type cytokines in Brown Norway rats that were administered either antigen-primed W3/25(CD4)+ or OX8(CD8)+ T cells. Donors were actively sensitized by subcutaneous injection of ovalbumin (OVA) in the neck and T cells were obtained from the cervical lymph nodes by immunomagnetic cell sorting for administration to unsensitized rats. Control rats received bovine serum albumin (BSA)-primed CD4+ and CD8+ T cells. Two days later, recipient rats were challenged with aerosolized OVA, and bronchoalveolar lavage (BAL) was performed 8 h after challenge. BAL cells expressing mRNA for IL-2, IL-4, IL-5, and INF-gamma were analyzed using the technique of in situ hybridization. Recipients of OVA-primed CD4+ T cells had an increase in the fraction of BAL cells expressing mRNA for IL-4 and IL-5 compared with BSA-primed CD4+ or OVA-primed CD8+ cells (P < 0.001). Recipients of CD8+ T cells had an increase in INF-gamma mRNA expression after OVA challenge compared with recipients of BSA-primed-CD8+ or OVA-primed CD4+ T cells (P < 0.001). In conclusion, T-cell-dependent allergen-induced late responses are associated with the expression of mRNA for IL-4 and IL-5, indicating Th2 cell activation. Furthermore, the increased expression of INF-gamma in allergen challenge recipients of antigen-primed CD8+ T cells suggests that CD8+ T cells may be important in modulating allergic responses.

Adoptive Transfer↗
PubMed1997

Effects of purine nucleotides and nucleoside on cytosolic calcium levels in rat tracheal smooth muscle cells.

Extracellular adenosine triphosphate (ATP) has a range of effects on a wide variety of cells through the activation of specific purinoceptors. The aim of this study was to establish whether P2 purinoceptors are present on airway smooth muscle cells. Experiments were conducted on cultured rat tracheal smooth-muscle cells (first through third passage). Intracellular Ca2+ ([Ca2+]i) was measured using Fura-2 and dual-excitation wavelength microfluorometry. The effects of ATP, adenosine diphosphate (ADP), uridine triphosphate (UTP), and adenosine (ADO) were measured in concentrations from 10(-6) to 10(-3) M. At a concentration of 10(-4) M, the peak [Ca2+]i was 502 +/- 92 nM for ATP and 543 +/- 76 nM for UTP (mean +/- standard error of the mean). ADO had no significant effect on Ca2+ release. Peak [Ca2+]i induced by ATP was not dependent on extracellular Ca2+ but was blocked by U-73122, an inhibitor of phospholipase C. Pretreatment with adenosine deaminase and desensitization with alphabeta-MeATP had no effect on ATP-induced Ca2+ release. The effects of ATP (10(-4) M) on peak [Ca2+]i were potentiated by the presence of ADO 10(-5) M (969 +/- 257 nM; P < 0.05). The presence of XAC, a blocker of A1 and A2 ADO receptors did not prevent this effect. In the presence of XAC, ADO 10(-6) M potentiated the effects of ATP (peak [Ca2+]i: 1,300 +/- 229 nM). The addition of 1433U83, a blocker of A3 ADO receptors, blocked the synergistic effect of ADO 10(-6) M on ATP. These data show that P2 purinoceptors, most likely of the P2U subtype, are present on airway smooth muscle cells and that the newly discovered A3 ADO receptor appears to be also present.

Animals↗
PubMed1997

Planning the milking center in expanding dairies.

This paper focuses on dairies that want to expand and milk more cows through an existing parlor or by building new parlor. The expansion process can be divided into the following three phases: 1) financial evaluation, 2) design, and 3) construction. A financial evaluation should be carried out first to determine the resources that are available for expanding the dairy operation. This phase is extremely important, considering that 68% of the dairies that expand have cash flow problems within the first 2 yr of operation. The next phase is to design the milking center, and options include expanding the present parlor or constructing a new parlor. The present parlor can be expanded by addition of stalls, but group size must also expand to maintain cow flow at the larger parlor size. Group size can often be increased by combining corrals or free-stall alleys. The third phase in the expansion is to determine the most efficient milking procedure during the construction or remodeling of the facilities.

Animals↗
PubMed1996

Mechanical responses of tracheal tissue in vitro: dependence on the tissue preparation employed and relationship to smooth muscle content.

