Yukihiko Homma

Beta 2 adrenergic receptor gene restriction fragment length polymorphism and bronchial asthma.

BACKGROUND--Beta 2 adrenergic dysfunction may be one of the underlying mechanisms responsible for atopy and bronchial asthma. The gene encoding the human beta 2 adrenergic receptor (beta 2ADR) has recently been isolated and sequenced. In addition, a two allele polymorphism of this receptor gene has been identified in white people. A study was carried out to determine whether this polymorphism is functionally important and has any relation to airways responsiveness, atopy, or asthma. METHODS--The subjects studied were 58 family members of four patients with atopic asthma. Restriction fragment length polymorphism (RFLP) with Ban-I digestion of the beta 2ADR gene was detected by a specific DNA probe with Southern blot analysis. Airways responses to inhaled methacholine and the beta 2 agonist salbutamol, the skin prick test, and serum IgE levels were also examined and correlated to the beta 2ADR gene RFLP. In addition, measurements of cAMP responses to isoproterenol in peripheral mononuclear cells were performed in 22 healthy subjects whose genotype for beta 2ADR was known. RESULTS--A two allele polymorphism (2.3 kb and 2.1 kb) of the beta 2ADR gene was detected in the Japanese population. Family members without allele 2.3 kb (homozygote of allele 2.1 kb) had lower airways responses to inhaled salbutamol than those with allele 2.3 kb. The incidence of asthma was higher in those without allele 2.3 kb than in those with allele 2.3 kb. The beta 2ADR gene RFLP had no relation to airways responses to methacholine and atopic status. cAMP responses in peripheral mononuclear cells of the subjects without allele 2.3 kb tended to be lower than those of the subjects with allele 2.3 kb. CONCLUSIONS--These results suggest that Ban-I RFLP of the beta 2ADR gene may have some association with the airways responses to beta 2 agonists and the incidence of bronchial asthma.

Can Interstitial Pneumonia as the Sole Presentation of Collagen Vascular Diseases Be Differentiated from Idiopathic Interstitial Pneumonia

We prospectively followed 68 patients diagnosed as idiopathic interstitial pneumonia (IIP) over a period of 1-11 years. Thirteen patients (19%) subsequently developed systemic manifestations of collagen vascular diseases (CVD) and were diagnosed as having had interstitial pneumonia as the sole presentation of CVD (CVD-IP). Compared with the 55 IIP patients, the 13 CVD-IP patients were relatively younger, predominantly female, and had a lower incidence of dust inhalation in their history. They also had a higher erythrocyte sedimentation rate, higher incidence of the x-ray finding of discoid atelectasis in the lower lung fields, and a better prognosis than the IIP patients. However, these features did not clearly distinguish the two groups. We conclude that the patients clinically and/or histologically defined as suffering from IIP cannot be distinguished from CVD-IP patients before systemic signs of CVD appear in the latter group.

Expression and alteration of Ras and P53 proteins in patients with lung carcinoma accompanied by idiopathic pulmonary fibrosis

The ras oncogene and the p53 tumor suppressor gene play important roles in the carcinogenic process of lung carcinoma. The authors evaluated whether alterations of the ras and p53 proteins may contribute to the development of lung carcinoma in patients with idiopathic pulmonary fibrosis (IPF) and whether such alterations may explain the high incidence of lung carcinoma among patients with IPF.

Enhancement of goblet cell hyperplasia and airway hyperresponsiveness by salbutamol in a rat model of atopic asthma

