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Biomedical subjects

J E Fish

Publications and source records attributed to J E Fish.

At least 37 records · Page 2Linked to original sources
PubMed1997

HSP27 elevated in mild allergic inflammation protects airway epithelium from H2SO4 effects.

Inflammation in allergic individuals is hypothesized to elevate stress proteins [heat shock proteins (HSP)] in airway epithelium, which may protect cells from further adverse conditions. Allergic, either asthmatic or not, and normal volunteers participated in a 2-day segmental allergen challenge bronchoscopic procedure. Bronchial epithelium was obtained before and after challenge. Epithelium was exposed to medium with H2SO4 (pH5), returned to medium at pH 7.4, and finally harvested for Western blotting with anti-27-kDa HSP (HSP27) antibody. Prechallenge epithelium of all subjects had significantly inhibited ciliary function by H2SO4 (pH 5) conditions (P < 0.001); only epithelium of normals recovered (P = 0.02). Allergic subjects with mild inflammation (< 50 micrograms/ml increase in albumin in bronchoalveolar lavage) had significantly increased HSP27 postchallenge (P = 0.01) and little ciliary dysfunction at pH 5, whereas subjects with severe inflammation (> 50 micrograms/ml increase in albumin) had little change in HSP27 and significant ciliary inhibition (P = 0.02). Normal epithelium had similar trends in HSP27 and equivalent inhibition of ciliary activity at pH 5 before and after allergen challenge. These data indicate that mild inflammation to allergen elevates HSP27 stress protein levels, thereby potentially protecting epithelial function from additional adverse conditions.

Adult↗
PubMed1997

Levels of amino acids and related compounds in bronchoalveolar lavage fluids of asthmatic patients.

The constituents of bronchoalveolar lavage (BAL) fluid have been shown to reflect the presence and possible etiology of several pulmonary diseases. Presently, although research studies have reported the concentrations of cytokines and compounds such as major basic protein in BAL fluids, only the cellular elements, total protein, albumin, and immunoglobulins have been well defined. We hypothesize that amino acids and related amino compounds, well known participants in physiologic and biochemical processes, are present in BAL fluid and may have involvement in asthma. Our objective was to extend knowledge of the total chemical profile and clinical value of BAL fluids in humans by measuring these amino compounds in normal control subjects and asthmatic patients. Analysis by high-pressure liquid chromatography revealed the presence of 25 compounds. A few compounds in control subjects and patients were found to have values > 1.0 nmol/ml, while the majority were present in comparatively low concentrations < 1.0 nmol/ml. Asparagine, phosphoethanolamine, and taurine were significantly increased in the asthmatic patients. We conclude that the present profile of amino acids and related amino compounds in BAL fluid serves as a potential diagnostic tool in the study of various pulmonary disorders. The significance of increased asparagine, phosphoethanolamine, and taurine in the asthmatic patients is discussed and deserves further study.

Adult↗
PubMed1997

Kinetics of the development and recovery of the lung from IgE-mediated inflammation: dissociation of pulmonary eosinophilia, lung injury, and eosinophil-active cytokines.

Events occurring up to 16 d after antigen challenge were characterized using a novel protocol employing four bronchoscopies, two segmental antigen challenge (SAC) procedures (on Days 1 and 2), and six bronchoalveolar lavages (BALs) (on Days 1, 2, 9, and 16) in three groups: ragweed allergic asthmatics with dual phase airway reactions (AA-D), allergic asthmatics with a single early airway reaction (AA-S), and nonallergic nonasthmatic control subjects. In AA-D subjects, SAC produced a marked eosinophilic inflammatory response at 24 h associated with eosinophil degranulation (eosinophil cationic protein [ECP] in BAL fluid) and lung injury, which largely resolved by Day 16. When the second antigen-challenged segment (SAC performed on Day 2) was lavaged 7 d after challenge (Day 9), a persistent pulmonary eosinophilia was noted accompanied by minimal elevations in ECP and albumin. Eosinophil-active cytokines showed unique patterns: interleukin-5 (IL-5) increased in the antigen segment on Day 2 then returned to baseline after 7 d; granulocyte-macrophage colony-stimulating factor (GM-CSF) peaked at Day 2 but was persistently elevated throughout Day 16 in antigen segments, and increased in control segments at late time points; IL-3 levels were constant and similar in antigen and control segments. Changes were specific to AA-D subjects in comparison with control subjects. Elements of the IgE-mediated pulmonary inflammatory response differ markedly in their development and resolution.

