Search PubMed⌕ Search

Biomedical subjects

J G Martin

Publications and source records attributed to J G Martin.

At least 19 recordsLinked to original sources
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

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

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↗
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↗
PubMed1996

Effect of nedocromil sodium on allergen-induced airway responses and changes in the quantity of airway smooth muscle in rats.

BACKGROUND: Allergen exposures induce growth of airway smooth muscle in the Brown Norway rat. OBJECTIVE: The purpose of the study was to examine the role of mediators associated with the early and late responses in the induction of airway smooth muscle growth. METHODS: Nedocromil sodium was administered to block early and late responses in ovalbumin-sensitized and ovalbumin-challenged rats undergoing single or multiple challenges (5 times at 5-day intervals) with ovalbumin. Airway smooth muscle was quantitated by morphometry on lungs removed 2 days after the final challenge. RESULTS: Nedocromil sodium administered before ovalbumin challenge blocked both the early and late responses. When administered 2 hours after ovalbumin challenge, it also blocked the late response. Rats undergoing challenge with aerosolized ovalbumin five times at 5-day intervals were also treated with nedocromil before (n = 10) or 2 hours after (n = 10) each ovalbumin inhalation, respectively. The quantity of airway smooth muscle standardized for size was greater after ovalbumin challenge (0.069 +/- 0.005) compared with saline controls (0.033 +/- 0.003, p < 0.005). Nedocromil significantly reduced the airway smooth muscle (0.036 +/- 0.003, p < 0.005) when administered before ovalbumin. However, the airway smooth muscle in rats that received nedocromil 2 hours after ovalbumin challenge (0.046 +/- 0.003), although lower than in ovalbumin-challenged rats (p < 0.01), was still significantly higher than in saline-treated rats (p < 0.05). CONCLUSIONS: Allergen-induced early responses, late responses, and airway inflammation are antagonized by nedocromil. The mediators of both the early and late responses contribute to allergen-induced airway smooth muscle growth, a process that can be prevented by administration of nedocromil.

Allergens↗
PubMed1996

The effect of amniotic sheet orientation on subsequent maternal and fetal complications.

The purpose of this investigation was two-fold, first, to determine the incidence of amniotic sheets in our obstetric population; and, second, to elucidate the maternal and fetal complications associated with this particular finding. In this retrospective study, we searched the computerized records of the ultrasound department for the presence of amniotic sheets in singleton pregnancies from 1 March 1991 to 17 September 1993. Sonographic criteria for an amniotic sheet included the findings that (1) a reflective membrane attached to the placenta at one end or the other, with measurable thickness, was identified traversing the amniotic fluid; and (2) the fetus was not attached to the membrane, and fetal ability to move without restriction was ascertained. An amniotic sheet was identified in 79 of 17,553 examinations (0.45%) performed between 12 and 28 weeks' gestation. Two subsets of amniotic sheets were identified: perpendicular and not perpendicular. The sheets in the first subset were orientated perpendicular to the placental surface and were more likely to be associated with an abnormal presentation at delivery (p < 0.001) and a history of pelvic inflammatory disease, but not with a history of prior Cesarean section, or previous dilatation and curettage. The second subset of amniotic sheets were non-perpendicular, either oblique or parallel, in orientation to the placental surface and were associated with fewer maternal complications. Of the study group, 40.7% had a history of vaginal bleeding. The incidence of vaginal bleeding was not significantly different between those patients with perpendicular or those with non-perpendicular amniotic sheets. We conclude that perpendicular, in contrast to non-perpendicular, amniotic sheets are more commonly associated with breech presentation at term and a past history of pelvic inflammatory disease.

Amnion↗
PubMed1996

Vibroacoustic stimulation enhances visualization of the four-chamber cardiac view in the third trimester.

