Biomedical subjects

Mark D Inman

Publications and source records attributed to Mark D Inman.

28 records · Page 2Linked to original sources

PubMed2002

Effects of montelukast and budesonide on airway responses and airway inflammation in asthma.

Inhaled corticosteroids are effective antiinflammatory therapy for asthma; however, they do not completely abolish allergen-induced airway inflammation. Leukotriene modifiers attenuate both early and late allergen responses and have antiinflammatory properties. We reasoned that treatment with budesonide and montelukast in combination might provide greater antiinflammatory effects than either drug alone, and the purpose of this study was to compare the effects of treatment with budesonide and montelukast, alone or in combination, on outcome variables after allergen inhalation. Ten subjects with asthma with dual responses after allergen inhalation were included in this randomized, double-blind, crossover study. Outcomes included early and late asthmatic responses, and changes in airway responsiveness and sputum eosinophilia, measured before and after challenge. Treatment with montelukast attenuated the maximal early asthmatic response compared with placebo (p < 0.001) and budesonide (p = 0.002). Both budesonide and montelukast, alone and in combination, attenuated the maximal late asthmatic response compared with placebo (p < 0.01). Budesonide and montelukast, alone and in combination, afforded protection against allergen-induced airway hyperresponsiveness (p < 0.05), although the treatment effect of budesonide was greater than that of montelukast (p < 0.05). Treatment with budesonide and montelukast, alone and in combination, also attenuated allergen-induced sputum eosinophilia. Thus, montelukast and budesonide attenuated allergen-induced asthmatic responses, airway hyperresponsiveness, and sputum eosinophilia, although combination treatment did not provide greater antiinflammatory effects than either drug alone.

Acetates↗

PubMed2002

Effect of interferon-gamma on allergic airway responses in interferon-gamma-deficient mice.

Interferon (IFN)-gamma reduces airway responses after allergen challenge in mice. The mechanisms of this effect are not clear. These studies investigate whether IFN-gamma can reverse prolonged airway responses after allergen challenge in IFN-gamma-deficient (IFN-gammaKO) mice. Sensitized mice (IFN-gammaKO and wild-type [WT]) were challenged with ovalbumin. Airway responsiveness, eosinophils in bronchoalveolar lavage fluid, and lung lymphocyte subsets (CD4(+) and CD8(+)) were measured 24 hours and 8 weeks after challenge. In further experiments, we treated IFN-gammaKO mice with recombinant IFN-gamma starting 4 weeks after the challenge for 1 week or 4 weeks. Airway responsiveness, bronchoalveolar lavage eosinophils, and lung CD4(+) cells were increased 8 weeks after challenge in IFN-gammaKO but not WT mice. IFN-gamma treatment returned lung CD4(+) cell numbers to values obtained in unchallenged mice. One week of IFN-gamma treatment also returned airway responsiveness to baseline levels; however, 4-week treatment with IFN-gamma failed to decrease airway responsiveness below levels observed in untreated animals. This suggests that IFN-gamma plays an essential role in reversing allergen-induced airway inflammation and hyperresponsiveness and that it may have dual actions on the latter. Observations that IFN-gamma reverses airway responses, even when administered after challenge, suggests that IFN-gamma treatment could control allergic disease, including asthma.

Airway Obstruction↗

PubMed2002

The effects of intranasal budesonide on allergen-induced production of interleukin-5 and eotaxin, airways, blood, and bone marrow eosinophilia, and eosinophil progenitor expansion in sensitized mice.