Adult↗
PubMed1997

An evaluation of colchicine as an alternative to inhaled corticosteriods in moderate asthma. National Heart, Lung, and Blood Institute's Asthma Clinical Research Network.

Colchicine demonstrates an array of anti-inflammatory properties of potential relevance to asthma. However, the efficacy of colchicine as an alternative to inhaled corticosteroid therapy for asthma is unknown. Five centers participated in a controlled trial testing the hypothesis that in patients with moderate asthma needing inhaled corticosteroids for control, colchicine provides therapeutic benefit as measured by maintenance of control when inhaled steroids are discontinued. Subjects were stabilized on triamcinolane acetonide (800 microg daily) and then enrolled in a 2-wk run-in during which all subjects took both colchicine (0.6 mg/twice a day) and triamcinolone. At the end of the run-in, all subjects discontinued triamcinolone and were randomized to continued colchicine (n = 35) or placebo (n = 36) for a 6-wk double-blind treatment period. The treatment groups were similar in terms of disease severity. After corticosteroid withdrawal, 60% of colchicine-treated and 56% of placebo-treated subjects were considered treatment failures as defined by preset criteria. No significant difference in survival curves was found between treatment groups (log rank = 0.38). Other measures, including changes in FEV1, peak expiratory flow, symptoms, rescue albuterol use, and quality of life scores, also did not differ between groups. Of note, subjects failing treatment had significantly greater methacholine responsiveness at baseline than did survivors (PC20, 0.81+/-1.38 versus 2.11+/-2.74 mg/ml; p = 0.01). An analysis of treatment failures suggested that the criteria selected for failure reflected a clinically meaningful but safe level of deterioration. We conclude that colchicine is no better than placebo as an alternative to inhaled corticosteroids in patients with moderate asthma. Additionally, we conclude that the use of treatment failure as the primary outcome variable in an asthma clinical trial where treatment is withdrawn is feasible and safe under carefully monitored conditions.

Administration, Inhalation↗
PubMed1996

Comparison of regularly scheduled with as-needed use of albuterol in mild asthma. Asthma Clinical Research Network.

BACKGROUND: Inhaled beta-agonists are the most commonly used treatment for asthma, but data suggest that regularly scheduled use of these agents may have deleterious effect on the control of asthma. We compared the effects of regularly scheduled use of inhaled albuterol with those of albuterol used only as needed in patients with mild chronic, stable asthma. METHODS: In a multicenter, double-blind study, we randomly assigned 255 patients with mild asthma to inhale albuterol either on a regular schedule (126 patients) or only as needed (129 patients). The patients were followed for 16 weeks. RESULTS: The primary outcome indicator, peak expiratory air flow measured in the morning, did not change significantly during the treatment period in the scheduled (416 liters per minute after the run-in period and 414 liters per minute after the treatment period) or the as-needed (424 liters per minute at both times) treatment groups (P=0.71). There were no significant differences between the two groups in peak flow variability, forced expiratory volume in one second, the number of puffs of supplemental albuterol needed, asthma symptoms, asthma quality-of-life score, or airway responsiveness to methacholine. The statistically significant differences between the groups in evening peak flow and in the short-term bronchodilator response to inhaled albuterol were small and judged to be clinically unimportant. CONCLUSIONS: In patients with mild asthma, neither deleterious nor beneficial effects derived from the regular use of inhaled albuterol beyond those derived from use of the drug as needed. Inhaled albuterol should be prescribed for patients with mild asthma on an as-needed basis.