The objective of this study was to determine whether vibroacoustic stimulation would improve the visualization rate of the four-chamber cardiac view. Patients between 26 and 42 weeks' gestation were considered to be candidates for this study if the amniotic fluid index (AFI) was between 8.0 and 24.0 cm, no malformations were detected on a careful fetal anatomical survey and a four-chamber cardiac view was not obtainable. Once a four-chamber view was considered to be not obtainable due to fetal position, the patient was asked to withdraw a sealed envelope and was assigned to either the study or the control group. The 164 study patients received one to three 3-s vibroacoustic stimulations. Five minutes later a second attempt was made to visualize the four-chamber view adequately. The control group consisted of another 198 subjects in whom a four-chamber view could not be obtained. The control group did not receive vibroacoustic stimulation. A similar 5-min time interval was allowed to elapse before an attempt was made to visualize the four-chamber view. The study and control groups were similar with respect to fetal presentation, placental location, fetal weight category, biophysical profile score, gestational age, AFI and estimated fetal weight. The rate of the four-chamber view was significantly higher among fetuses receiving vibroacoustic stimulation (20.1%), in comparison to the control group (11.1%) (p = 0.019). Successful repositioning was more likely among fetuses with estimated fetal weight between 2251 and 3050 g, and at a gestational age between 33.1 and 37.0 weeks. We conclude that in a selected group of patients vibroacoustic stimulation can be used to enhance visualization of the four-chamber view.

Female↗
PubMed1996

Endogenous nitric oxide contributes to strain-related differences in airway responsiveness in rats.

The effects of N(omega-nitro-L-arginine (L-NNA), a nitric oxide synthase inhibitor, on airway responsiveness were studied in the spontaneously hyperresponsive Fischer and the control normoresponsive Lewis rat strains to investigate the role of the endogenous nitric oxide (NO) pathway in strain-related differences in airway responsiveness. Responsiveness to inhaled methacholine was significantly increased in L-NNA-treated Lewis rats but not in Fischer rats. L-NNA increased carbachol-induced tracheal contractions in vitro to a larger extent in Lewis rats compared with Fischer rats. The effect of L-NNA was abolished by removal of the epithelium. Carbachol induced a NO-dependent increase in guanosine 3',5'-cyclic monophosphate levels in tracheal tissues but to a lesser extent in Fischer (2.1-fold increase) than in Lewis (3.7-fold increase) rats. In conclusion, endogenous NO is involved in the regulation of airway responsiveness to cholinergic agonists in rats. A relatively ineffective NO-guanosine 3',5'-cyclic monophosphate regulatory mechanism in Fischer rats contributes, in part, to strain-related differences in airway responsiveness between Fischer and Lewis rats.

Animals↗
PubMed1996

Methacholine-induced bronchoconstriction and airway smooth muscle in the guinea pig.

We examined the role of airway smooth muscle (ASM) as a determinant of the site and extent of methacholine (MCh)-induced airway narrowing in anesthetized and mechanically ventilated guinea pigs. The sites of airway narrowing and ASM were determined in animals (n = 4) bronchoconstricted to 75, 60, 40, or 15% of the maximal lung resistance (RL,max) induced by aerosolized MCh and compared with a saline-challenged animal. The median luminal area of each animal was significantly inversely correlated to the percentage of RL,max (r = -0.95; P < 0.01). However, there was no correlation between the degree of narrowing of any given airway and the quantity of ASM of any given airway. The relationship between the amount of ASM and responsiveness to MCh was studied in different animals (n = 13). The range of the concentration of MCh required to reach 50% of RL,max (EC50) varied by 254-fold, but the RL,max had only a 3.6-fold range. There was no correlation between RL,max and ASM. However, there was a correlation between the log EC50 and ASM (r = -0.541; P<0.05) in intraparenchymal cartilaginous airways. In conclusion, morphometric measurements of airway narrowing are correlated with pulmonary resistance. Variability in the quantity of ASM does not appear to be a determinant of the heterogeneity of airway narrowing or of maximal bronchoconstriction among normal guinea pigs. However, the sensitivity to MCh is associated with differences in the amount of ASM in intraparenchymal cartilaginous airways.

Airway Resistance↗
PubMed1996

The role of endogenous corticosterone in the late-phase response to allergen challenge in the brown Norway rat.