We have previously demonstrated that allergen inhalation induces expansion of bone marrow eosinophil progenitors in sensitized mice and subjects with asthma and that the inhaled corticosteroid, budesonide, reduced baseline but not allergen-induced increase in bone marrow eosinophil/basophil progenitors (EoB-CFU) in subjects with asthma. Here, we evaluated the effects of intranasal budesonide on allergen-induced increases in interleukin (IL)-5 and eotaxin in the airway and peripheral blood, expansion of bone marrow Eo-CFU and eosinophilia in bone marrow, peripheral blood and airway, as well as airway hyperresponsiveness, in ovalbumin (OVA)-sensitized mice. Budesonide treatment attenuated allergen-induced eosinophilia in bone marrow, peripheral blood, and airways as well as allergen-induced increases in bone marrow eosinophil progenitors but not allergen-induced increases in IL-5 or eotaxin 12 h following the second of two daily exposures to allergen; at later time points treatment was associated with attenuation of IL-5, eosinophilia, Eo-CFU, and airway hyperresponsiveness. These results suggest that a component of the mechanism by which corticosteroid treatment attenuates allergen-induced airway inflammation is through suppression of bone marrow eosinophilopoiesis, and that this is likely not mediated simply through the blocking of IL-5 production at the airway.

Administration, Intranasal↗

PubMed2002

Beta2-agonist tolerance and exercise-induced bronchospasm.

The effect of regular inhaled beta-agonist on the treatment of exercise-induced bronchoconstriction was studied. Eight subjects with exercise-induced bronchoconstriction took 1 week each of salbutamol 200 microg qid or placebo in a random-order, double-blind, crossover study. They then withheld this treatment for 8 hours before performing a dry-air, sub-maximal exercise challenge at a work-rate previously shown to induce a 15% fall in forced expiratory volume in 1 second (FEV1). Five minutes after exercise, they inhaled salbutamol 100, 100, and 200 microg at 5-minute intervals. The mean pre-exercise FEV1 was similar on both study days. However, pretreatment for 1 week with salbutamol led to a significantly greater fall in FEV1 after exercise. The FEV1 remained lower than during the placebo arm despite the administration of salbutamol after exercise. This difference persisted 25 minutes after exercise. It is concluded that regular beta-agonist treatment leads to increased exercise-induced bronchoconstriction and a suboptimal bronchodilator response to beta-agonist. The data suggest that previous regular beta-agonist treatment may lead to a failure to respond to emergency bronchodilator treatment during an acute asthma attack and support current opinion that regular short-acting beta-agonist therapy should not be used to treat asthma.

Adolescent↗

PubMed2002

Pathogenesis of murine experimental allergic rhinitis: a study of local and systemic consequences of IL-5 deficiency.

Recent studies have demonstrated an important role for IL-5-dependent bone marrow eosinophil progenitors in allergic inflammation. However, studies using anti-IL-5 mAbs in human asthmatics have failed to suppress lower airway hyperresponsiveness despite suppression of eosinophilia; therefore, it is critical to examine the role of IL-5 and bone marrow responses in the pathogenesis of allergic airway disease. To do this, we studied the effects of IL-5 deficiency (IL-5(-/-)) on bone marrow function as well as clinical and local events, using an established experimental murine model of allergic rhinitis. Age-matched IL-5(+/+) and IL-5(-/-) BALB/c mice were sensitized to OVA followed by 2 wk of daily OVA intranasal challenge. IL-5(-/-) OVA-sensitized mice had significantly higher nasal mucosal CD4(+) cells and basophilic cell counts as well as nasal symptoms and histamine hyperresponsiveness than the nonsensitized group; however, there was no eosinophilia in either nasal mucosa or bone marrow; significantly lower numbers of eosinophil/basophil CFU and maturing CFU eosinophils in the presence of recombinant mouse IL-5 in vitro; and significantly lower expression of IL-5Ralpha on bone marrow CD34(+)CD45(+) progenitor cells in IL-5(-/-) mice. These findings suggest that IL-5 is required for normal bone marrow eosinophilopoiesis, in response to specific Ag sensitization, during the development of experimental allergic rhinitis. However, the results also suggest that suppression of the IL-5-eosinophil pathway in this model of allergic rhinitis may not completely suppress clinical symptoms or nasal histamine hyperresponsiveness, because of the existence of other cytokine-progenitor pathways that may induce and maintain the presence of other inflammatory cell populations.