Administration, Inhalation↗
PubMed1996

IL-1 beta release from cultured bronchial epithelial cells and bronchoalveolar lavage cells from allergic and normal humans following segmental challenge with ragweed.

This work investigated whether interleukin 1 beta (IL-1 beta) release from epithelial cells is modulated by antigen challenge in vivo, and inflammatory cells in vitro. Bronchial epithelial cells were obtained before and after segmental allergen challenge in allergic and normal individuals, and were cultured with and without autologous bronchoalveolar lavage (BAL) cells. IL-1 beta in culture medium was quantitated by enzyme-linked immunoabsorbent assay (ELISA). Pre-challenge IL-1 beta levels from epithelial cells were similar in allergic (4.4 +/- 0.8 pg/ml, n = 32) and normal (6.8 +/- 1.7 pg/ml, n = 17) subjects. IL-1 beta levels were significantly elevated from epithelium with BAL cell co-culture vs without co-culture in both subject groups (allergic, 13.2 +/- 2.3 pg/ml, P = 0.006; normal: 16.4 +/- 4.0 pg/ml, P = 0.007). Post-challenge IL-1 beta from epithelial cells without BAL cells was increased in both groups, but significant only for allergic subjects (P = 0.003). Post-challenge IL-1 beta from epithelial with BAL cells changed little for allergic subjects (13.8 +/- 2.4 pg/ml), and increased for normal subjects (20.0 +/- 4.8 pg/ml). Decreased production of tumour necrosis factor alpha (TNF-alpha) was observed in allergic subjects (day 1: 447 pg/ml vs day 2: 258 pg/ml). Moreover, pre-challenge release of TNF-alpha and IL-1 beta levels from epithelial + BAL cells correlated well for allergic (r = 0.84) and normal subjects (r = 0.6), but post-challenge release correlated only in normal subjects (r = 0.90). These results indicate that bronchial epithelial cells and BAL cells interact, modulating release of these inflammatory cytokines.

Adult↗
PubMed1996

A controlled trial of the effect of the 5-lipoxygenase inhibitor, zileuton, on lung inflammation produced by segmental antigen challenge in human beings.

BACKGROUND: Segmental antigen challenge (SAC) and bronchoalveolar lavage (BAL) have been proven useful for investigating IgE-mediated lung inflammation in volunteers with allergies. OBJECTIVE: This model was used to evaluate the pulmonary antiinflammatory effects of an experimental 5-lipoxygenase inhibitor (zileuton) in subjects allergic to ragweed. We hypothesized that decreased generation of leukotrienes by inhibition of the 5-lipoxygenase pathway of arachidonic acid metabolism would diminish the subsequent inflammatory response resulting from antigen challenge. METHODS: Ten subjects with allergies received zileuton or placebo, 600 mg administered orally four times a day for 8 days, and then underwent bronchoscopy, BAL of a control segment, and SAC in the contralateral lung followed by BAL of the challenged segment 24 hours later in a double-blind, placebo-controlled, crossover protocol. Urinary excretion of leukotriene E4 induced by antigen challenge plus total and differential cell counts and the amount of total protein, albumin, urea, and eosinophil cationic protein in BAL fluid were determined. RESULTS: A significant inhibition of leukotriene production (approximately 86%) was observed in subjects receiving zileuton. In addition, there was a statistically significant increase in eosinophils after antigen challenge (0.6 +/- 0.2 x 10(4) eosinophils/ml increasing to 49.0 +/- 25.0 x 10(4) in subjects receiving placebo, whereas the influx of eosinophils in subjects receiving zileuton was not statistically different from baseline (1.1 +/- 0.7 x 10(4) eosinophils/ml increasing to 16.5 +/- 4.1 x 10(4); analysis of variance for repeated measures with post hoc comparisons). CONCLUSIONS: Treatment with zileuton altered the inflammatory response after antigen challenge. Products of the 5-lipoxygenase pathway appear to be important in recruiting eosinophils to the lung after SAC.

