Prognostic value of serum surfactant protein D level prior to transplant for the development of bronchiolitis obliterans syndrome and idiopathic pneumonia syndrome following allogeneic hematopoietic stem cell transplantation.

Bronchiolitis obliterans syndrome (BOS) and idiopathic pneumonia syndrome (IPS) cause high mortality and impaired survival after allogeneic hematopoietic stem-cell transplantation (allo-HSCT). Early recognition of patients at high risk of developing BOS/IPS may lead to improving the outcome of allo-HSCT. We retrospectively analyzed serum surfactant protein A, D (SP-A, -D) and Kerbs von Lungren 6 Ag (KL-6) levels before allo-HSCT in 56 patients who survived more than 90 days after allo-HSCT and compared values of these serum markers and other transplant factors in BOS/IPS patients with those in non-BOS/IPS patients. Five patients developed BOS and two developed IPS at a median interval of 303 and 117 days (range, 100-452 and 95-153) from transplantation. As a result of univariate analysis, pretransplant serum SP-D levels but not SP-A, KL-6 in BOS/IPS patients were significantly lower than those in non-BOS/IPS patients (P=0.03). In multivariate analysis, the patients with lower pretransplant serum SP-D level had a trend toward frequent development of BOS/IPS (P=0.08). Constitutive serum SP-D level before allo-HSCT may be a useful, noninvasive predictor for the development of BOS/IPS.

Correlations of health-related quality of life questionnaire results in asthma and allergic rhinitis: effects of a leukotriene receptor antagonist.

Bronchial asthma and allergic rhinitis frequently coexist. This study investigated correlations of health-related quality of life (QOL) questionnaires for these diseases, assessing whether the selective leukotriene receptor antagonist (LTRA), pranlukast, had additional benefits to overall asthma control when there was concomitant allergic rhinitis. Patients with asthma-associated allergic rhinitis were randomly allocated to either LTRA(+) (n = 21, treated for 3 months with pranlukast), or LTRA(-) (n = 8, no pranlukast). At study start and at 3 months, pulmonary function was evaluated and QOL assessments were made using the Asthma Health Questionnaire-Japan (AHQ-Japan) and the Japan Rhino-conjunctivitis Quality of Life Questionnaire (JRQLQ). Total scores were significantly correlated both before and after therapy. After 3 months' therapy, pulmonary function and total AHQ-Japan and JRQLQ scores significantly improved in the LTRA(+) group, but not in the LTRA(-) group. A significant correlation between change at 3 months in the AHQ-Japan and JRQLQ scores from baseline values was seen in the LTRA(+) group. LTRA therapy improved allergic rhinitis symptoms, asthma symptoms and pulmonary function.

IV. Clinical aspects of delayed hypersensitivity in lungs: pathophysiology of hypersensitivity disorders in clinics.

Hypersensitivity pneumonitis (HP) is an immunologically mediated lung disease of inhaled antigens. HP is not a uniform disease but rather a clinical complex syndrome characterized by varying intensities of responsiveness to different organic antigens. The main aetiological agents include thermophilic bacteria, fungi, animal proteins, and chemical compounds. A combination of host and environmental factors should be considered as a requisite to developing this disease. Although the antigens differ widely, the clinical syndromes that results are very similar. HP occurs mainly in non-smokers, and clinically it may be in acute, subacute, or chronic forms. The diagnosis of HP requires a constellation of clinic, radiographic, physiologic, pathologic, and immunologic criteria. HP is characterized by a diffuse and predominantly mononuclear cell inflammation, a partly granulomatous, immune disorder of alveolar regions that often involves the small airway. A strong evidence supports that delayed cell-mediated hypersensitivity mechanisms play a role in pathogenesis of HP. Studies performed on lung cells have demonstrated that cells bearing suppressor/cytotoxic phenotype characterize the lymphocytic alveolitis in patients with hypersensitivity pneumonitis. And also recently evidence has been provided indicating that a prominent role of T-helper 1 cell-mediated hypersensitivity with an imbalance in T-lymphocyte subsets, although the deposit of immune complex may participate in an acute form of the disease as well as in the early phase of the chronic form.