BACKGROUND Goblet cell hyperplasia (GCH) is a prominent feature in animal models of atopic asthma produced by immunisation and following multiple challenges with antigens. The aim of this study was to examine the effect of a β2 agonist on the development of GCH induced by the immune response. METHODS Brown Norway rats were immunised and challenged with an aerosol of ovalbumin for four weeks. Salbutamol (0.5 mg/kg/day) or vehicle was continuously delivered for the four weeks using a subcutaneously implanted osmotic minipump. The density of goblet cells, other morphological changes, and airway responsiveness to methacholine were evaluated 24 hours after the final challenge. RESULTS Treatment with salbutamol induced a more than twofold increase in the mean (SE) number of goblet cells (53.7 (7.3) vs 114.5 (11.8) cells/103epithelial cells, p<0.01) while it did not significantly influence airway wall thickening and eosinophilic infiltration. Airway responsiveness to methacholine expressed as the logarithmic value of the concentration of methacholine required to generate a 50% increase in airway pressure (logPC150Mch) was also enhanced by the β2 agonist (–0.56 (0.21) vs –0.95 (0.05), p<0.05). Additional experiments revealed that the same dose of the β2 agonist alone did not cause GCH in non-immunised rats and that the enhancement of GCH by salbutamol was completely abolished by simultaneous treatment with methylprednisolone (0.5 mg/kg/day). CONCLUSIONS These data suggest that salbutamol enhances goblet cell hyperplasia and airway hyperresponsiveness in this rat model of atopic asthma.

Autoantibody to alanyl-tRNA synthetase in patients with idiopathic pulmonary fibrosis

Background and objectives:  The pathogenesis of IPF is unknown and it is hypothesized that immunological responses are involved. The purpose of this study was to detect autoantibodies in IPF patients and to identify the relevant antigens.

Gamma-interferon modifies guinea pig airway functions in vitro

Cytokines produced by T-lymphocytes may have significant roles in the airway inflammation seen in bronchial asthma. Gamma interferon (IFN-gamma), a T-cell derived cytokine, is known to modify functions of both immune and non-immune cells. In this study, we investigated whether IFN-gamma can modify guinea pig airway functions in vitro. The isometric tension of guinea pig airway strips was measured in a tissue bath filled with Krebs-Henseleit solution. Contracting responses to carbachol and KCl, and the relaxing response to isoproterenol (ISO) were examined. Effects of IFN-gamma were examined by comparing responses of the strips incubated with or without IFN-gamma (1000 U.ml-1; 25,000 U.ml-1). Contracting responses to carbachol and KCl were not affected by the incubation with IFN-gamma other than slight increased in maximum contraction by carbachol after 5 hours incubation with 25,000 U.ml-1 of IFN-gamma. Both 1 and 5 h incubation of strips with 25,000 U.ml-1 IFN-gamma significantly increased the sensitivity to ISO (p < 0.01 and p < 0.05, respectively) without affecting maximum relaxation. The effect of IFN-gamma on ISO relaxation was abolished by the denudation of airway epithelium from strips, indomethacin (2 microM), and cycloheximide (70 microM) but not by N omega-nitro-L-arginine methyl ester (30 microM). In addition, heat-inactivated IFN-gamma and bacterial endotoxin (LPS, 0.625 pg.ml-1) had no effect on ISO relaxation. These results suggest that IFN-gamma is able to modify airway smooth muscle response to beta-adrenergic agonist by inducing release of prostanoids from airway epithelium.

Incidence of serum-precipitating antibodies to farmer's lung antigens in Hokkaido.

The prevalence of serum-precipitating antibodies to Micropolyspora faeni and Thermoactinomyces vulgaris was studied by immunoelectrophoresis in 442 dairy farmers living in Hokkaido, the northernmost district of Japan. The prevalence rates of antibodies to M. faeni and T. vulgaris were 24.2 and 11.6%, respectively. The rate of antibodies to M. faeni was higher among females than males. This difference may be due to the large number of nonsmokers among females. Prevalence of antibodies to M. faeni or M. faeni and T. vulgaris was associated with a higher hay acreage and longer working hours per day in the cowshed, and not to the size of the dairy herd. These results were partly different from those reported from other countries.

Mechanisms of epidermal growth factor-induced contraction of guinea pig airways.