Adult↗
PubMed1996

Lung involvement in systemic sclerosis (scleroderma): relation to classification based on extent of skin involvement or autoantibody status.

Lung involvement accounts for significant morbidity and is a leading cause of mortality in patients with systemic sclerosis (SSc). It has been shown that different patterns of pulmonary involvement are seen in different subtypes of SSc. This paper reports a retrospective review of 72 patients with SSc to determine whether disease classification according to the extent of skin involvement alone (diffuse vs. limited) or autoantibody status was predictive of pulmonary parenchymal involvement. The diagnosis of interstitial lung disease was based on pulmonary function tests and chest radiographs. Restrictive lung disease was common in both limited SSc (lSSc) and diffuse SSc (dSSc), occurring in 30% and 50% of these patients respectively (P = 0.16). Radiographic evidence of significant interstitial disease was also comparable between the groups [nine of 32 lSSc patients (28%) vs. six of 17 dSSc patients (32%), P = n.s.]. No significant difference in mean lung function was found between patients with anti-Scl 70 antibody (n = 12) compared to those without (n = 60) (TLC 79.0 +/- SE 5.1% predicted vs. 82.8 +/- 2.2, P = n.s.; DLCO 63.0 +/- 5.1 vs. 59.7 +/- 2.5, P = n.s.). By contrast, statistically significant differences in mean lung function were found between patients with anticentromere antibody (ACA) (n = 24) and those without ACA (n = 48) (TLC 98.6 +/- SE 3.9% predicted vs. 79.7 +/- 3.1%, P < 0.001); and less frequent radiographic evidence of severe interstitial disease (0 of 17 with significant interstitial changes on chest radiograph vs. 15 of 32 (47%), P = 0.002). It is concluded that classification of SSc patients on the basis of the distribution of skin involvement poorly predicts the occurrence of interstitial lung disease. On the other hand, ACA is highly associated with the absence of interstitial lung disease.

Adult↗
PubMed1996

Effects of inflammation and acute beta-agonist inhalation on beta 2-AR signaling in human airways.

Although alterations in beta 2-adrenergic receptor (AR) responsiveness may in part explain reports linking deterioration of asthma control with beta-agonist treatment of asthmatics, few data exist on beta 2-AR regulation in human airway cells. We have employed a bronchoscopy model to examine inflammation- and beta-agonist-induced alterations in human bronchial epithelial cell beta 2-AR density and responsiveness. Allergic asthmatic subjects participated in 2-day protocols examining airways before and 24 h after segmental antigen challenge (SAC) with ragweed. To assess the effect of acute beta-agonist exposure, bronchoscopies were performed both with (+ beta-Ag) and without (-beta-Ag) inhalation of beta-agonist 30 min before the procedure. Measurements of inflammatory cell infiltration were obtained by analysis of bronchoalveolar lavage fluid, and beta 2-AR density and responsiveness were examined in bronchial epithelial cells obtained by bronchoscopic brushing. Neither SAC nor acute beta-agonist administration alone significantly affected epithelial cell beta 2-AR density. beta-Agonist-stimulated adenosine 3', 5'-cyclic monophosphate (cAMP) generation was significantly lower in the + beta-Ag groups compared with the-beta-Ag group, demonstrating acute agonist-specific beta 2-AR desensitization in vivo. SAC caused a small, statistically insignificant reduction in beta-Agonist-stimulated cAMP production in both -beta-Ag or + beta-Ag groups. These lata suggest that acute beta-agonist inhalation, but not airway inflammation, significantly reduces maximal beta 2-AR responsiveness in airway cells.

Albuterol↗
PubMed1995

Inhaled albuterol does not inhibit cellular influx or lung injury produced by segmental antigen challenge in humans.

