Hitoshi Maeda

β2-Adrenergic Receptor Polymorphisms Affect Airway Responsiveness to Salbutamol in Asthmatics

We examined the beta2-adrenergic receptor (beta2AR) polymorphisms (Arg16-->Gly, Gln27-->Glu) and clinical status for 117 asthmatics. Airway responsiveness to methacholine and beta2-agonists was evaluated with Astograph. The atopic factors, pulmonary function test, and airway responsiveness to methacholine did not differ significantly among the different beta2AR genotypes. Asthmatics homozygous for Gly16 showed significantly lower airway responsiveness to inhaled salbutamol than those heterozygous for Arg/Gly16 or homozygous for Arg16. Asthmatics heterozygous for Gln/Glu27 had significantly later asthma onsets than those homozygous for Gln27. These results suggest that beta2AR polymorphisms play an important role in the airway responsiveness to inhaled beta2-agonist and the initial asthma onset.

Assessment of Magnesium Status in Patients with Bronchial Asthma

To elucidate the contribution of magnesium to bronchial hyperreactivity in patients with stable bronchial asthma, magnesium concentrations in serum (S-Mg), erythrocytes (R-Mg), and lymphocytes (L-Mg) were measured in 25 patients with bronchial asthma (BA group) and 9 age-matched healthy subjects (control group). A parenteral magnesium loading test, a continuous low-dose magnesium infusion of 0.2 mEq/kg over 4 hr, was performed in 10 of 25 asthmatic patients and in the control group. R-Mg was significantly lower in the BA group than in the control group (4.96 ± 0.47, 6.13 ± 0.62 mEq/L, p < 0.001, respectively), although S-Mg (2.4 ± 0.1, 2.4 ± 0.2 mg/dL) and L-Mg (1.28 ± 0.26, 1.15 ± 0.13 μg/mg/protein) were not significantly different between the two groups. Magnesium deficiency in total body stores was revealed in 40% of patients (4/10 patients) and 11% of control subjects (1/9 subjects) by parenteral magnesium loading test. The ratio of magnesium retention to urinary excretion through the parenteral magnesium loading test showed a significant inverse correlation with R-Mg (r = -0.78, p < 0.01). Bronchial reactivity to inhaled methacholine had a significant inverse correlation with R-Mg (r = -0.42, p < 0.05). We conclude that 40% of asthmatic patients demonstrated magnesium deficiency, and that the low magnesium concentration in erythrocytes reflects decreased magnesium stores in patients with bronchial asthma.

Mixed connective tissue disease with fatal pulmonary hypertension and a review of literature

The paper presents an autopsy case of mixed connective tissue disease (MCTD) with pulmonary hypertension (PH) and a review of literature. A 33-year-old woman with Raynauds phenomenon and dyspnea of one year duration was diagnosed as having MCTD on the basis of a higher titer (1:163,840) of serum antibodies to the ribonucleoprotein (RNP). Cardiac catheterization showed complicating PH, confirmed an autopsy by the findings of concentric intimal cellular proliferation and typical plexiform lesions in the small arteries and arterioles of the lung, suggesting primary PH. Fatal PH with MCTD has been reported only 6 cases in literature including our case. All were young females, with histopathological findings consistent with plexogenic pulmonary arteriopathy in 5 cases and with recurrent pulmonary thromboembolism in the other. The aetiology of PH is still unknown, but it may be due to vasoconstriction evoked by the hyper-reactivity of the vessels.

Tumor necrosis factor-α augments contraction and cytosolic Ca2+ sensitivity through phospholipase A2 in bovine tracheal smooth muscle

Abstract To elucidate the effects of tumor necrosis factor-α (TNF-α) on tracheal smooth muscle contraction, we simultaneously measured isometric tension and intracellular Ca 2+ ([Ca 2+ ] i ) in fura 2-loaded muscle strips. Smooth muscle force generation was evaluated in a high potassium (K + ; 20.0–80.0 mM) solution and with acetylcholine (3 nM–10 μM ). TNF-α (1–100 ng/ml) did not directly contract muscle strips. The contractile response to acetylcholine was enhanced after application of 10 ng/ml of TNF-α for 30 min but not the response of [Ca 2+ ] i . The contractile response and the response of [Ca 2+ ] i to a high K + solution were not altered after application of TNF-α. The [Ca 2+ ] i –tension curve indicated that TNF-α enhanced the responsiveness of tracheal smooth muscle through the acetylcholine-mediated Ca 2+ sensitivity of intracellular contractile elements. The augmentation of the acetylcholine concentration–response curves for muscle tension in the presence of TNF-α (10 ng/ml) was inhibited in part after application of manoalide, a phospholipase A 2 inhibitor. We conclude that a low concentration of TNF-α enhances smooth muscle responsiveness to acetylcholine by agonist-mediated Ca 2+ sensitivity facilitated by phospholipase A 2 .

Bronchial hyperresponsiveness and exhaled nitric oxide in patients with cardiac disease.

Background: Increased concentrations of exhaled nitric oxide (NO) correlate with increased airway inflammation and measurement of exhaled NO is a noninvasive method for the management of bronchial asthma. In various cardiac diseases, bronchial hyperresponsiveness is observed, as is bronchial asthma. However, there have been few studies on the relationship between exhaled NO and bronchial responsiveness in cardiac diseases. Objective: The aim of this study was to clarify the association between exhaled NO and bronchial hyperresponsiveness in patients with cardiac disease. Methods: We measured expired NO and bronchial responsiveness to inhaled methacholine in 19 patients with cardiac diseases and 17 with bronchial asthma. We divided the cardiac disease patients into two groups according to their bronchial responsiveness to inhaled methacholine: BHR(+) group consisted of 12 patients with bronchial hyperresponsiveness and BHR(–) group consisted of 7 patients without bronchial hyperresponsiveness. Results: The concentration of exhaled NO in the asthmatic patients was significantly higher than that in the BHR(+) and BHR(–) groups (142.0 ± 17.0, 33.6 ± 6.4 and 42.3 ± 10.3 ppb, respectively, p < 0.01). There was no significant difference in exhaled NO between BHR(+) and BHR(–) groups. There were also no significant differences in the parameters of bronchial hyperresponsiveness between the cardiac BHR(+) and bronchial asthma groups. These results indicate that bronchial hyperresponsiveness in patients with cardiac diseases is not a consequence of eosinophilic inflammation or of exhaled NO. Conclusion: We conclude that bronchial hyperresponsiveness in patients with cardiac diseases can occur independently of NO production.