The macrolide antibacterial roxithromycin reduces bronchial hyperresponsiveness and superoxide anion production by polymorphonuclear leukocytes in patients with asthma.

We investigated the effects of a macrolide antibacterial, roxithromycin, on the generation of free radicals by peripheral polymorphonuclear leukocytes (PMNs) and on the severity of bronchial hyperresponsiveness. Ten asthmatic patients were treated for 3 months with roxithromycin, 150 mg orally once daily; such treatment significantly reduced the production of superoxide anion by PMNs (p = 0.0029) and reduced the bronchial hyperreactivity (p = 0.0016), as compared with results in healthy controls. Most of the patients required at least 2 months of treatment with roxithromycin for clinical improvement. We conclude that long-term, low-dose administration of roxithromycin may be useful in treatment of patients with bronchial asthma.

Adrenomedullin inhibits the secretion of cytokine-induced neutrophil chemoattractant, a member of the interleukin-8 family, from rat alveolar macrophages.

This study was undertaken to determine the effects of adrenomedullin (AM) on the secretion of cytokine-induced neutrophil chemoattractant (CINC), a member of the interleukin-8 family, from lipopolysaccharide-stimulated rat alveolar macrophages in vitro. AM significantly increased cAMP levels in alveolar macrophages in a dose-dependent fashion. On the other hand, AM significantly inhibited CINC secretion from alveolar macrophages in a dose-dependent fashion, and 8-bromo-cyclic adenosine monophosphate (8-Br-cAMP) also significantly inhibited CINC secretion. These findings suggest that AM may play important roles in the regulation of airway inflammation via a cAMP-dependent mechanism.

Increased levels of vascular endothelial growth factor in induced sputum in asthmatic patients.

BACKGROUND: Vascular endothelial growth factor (VEGF) is highly expressed in the airway of asthmatic patients. As VEGF increases airway vascular permeability, consequent thickening of the airway wall mucosa may lead to narrowing of the airway lumen. OBJECTIVE: We evaluated the relationship between VEGF levels in induced sputum and eosinophilic inflammatory profiles, and the degree of airway vascular permeability in asthmatic patients and we evaluated the effect of inhaled corticosteroids on VEGF levels in induced sputum. METHODS: Induced sputum specimens were obtained from 28 glucocorticosteroids free asthmatics and 11 healthy control subjects. We examined VEGF levels and airway vascular permeability index in induced sputum. After the initial sputum induction, 21 asthmatics received 8-week inhaled beclomethasone dipropionate (BDP, 800 micro g/day) therapy, then sputum induction was repeated. RESULTS: The VEGF levels in asthmatics were significantly higher than in healthy control subjects (P < 0.0001). The VEGF levels were negatively correlated with forced expiratory volume of 1 s (FEV1, % predicted, r = - 0.68, P < 0.001), the percentage of eosinophils (r = 0.51, P < 0.01) and ECP levels (r = 0.39, P < 0.05). Moreover, the VEGF levels were significantly correlated with airway vascular permeability index (r = 0.61, P < 0.001). After 8-week inhaled BDP therapy, the VEGF levels were significantly decreased compared to pretreatment levels (P < 0.0001) and the VEGF levels were significantly correlated with airway vascular permeability index even in post-treatment asthmatics (r = 0.62, P < 0.01). CONCLUSION: The VEGF levels in induced sputum were increased in asthmatics and its levels were associated with degree of airway narrowing and airway vascular permeability. These findings provide strong evidence that VEGF may play an important role in the pathogenesis of bronchial asthma.

Phagocytic function of salivary PMN after smoking or secondary smoking.