Many experimental protocols and published guidelines for performing bronchoscopy, bronchoalveolar lavage (BAL), bronchial biopsies, and segmental antigen challenge (SAC) of allergic asthmatic subjects recommend treating subjects with a beta-agonist prior to the procedure. However, the effect of beta-agonist pretreatment has not been reported. In a retrospective analysis of ragweed allergic subjects undergoing bronchoscopy, SAC, and BAL, we examined the effect of albuterol pretreatment on cellular influx and lung injury produced by antigen challenge. Forty-eight subjects, 17 who received no pretreatment and 31 who received four puffs of albuterol prior to bronchoscopy, comprised the study groups. No parameter monitored in BAL fluid 24 h after SAC (total cells, macrophages, neutrophils, eosinophils, lymphocytes, total protein, albumin, or eosinophil cationic protein) differed in subjects pretreated with albuterol when compared with subjects who were not pretreated. Although additional, prospective studies are warranted, we conclude that beta-agonist pretreatment of experimental subjects does not alter many aspects of the inflammatory response produced by SAC.

Administration, Inhalation↗
PubMed1995

Insights into IgE-mediated lung inflammation derived from a study employing a 5-lipoxygenase inhibitor.

We have recently reported that the 5-lipoxygenase (5-LO) inhibitor, zileuton, alters lung inflammation produced by segmental antigen challenge in ragweed-allergic human subjects. Specifically, zileuton inhibited the urinary excretion of leukotriene E4 produced by antigen challenge, and the significant increase in bronchoalveolar lavage (BAL) eosinophils observed in subjects on placebo was not seen in subjects on zileuton. In this manuscript, we report additional data obtained during that study which provide information about mechanisms important during IgE-mediated inflammatory reactions in the lung. Three different areas are addressed: 1) the time to recovery of the lung from an IgE-mediated inflammatory response; 2) mechanisms related to the generation of cyclooxygenase products in the lung after antigen challenge and the effect of 5-LO inhibition on the production of cyclooxygenase metabolites; and 3) mechanisms responsible for the production of peptide leukotrienes in the lung and lung injury (as shown by albumin influx into the alveolar air space) 24 h after antigen challenge. We observed the following: 1) a significant BAL eosinophilia and basophilia remained 31 days (range 21-48) after segmental antigen challenge and bronchoalveolar lavage; 2) a decreased quantity of BAL cyclooxygenase products, as well as lipoxygenase products, in the presence of 5-LO inhibition; and 3) correlative analyses which suggest that while eosinophils appear most important for the production of peptide leukotrienes and lung injury 24 h after antigen challenge in subjects taking placebo, other effector mechanisms, perhaps those involving basophils and the initial mast cell triggering event, appear to gain in importance when the IgE-mediated inflammatory reaction is blunted by 5-LO inhibition.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1995

Prospective study of occupational asthma to laboratory animal allergens: stability of airway responsiveness to methacholine challenge for one year.

The stability of airway hyperresponsiveness was studied in a group of 178 young adults working with laboratory animals. At the time of their entry into the study, 132 of 178 subjects (74%) had less than 20% response to the inhalation of 25 mg/ml methacholine, whereas 26 (15%) had a methacholine dose causing a 20% fall in forced expiratory volume in 1 second after fewer than 80 breath units. The distribution of methacholine responsiveness did not differ at 6 months and 1 year; 155 of 178 volunteers (90.4%) responded during the repeated challenges to doses within one dilution of their results at entry. One hundred forty-one subjects were consistently unreactive during the year, and 17 were consistently reactive. Approximately equal numbers gained and lost reactivity. Those with consistently positive responses to methacholine were more likely to have skin test reactivity and chest symptoms. The presence of consistent chest symptoms was loosely associated with consistent methacholine responsiveness; 55% of those with consistent hyperresponsive airways had symptoms, and 24% of those who consistently had symptoms had hyperresponsive airways. We concluded that the methacholine response is relatively stable during the course of a year in laboratory animal workers who remain at their jobs and that the presence of a positive skin test response to laboratory animals or of chest symptoms does not change the pattern of stable responsiveness.