We investigated the functional effects of epidermal growth factor (EGF) on guinea pig airways in vitro. EGF (3 ng/ml to 1 microgram/ml) induced a concentration-dependent contraction in epithelium-denuded strips. The average maximal contraction was 0.64 +/- 0.1 g (mean +/- S.E., for n = 27), which was 72.0 +/- 9.5% of the 100 mM KCl-induced contraction. The EC50 was 12.3 +/- 1.6 ng/ml. The presence of the epithelium significantly suppressed the EGF-induced contraction (P < 0.01). EGF-induced contraction was abolished by cyclooxygenase inhibitors (indomethacin and ibuprofen) and a 5-lipoxygenase inhibitor, 2-(12-hydroxydodeca-5,10-diynyl)-3,5,6-trimethyl-1,4-benz oqu inone (AA-861). It was also inhibited by a leukotriene-receptor antagonist, 8-[p-(4-phenylbutyloxy)benzoyl]amino-2-(tetrazol-5-yl)-4-oxo -4H-1-benzopyran hemihydrate (ONO-1078) but not affected by a thromboxane A2-synthetase inhibitor, (E)-3-[4-(1-imidazolylmethyl)phenyl]-2-propenoic acid (OKY-046) or a thromboxane A2-receptor antagonist, 9,11-epithio-11,12-methano-thromboxane A2 (ONO-3708). A phospholipase A2 inhibitor (mepacrine) inhibited the EGF-induced contraction but a diacylglycerol-lipase inhibitor, 1,6-di-(O-(carbamoyl)cyclohexanone oxime)hexane (U-57908) and a phospholipase D inhibitor (wortmannin) did not affect it. A tyrosine kinase inhibitor (genistein) abolished it. Measurement of prostanoids showed that EGF (300 ng/ml) did not increase the prostaglandin F2 alpha level in either epithelium-intact or epithelium-denuded strips. In epithelium-intact strips, EGF significantly increased the prostaglandin E2 concentration (P < 0.01). These results suggest that EGF causes contraction of guinea pig airway smooth muscle by activating tyrosine kinase followed by phospholipase A2 activation, and that arachidonic acid metabolites, especially leukotrienes, may have important roles in this contraction.

Pulmonary dysanapsis, methacholine airway responsiveness and sensitization to airborne antigen.

Abstract Whether the disproportional growth of airways relative to lung parenchyma (dysanapsis) has any relationship to the development of non‐specific bronchial hyperresponsiveness and atopy was investigated in 45 family members of the patients with atopic asthma. As indices of pulmonary dysanapsis, forced expiratory flow25‐75/forced vital capacity (FEF25‐75/FVC) and the tracheal cross sectional area divided by the forced expiratory volume (X‐SA/FVC) were examined. As an index of non‐specific airway responsiveness, the cumulative dose of inhaled methacholine needed to induce 35% reduction of respiratory conductance (PD35) was determined by continuous respiratory resistance measurement. For examination of atopy, skin prick tests were conducted, and total serum IgE and IgE specific to common inhaled antigens were measured. FEF25‐75/FVC showed no significant correlation to FVC but showed a significant correlation to log (PD35). When the analysis was done in the subjects whose FEVI/FVC was more than 0.8, FEF25‐75/FVC showed a significant negative correlation to FVC but lost its correlation to log(PD35). X‐SA/FVC showed a significant negative correlation to FVC but had no significant correlation to log(PD35). These relations were conserved when the analysis was done in subjects without airway obstruction. In addition, FEV1/FVC had a significant correlation to log(PD35) and FEF25‐75/FVC. However, subjects who had a positive IgE(MAST) had a significantly smaller X‐SA/FVC than those with a negative IgE(MAST) (0.60 ± 0.14[SD] and 0.72 ± 0.18, respectively, P<0.02). These results suggest that although pulmonary dysanapsis does not have a significant relation to airway responsiveness to inhaled methacholine, it may be associated with sensitization to airborne antigens.

Pulmonary fibrosis in a carpenter with long-lasting exposure to fiberglass

A 56-year-old male carpenter had a history of glass fiber inhalation for 41 years without any protective device. His chest radiograph showed small nodular opacities in lower lung fields and multiple cystic lesions and low attenuation areas in upper lung fields. Light and polarizing microscopic examinations of his transbronchial lung biopsy specimen revealed mild interstitial fibrosis and mononuclear cell infiltration in alveolar walls without birefringent substances. However, widespread depositions of small glass fibers (< 2.5 microns in length and 0.3 micron in diameter) were detected by analytical electron microscopy, which suggested their possible contribution to the development of his pulmonary fibrosis.