The aim of this study was to assess the role of endogenous corticosterone (CCST) concentrations on the late airway response (LAR) to ovalbumin (OA). Thirty-two Brown Norway (BN) rats were sensitized to OA on Day 0, then divided into three groups. Group 1 (n = 11) received saline (1 ml, subcutaneously) at time (T) = -24, -12, and 0 h prior to a 5% OA challenge on Day 14. Group 2 (n = 11) received metyrapone (MTP), an 11 beta-hydroxylase inhibitor, (10 mg/100 g in 1 ml saline, subcutaneously) at time (T) = -24, -12, and 0 h. Group 3 (n = 10) received MTP on the same schedule as Group 2, plus CCST in the drinking water (16 micrograms/ml) from T = -24 to T = 0 h. Pulmonary resistance (RL) was measured for 8 h following OA challenge to determine early (EAR) and LAR. Blood samples were taken at T = 0 and T = 8 h to determine serum CCST levels. Bronchoalveolar lavage (BAL) fluid was collected at T = 8 h. Serum CCST levels were significantly reduced in the MTP group (235 ng/ml +/- 14 SEM) compared with control (564 +/- 38, p < 0.0001) and MTP+CCST animals (349 +/- 19, p < 0.0005). There were no differences in either baseline RL or EAR between the groups. However, the MTP group had a smaller LAR (6 ml/cm H2O/s*min +/- 2 SEM) than the control group (19 +/- 5, p < 0.02). The effect of MTP on LAR was reversed by treatment with CCST (21 +/- 3, p < 0.005). Total cell counts (p < 0.05) and eosinophils (p < 0.01) were increased in the BAL fluid of MTP rats versus control and MTP+CCST animals. We conclude that depletion of endogenous CCST in the BN rat diminishes the LAR to allergen challenge. These results indicate that physiologic levels of CCST are not necessary for development of the EAR, but they play a permissive role in the LAR to inhaled allergen.

Airway Resistance↗
PubMed1996

Nutritional status and mortality in chronic obstructive pulmonary disease.

The role of nutritional status in the prognosis of subjects with severe chronic obstructive pulmonary disease was studied in a cohort of Canadian men and women followed for 3 to 5 yr. A total of 348 subjects who were recruited for a study of negative pressure ventilation were evaluated for lung function and body weight, and a subset who entered hospital for the study (n=184) had baseline measures of diffusing capacity, maximal inspiratory and expiratory mouth pressure (PImax and PEmax), and blood gases. Predictors of survival were analyzed using Cox regression models. In the total cohort, low body mass index (BMI) and use of home oxygen were independently associated with reduced survival. In the hospitalized group, predictors of respiratory mortality were elevated PaCO2 and low BMI, PImax, and diffusing capacity. PaO2 (measured on oxygen therapy), FEV1, PEmax, age, smoking behavior, and gender were not associated with survival. The predictors of total mortality were similar, except that BMI was no longer significant. In conclusion, low body weight, a potentially modifiable factor, was associated with respiratory mortality, but whether it has a casual effect or is a marker of declining health can only be resolved through an intervention trial.

Adult↗
PubMed1996

Effects of depletion of cells bearing the interleukin-2 receptor on immunoglobulin production and allergic airway responses in the rat.

Lymphocytes, key cells in chronic inflammation, are increased in the airways of asthmatics and have increased expression of the interleukin-2 (IL-2) receptor, a sign of activation. We determined the effects of depleting cells bearing IL-2 receptors on immunoglobulin (Ig) production, airway inflammation, and airway responses after antigen challenge of Brown Norway rats that were sensitized to ovalbumin (OA). Both control and ART-18 (antirat IL-2 receptor) antibodies inhibited plasma specific IgE and the early (ER) and late (LR) airway responses to antigen when given from zero to 14 d after sensitization. When ART-18 was administered from 4 to 14 d after sensitization and compared with control animals, it inhibited OA specific IgE production from Day 21 onward, but it increased total IgE and specific IgG. These changes followed a significant increase in blood CD4+ lymphocytes (%) in ART-18-treated animals 14 d after sensitization. The same protocol of administration did not affect Ig levels at 14 d, but it decreased neutrophil influx into the lungs 8 h after antigen challenge without any effects on the ER and LR. Administration of ART-18 at the time of antigen challenge did not affect the subsequent airway inflammation or the increased responsiveness to methacholine that occurs 32 h after antigen challenge. In summary, depletion of IL-2-receptor-bearing cells affects lymphocyte subsets and immunoglobulin production and it decreases the influx of neutrophils into the lungs 8 h after OA challenge, but it does not significantly inhibit the ER, LR, or increased airway responsiveness after antigen challenge.

Animals↗