Adult↗
PubMed1995

sVCAM-1 levels after segmental antigen challenge correlate with eosinophil influx, IL-4 and IL-5 production, and the late phase response.

Evidence from in vitro studies suggests a potential role for vascular cell adhesion molecule-1 (VCAM-1) in eosinophil trafficking. We hypothesized that induction of VCAM-1 occurs in the lung during IgE-mediated airway inflammation in humans. The technique of segmental antigen provocation followed by bronchoalveolar lavage (BAL) at 24 h was used to study 27 ragweed-allergic asthmatics (AA) and 18 atopic nonasthmatics (ANA). Total and differential cell counts were performed, and IL-4, IL-5, and soluble (VCAM) (sVCAM) levels in concentrated BAL fluid were measured by ELISA. A large increase in sVCAM levels after segmental challenge in both AA and ANA (1.79 +/- 0.31 to 139.39 +/- 68.58 ng/ml, p < 0.0005 and 2.85 +/- 0.80 to 98.25 +/- 77.35 ng/ml, p < 0.05, respectively) was observed. BAL IL-4 and IL-5 also increased after challenge (IL-4: 51.7 +/- 17.72 to 150.1 +/- 58.82 pg/ml, 0.05 < p < 0.10, n = 20 for AA, and 36.6 +/- 9.05 to 116.8 +/- 51.5 pg/ml, 0.05 < p < 0.10, n = 15 for ANA; IL-5: 0 to 2.67 +/- 1.62 ng/ml, p < 0.01, n = 16 for AA, and 0 to 2.87 +/- 2.16 ng/ml, 0.05 < p < 0.10, n = 10 for ANA). In both groups, the majority of the increase in sVCAM, IL-4, and IL-5 was accounted for by subjects who displayed a dual phase response after whole-lung antigen inhalation. This fact, plus the strong correlation observed between postchallenge sVCAM, IL-4, and IL-5 levels and eosinophil influx, suggests that VCAM, IL-4, and IL-5 play important roles in the recruitment of eosinophils to the lung of humans after antigen challenge.

Adult↗
PubMed1995

Pulmonary inflammation after segmental ragweed challenge in allergic asthmatic and nonasthmatic subjects.

Inflammatory reactions in the airways are thought to play an important role in asthma pathogenesis. The goal of this work was to test prospectively the hypothesis that the pulmonary inflammatory response to segmental antigen challenge is greater in allergic asthmatic (AA) subjects than in allergic nonasthmatic (ANA) subjects. A total of 46 ragweed-allergic subjects, 27 AA and 19 ANA, took part in these studies. Subjects had normal or nearly normal pulmonary function, were on no chronic medication, and were characterized as to their skin sensitivity to intradermal ragweed injection, their nonspecific responsiveness to methacholine, and the presence (or absence) of a late asthmatic response after whole-lung antigen challenge. Subjects then underwent bronchoscopy, bronchoalveolar lavage (BAL) of a control lung segment, antigen lung challenge of a contralateral lung segment with 5 ml of a concentration of ragweed solution 100-fold higher than that required to produce a positive skin reaction, and finally, BAL of the challenged segment after 24 h. AA did not differ from ANA in any inflammatory parameter measured in BAL fluid (total cells/ml, macrophages/ml, lymphocytes/ml, eosinophils/ml, neutrophils/ml, total protein, albumin, urea, or eosinophil cationic protein) 24 h after challenge. In addition, there was no relationship between nonspecific bronchial responsiveness to methacholine and eosinophils recruited to the lung by segmental antigen challenge. Rather, in both groups a marked inflammatory response was seen only in the subgroup of subjects who demonstrated a late airway reaction after whole-lung antigen challenge, regardless of disease classification.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