Asthma, a family of airway disorders characterized by airway inflammation, has an increasing incidence worldwide. Platelet-activating factor (PAF) may play a role in the pathophysiology of asthma. Its proinflammatory actions are antagonized by PAF acetylhydrolase. A missense mutation (V279F) in the PAF acetylhydrolase gene results in the complete loss of activity, which occurs in 4% of the Japanese population. We asked if PAF acetylhydrolase deficiency correlates with the incidence and severity of asthma in Japan. We found that the prevalence of PAF acetylhydrolase deficiency is higher in Japanese asthmatics than healthy subjects and that the severity of this syndrome is highest in homozygous-deficient subjects. We conclude that the PAF acetylhydrolase gene is a modulating locus for the severity of asthma. J. Clin. Invest. 103:989-997

Surfactant proteins (SP)-A and SP-D are collagen-like glycoproteins belonging to the "collectin" class of C-type lectins, which are primarily synthesized in type II cells. Recent studies reported the possibility of local production of SP-A and SP-D in the airways, but the amounts of surfactant proteins in patients with bronchial asthma have not been studied.The composition of surfactant proteins in mild, stable asthmatics in the first lavage as bronchial lavage (BL) and the second and third lavages consecutively as alveolar lavages (AL) were therefore, analysed separately. The co-relationships in the BL between the amounts of surfactant proteins and those of fucose, which is one of the markers of submucosal secretion were also analysed.Increased amounts of SP-A in BL and AL of in asthmatics were found as compared with those in controls. A high concentration of SP-D in the AL asthma patients was also found. The levels of SP-A correlated with those of fucose in patients with bronchial asthma (r=0.849, p<0.01).The observations in the present study suggested that surfactant protein A may be secreted from the airways with allergic inflammation in a different manner from the alveoli. The increased levels of surfactant proteins A and D may play a protective role in an allergic inflammation in the pathogenesis of bronchial asthma. Eur Respir J 2000; 16: 831±835.

Recent in vitro studies have suggested that interleukin-4 (IL-4) may be involved in the preferential migration of eosinophils into the airways in allergic asthma through its capacity to selectively increase vascular cell adhesion molecule-1 (VCAM-1) expression on vessels. To test this hypothesis, we studied the expression of VCAM-1, E-selectin, and intercellular adhesion molecule-1 (ICAM-1) on vascular endothelium in bronchial mucosal biopsies from 20 allergic asthmatics using an immunohistochemistry technique and related the observations to IL-4 levels in bronchoalveolar lavage (BAL) fluid simultaneously obtained and to eosinophil infiltration in the bronchial mucosa. IL-4 was detectable in BAL fluid from nine subjects (range, 15.1 to 110 pg/ml in 20-fold concentrated BAL fluid) (IL-4-positive asthmatics) but unmeasurable in the remaining 11 subjects (IL-4-negative asthmatics). The IL-4-positive asthmatics showed a significantly increased expression of VCAM-1 but not E-selectin and ICAM-1 on vessels as compared with both IL-4-negative asthmatics (P < 0.001) and diseased control subjects (P < 0.001). In asthmatics, VCAM-1 expression was positively correlated with BAL IL-4 levels (rs = 0.89; P < 0.0001). Moreover, there was a significant correlation between the endothelial expression of VCAM-1 and the number of eosinophils, but not neutrophils, in the bronchial submucosa (r2 = 0.76; P < 0.001). A significant correlation was also found between BAL IL-4 levels and the number of eosinophils. These results suggest that IL-4 is a VCAM-1-selective activator also in human airways and the VCAM-1-dependent pathways play a role in selective migration of eosinophils into the airways in allergic asthma, and support the hypothesis described above.

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The effect of dihydropyridine calcium channel blocker (CCB) on baroreflex sensitivity (BRS) is not well described. We studied the effect of a new CCB, azelnidipine, compared with amlodipine, on BRS and ambulatory blood pressure (BP) in newly diagnosed untreated hypertension. This study was a prospective, randomized, and open-label study. We randomized patients to either azelnidipine or amlodipine treatment. Azelnidipine 8 to 16 mg (average 14.5 mg) and amlodipine 2.5 to 7.5 mg (average 4.9 mg) were used to lower the clinical BP <140/90 mm Hg. BRS, evaluated by the spontaneous and the Valsalva methods, and clinical and ambulatory BP were evaluated at baseline and after 13 weeks of each treatment. A total of 47 patients (age 53.1 +/- 10.8 years, 51% male), 26 in the azelnidipine group and 21 in the amlodipine group, completed the study. For baseline and after therapy respectively, both Valsalva-BRS (4.8 +/- 1.7 vs. 8.4 +/- 3.1 msec/mm Hg, P = 0.001) and spontaneous-BRS (5.5 +/- 2.5 vs. 8.2 +/- 5.6 msec/mm Hg, P = 0.019) were increased by azelnidipine, but amlodipine did not change them. Clinical and awake BPs were similarly reduced by each drug therapy. In conclusion, BRS was increased by azelnidipine therapy, but not by amlodipine therapy. This differential effect may be important in cardiovascular risk reduction.

We measured the serum concentration of soluble interleukin-2 receptor (sIL-2R) in asthma patients and healthy controls to evaluate T-lymphocyte activation in this disease. The SIL-2R concentrations in patients with asthma irrespective of presence of acute attacks were significantly higher than those of the controls (p < 0.001). Although the sIL-2R concentrations were similar in the patients with acute asthma and those in remission, levels in patients with moderate and severe asthma attacks were significantly higher than levels for patients in remission (p < 0.001). These results suggest that T-lymphocyte activation occurs in asthma patients and becomes more prominent during moderate and severe acute attacks.

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To investigate the role of neuropeptides in allergic inflammation, we examined the effect of peptides on eosinophil chemotaxis. Eosinophils were purified from the blood of allergic and normal subjects using a discontinuous Percoll density gradients. Chemotaxis was induced by platelet-activating factor (PAF) and leukotriene B4, and was assayed by a modified Boyden's chamber technique. Four neuropeptides were examined in this study: substance P (SP), neurokinin A, calcitonin gene-related peptide (CGRP), and cholecystokinin octapeptide. Peptides alone (10 nM to 10 microM) were not chemotactic for eosinophils. However, when eosinophils were pre-treated with peptides (100 nM) at 37 degrees C for 30 min, chemotactic response to PAF (10 nM) was significantly enhanced (p &lt; 0.01) in allergic subjects; % control by SP, neurokinin A, CGRP and cholecystokinin octapeptide was 269 +/- 42, 243 +/- 32, 227 +/- 21, and 251 +/- 42, respectively (n = 8). Similar results were obtained in leukotriene B4-induced eosinophil chemotaxis. In contrast, no enhancement was observed in normal subjects. Potentiating effect of SP and CGRP on PAF-induced eosinophil chemotaxis in allergic subjects was significantly attenuated by SP antagonist [D-Pro2,D-Trp7,9]-SP and human CGRP (8-37) receptor antagonist, respectively. Neutral endopeptidase inhibitors (phosphoramidon, leupeptin, and bestatin) failed to significantly augment the PAF-induced eosinophil chemotaxis when the cells were pretreated with various peptides and neutral endopeptidase inhibitors. The C-terminal fragment of SP (SP6-11) had an effect similar to that of the intact SP molecule, whereas no potentiating effect by the N-terminal of SP (SP1-9) was observed. These results suggest that neuropeptides may play a significant role in eosinophil infiltration by priming cells in allergic inflammation.