Animals↗

PubMed2002

Anti-allergic therapies: effects on eosinophil progenitors.

Marked eosinophilic infiltration is the typical inflammatory response associated with allergic inflammation. Previous research involving animal and human models has established a role for the eosinophil/basophil hematopoietic progenitor in a systemic process of allergic inflammation. In this article, we will review the evidence implicating eosinophil/basophil progenitors in this systemic response and will discuss the rationale for targeting this cell in the treatment of allergic disease. In this context, we discuss corticosteroid treatment of allergic diseases, such as asthma and its effects on hematopoietic mechanisms, the effects of therapies that inhibit the actions of cysteinyl leukotrienes, the effects of in vivo blockade of the eosinophil-active cytokine interleukin-5, and the effects of antihistamines on hematopoiesis. It is suggested that several anti-allergic therapies exert their beneficial effects on allergic inflammation by influencing eosinophil production systemically. Therefore, targeting the systemic hematopoietic response may provide additional, more beneficial, therapeutic effects.

Animals↗

PubMed2002

Influence of zafirlukast and loratadine on exercise-induced bronchoconstriction.

BACKGROUND: Airway obstruction induced by physical exercise is a common feature in asthma, and conventional treatments do not offer optimal protection. There is thus a need for additional therapies for optimal control of exercise-induced bronchoconstriction (EIB). OBJECTIVE: The influence of treatment with the antihistamine loratadine and the antileukotriene zafirlukast alone and in combination on EIB was investigated. This combination has previously shown beneficial additive effects in allergen-induced bronchoconstriction. METHODS: In a double-blind cross-over study loratadine (10 mg twice daily) and zafirlukast (80 mg twice daily) were evaluated alone and in combination in 16 nonsmoking patients with mild asthma, previously documented EIB, and airways hyperresponsiveness to histamine. RESULTS: The mean +/- SE maximum decrease in FEV1 after a standardized exercise provocation was 21.6% +/- 3% after placebo, 22.8% +/- 3% after loratadine, 13.9% +/- 2% after zafirlukast (P <.05 vs placebo), and 10.3% +/- 2% after the combination of loratadine and zafirlukast (P <.05 vs placebo). Expressed as the area under the FEV1 percentage change versus time curve, the mean protection produced by zafirlukast and the combination of zafirlukast and loratadine was 57% and 65%, respectively, whereas loratadine alone had no significant protective effect. There was also no significant difference between the effect of zafirlukast alone or in combination with loratadine. CONCLUSION: The study confirmed the beneficial effect of a leukotriene receptor antagonist in EIB but failed to obtain evidence that H1-receptor antagonism alone or together with the cysteinyl-leukotriene 1 receptor antagonist zafirlukast offers a protective effect.

Bronchial Diseases↗

PubMed2002

The effect of cysteinyl leukotrienes on growth of eosinophil progenitors from peripheral blood and bone marrow of atopic subjects.

BACKGROUND: The accumulation of eosinophils into the peripheral blood and airways of asthmatic subjects is, in part, dependent on cysteinyl leukotrienes (cysLTs). However, the effect of cysLTs on peripheral blood and bone marrow eosinophil pro-genitor cells in allergic subjects is not known. OBJECTIVE: The purpose of this study was to evaluate the effects of leukotriene (LT) D(4) and LTE(4) and the cysLT(1) receptor antagonist montelukast on peripheral blood and bone marrow eosinophil-basophil progenitor growth and development in atopic subjects. METHODS: Semisolid methylcellulose cultures for peripheral blood and bone marrow eosinophil-basophil colonies were counted after incubation with or without addition of LTD(4), LTE(4), and montelukast in the presence of suboptimal concentrations of GM-CSF, IL-3, and IL-5. RESULTS: Peripheral blood eosinophil-basophil colony-forming unit cultures grown in the presence of GM-CSF and bone marrow eosinophil-basophil colony-forming units grown in the presence of IL-5 were significantly increased by the addition of LTD(4) (0.1 micromol/L). This increase was suppressed by montelukast (1 micromol/L). CONCLUSION: This study has demonstrated that the cysLT LTD(4) can stimulate proliferation of eosinophil hematopoietic progenitor cells in the presence of eosinophilopoietic cytokines. The suppressive effect by montelukast demonstrates that this is a cysLT(1) receptor-mediated effect.