We examined the relationship between the quantity of smooth muscle in isolated tracheal preparations and their responses to contractile agonists. The responses of two different tracheal preparations, rings and tubes, to carbachol and serotonin were compared both intra-species (Fisher vs. Lewis strain rats) and inter-species (rat vs. guinea-pig). The rank order for carbachol-induced maximal isometric tensions was Fisher > Lewis > guinea-pig and for serotonin Fisher > guinea-pig > Lewis for tracheal rings. The sensitivities to carbachol and serotonin were greater in Fisher than in Lewis rats. Guinea-pig tracheal rings were comparable to Fisher in sensitivity to carbachol, but were more sensitive to serotonin than either Fisher or Lewis rings. In both species, agonist-independent differences were found in the maximal tension of rings taken from different regions of trachea. For whole tracheal tubes under isovolumetric conditions, the rank order for carbachol-induced changes in the intraluminal pressure was guinea-pig > Lewis > or = Fisher. The sensitivity to carbachol was greater in guinea-pig tubes than in rat. The quantity of tracheal smooth muscle estimated from myosin was greater in guinea-pigs than in either Fisher or Lewis rats. In addition, the area of cartilage determined by morphometry in guinea-pig trachea was greater than that in the rat. We conclude that a concordance between the magnitude of contraction and the amount of tracheal smooth muscle is obtained only in whole tracheal tubes and not in tracheal rings. Several factors could contribute to the observed discrepancies in tracheal rings, including regional differences in efficacy and sensitivity to contractile agonists and the thickness of cartilage.

Animals↗
PubMed1996

Sonographic visualization of the ovaries throughout pregnancy.

OBJECTIVE: To determine the frequency with which one or both normal ovaries can be visualized during a routine obstetric ultrasound examination. METHODS: The population consisted of 5617 pregnant women at 5.0-39.9 weeks' gestation, studied cross-sectionally. The sonographic visualization rate for one or both normal ovaries, as well as their position above or below the level of the umbilicus, was recorded for one examination in each patient. RESULTS: The study population was divided into three groups according to gestational age: first trimester, 5.0-12.9 weeks; second trimester, 13.0-26.9 weeks; and third trimester, 27.0-39.9 weeks. There were 829, 3195, and 1593 women in the first, second, and third trimesters, respectively. Most women were examined transvaginally in the first trimester; transabdominal sonography was used in the second and third trimesters. The ability to visualize one or both ovaries declined significantly (P < .05) from the first trimester to the second, as well as from the second trimester to the third (P < .001). The percentage of ovaries that were visualized above the umbilicus increased from 2.4% in the first trimester to 10.1% in the second trimester (P < .001), and to 21.7% in the third trimester (P < .001). CONCLUSION: As gestational age advances, there is a significant reduction in the ultrasound visualization rate of normal ovaries. This investigation provides normative data for ovarian visualization throughout pregnancy that may be helpful in establishing ultrasound laboratory standards.

Female↗
PubMed1996

Depletion of CD8+ T cells enhances pulmonary inflammation but not airway responsiveness after antigen challenge in rats.

BACKGROUND: CD8+ (OX-8+) T cells may suppress airway inflammation and airway responsiveness after allergen challenge. OBJECTIVE: We studied the effects of depletion of OX-8+ T cells on allergen-induced lung eosinophilia and airway responsiveness in the Sprague-Dawley rat. METHODS: Sprague-Dawley rats were sensitized to ovalbumin and challenged by aerosol 14 days later. Test animals received either low-dose (2 mg, n = 9) or high-dose (3 mg, n = 7) OX-8 monoclonal antibody (mAb), whereas controls (n = 8) received BALB/c ascites fluid. A fourth group of animals (n = 10) was not sensitized to ovalbumin and also received ascites fluid. Twenty-four hours after ovalbumin challenge, responsiveness to methacholine was measured, and lung inflammation was assessed in the large airways and small airways and parenchyma. RESULTS: Circulating and airway CD8+ T cells were decreased by OX-8 mAb administration with greatest changes in animals treated with high-dose OX-8 mAb compared with controls (blood: 1.0% +/- 3.6% vs 18.7% +/- 3.9%, p < 0.05); (large airways: 2.5% +/- 1.2% vs 13.8% +/- 1.2%, p < 0.05). Ovalbumin challenge resulted in increases in macrophages and neutrophils in the small airways and parenchyma of sensitized compared with unsensitized rats (p < 0.05). High-dose OX-8 mAb further increased total leukocytes, attributable to increases in neutrophils and eosinophils, retrieved from the large airways and small airways and parenchyma compared with other groups (p < 0.05). Airway responsiveness to methacholine was not significantly different between control and ovalbumin-challenged animals and was not augmented by OX-8 pretreatment. CONCLUSION: CD8+ T cells modulate the extent of allergen-induced airway inflammation. However, the enhancement of inflammation was not sufficient to affect airway responsiveness.

Animals↗