Alterations in polymorphonuclear leukocyte (PMN) functions, such as phagocytosis, chemotaxis, and oxidative burst, play a pivotal role in periodontal pathogenesis. In addition, previous studies have demonstrated a strong relationship between smoking and periodontal disease. In the present study, the effect of cigarette smoking or passive smoking (secondary smoking) on the phagocytic function of salivary PMN (SPMN) was investigated. Twenty volunteers with clinically healthy gingiva (10 smokers, 10 non-smokers) participated in this study. In a small room, the smokers and passive smokers (non-smokers) were instructed to smoke and breathe, respectively, in an identical, specific way for about 4 minutes. SPMN was isolated immediately before and after smoking or passive smoking. PMN was then incubated with fluoresbrite beads for 45 minutes at 37 degrees C and the phagocytic status estimated by using a flow cytometer. Cell viability was determined by trypan blue exclusion (smokers before smoking: 88.3%: smokers after smoking: 89.6%: non-smokers before passive smoking: 89.0%; non-smokers after passive smoking: 89.4%). In both smokers and passive smokers, the proportion of phagocytic cells increased between before and after smoking (smokers before: 33.2%; after: 42.1%: passive smokers before: 36.2%: after: 44.1%). Both increases were statistically significant (P < 0.01). These results demonstrate that the phagocytic activity of SPMN intensifies after smoking and passive smoking. They also suggest that certain substances in cigarette smoke, perhaps nicotine, overstimulate the host response in the oral cavity.

PAMP is a novel inhibitor of the tachykinin release in the airway of guinea pigs.

Proadrenomedullin NH2-terminal 20 peptide (PAMP), a newly identified hypotensive peptide, may play physiological roles in airway and cardiovascular controls. This study was designed to determine the mechanism responsible for the bronchoprotective effects of PAMP on capsaicin-induced bron-choconstriction in anesthetized guinea pigs. PAMP (10(-8)-10(-6) M) significantly inhibited capsaicin-induced bronchoconstriction in a dose-dependent manner. The bronchoprotective effect of PAMP (10(-6) M) was as large as that of isoproterenol (10(-7) M) and lasted > 10 min. The concentration of immunoreactive substance P (SP) in bronchoalveolar lavage fluid after administration of capsaicin (4 x 10(-6) M) was 120 +/- 10 fmol/ml. PAMP significantly inhibited the release of immunoreactive SP in a dose-dependent manner (60 +/- 6 fmol/ml for (10(-6) M PAMP, P < 0.01; 84 +/- 6 fmol/ml for 10(-7) M PAMP, P < 0.01; and 95 +/- 6 fmol/ml for 10(-8) M PAMP, P < 0.05). PAMP (10(-6) M) did not significantly affect exogenous neurokinin A (NKA) or NKA + SP-induced bronchoconstriction, whereas isoproterenol (10(-7) M) significantly inhibited exogenous tachykinin-induced bronchoconstriction. These findings suggest that the bronchoprotective effects of PAMP are mainly due to inhibition of the release of tachykinins at airway C-fiber endings.

Calcitonin gene-related peptide antagonizes the protective effect of adrenomedullin on histamine-induced bronchoconstriction.

1. In the present study the possible relationship between adrenomedullin (AM) and calcitonin gene-related peptide (CGRP) in the regulation of airway functions in anaesthetized guinea-pigs was examined in vivo. 2. We found that AM significantly inhibited histamine-induced bronchoconstriction in a dose-dependent manner. CGRP or the CGRP receptor antagonist (CGRP [8-37]) alone did not affect pulmonary resistance and pretreatment with CGRP or CGRP [8-37] did not significantly affect histamine-induced bronchoconstriction. However, AM-induced bronchoprotection was significantly inhibited by pretreatment with CGRP or CGRP [8-37] in a dose-dependent manner. 3. It is therefore possible that CGRP may be competitive, at least in part, with binding sites of AM in the guinea-pig airway. Exogenous AM may be useful for the management of bronchial asthma, not only as a potent bronchodilator, but also as a functional antagonist of CGRP.