Acetates↗

PubMed2002

Dysfunction and remodeling of the mouse airway persist after resolution of acute allergen-induced airway inflammation.

The mechanisms underlying airway hyperresponsiveness remain unclear, although airway inflammation and remodeling are likely important contributing factors. We hypothesized that airway physiology would differ between mice subjected to brief or chronic allergen exposure, and that these differences would be associated with characteristic inflammatory markers and indices of airway remodeling. BALB/c mice were sensitized to ovalbumin and studied at several time points following brief or chronic allergen challenge protocols. By measuring airway responses to methacholine, we demonstrated increases in maximal inducible bronchoconstriction that persisted for 8 wk following either brief or chronic allergen challenge; we also observed increases in airway reactivity, although it was only in chronically challenged mice that these changes persisted beyond the resolution of allergen-induced inflammation. Using airway morphometry, we further demonstrated that increases in maximal bronchoconstriction were associated with increases in airway contractile tissue in both models, and that chronic, but not brief, allergen challenge resulted in subepithelial fibrosis. Our observations that different aspects of sustained airway dysfunction and remodeling persist beyond the resolution of acute inflammatory events support the concept that remodeling occurs as a consequence of allergic airway inflammation, and that these structural changes contribute independently to the persistence of airway hyperresponsiveness.

Actins↗

PubMedDate not supplied

Increased levels of airway neutrophils reduce the inhibitory effects of inhaled glucocorticosteroids on allergen-induced airway eosinophils.

BACKGROUND: Treatment with inhaled glucocorticosteroids attenuates allergen-induced airway inflammation but is less effective in people with asthma who have noneosinophilic airway inflammation. OBJECTIVE: Studies in which glucocorticosteroid treatment was used before allergen challenges were re-examined to determine whether the efficacy of steroid treatment could be predicted by baseline levels of sputum inflammatory cells. PATIENTS AND METHODS: Twenty-eight nonsmoking subjects with atopic asthma controlled by beta2-agonists participated in only one of three studies, each carried out with a double-blind, placebo controlled, randomized, crossover design. Subjects were treated with glucocorticosteroids or placebo for six to eight days and then underwent allergen inhalation challenge. Spirometry was measured for 7 h after allergen challenge, and then sputum inflammatory cells were measured. Sputum inflammatory cells were also measured before and after treatment, and 24 h after allergen challenge. The per cent inhibition of the allergen-induced airway responses by glucocorticosteroids was calculated. RESULTS: Inhaled glucocorticosteroids significantly attenuated the early and late asthmatic responses, and the number of allergen-induced sputum eosinophils (P<0.05). There was a significant negative relationship between the number of sputum neutrophils at baseline, and the per cent inhibition of allergen-induced sputum eosinophils measured at 7 h (r=-0.61, P<0.001) and 24 h (r=-0.73, P<0.0001) after challenge, suggesting that glucocorticosteroids are less effective in attenuating allergen-induced airway inflammation in subjects with high levels of neutrophils. There was no correlation between the number of sputum eosinophils at baseline and the per cent inhibition of allergen-induced responses. CONCLUSIONS: Baseline airway neutrophils, not eosinophils, can be used to predict the efficacy of inhaled steroids on allergen-induced sputum eosinophils.

Administration, Inhalation↗