Cold air as a bronchial provocation technique. Reproducibility and comparison with histamine and methacholine inhalation

Bronchial provocation testing with cold air was carried out on 36 asthmatic and 13 normal subjects in order to assess the reproducibility and clinical relevance of the technique as a test of airways reactivity. Sixteen subjects underwent repeat testing after an interval of two to three weeks. Using a least squares linear regression analysis, the technique was highly reproducible, with a correlation of r = 0.93 (p less than 0.001). The 21 asthmatic subjects who had exercise-provoked symptoms required a significantly lower level of ventilation of cold air to produce a 35 percent drop in specific airways conductance (PD35) than did those who had no exercise-induced asthma (33.9 L min-1 vs 45.8 L min-1; p less than 0.02). Subjects requiring no regular treatment for their asthma had a geometric mean PD35 of 62.6 L min-1, significantly higher than those requiring inhaled therapy (44.9 L min-1; p less than 0.005). Subjects requiring oral in addition to inhaled treatment had the lowest PD35 (23.6 L min-1; p less than 0.02). Atopic status did not appear to influence the response. There was a strong correlation between the PD35 to cold air and to histamine (r = 0.92; p less than 0.001) and between the PD35 to cold air and to methacholine (r = 0.86; p less than 0.001). The three techniques of assessing bronchial reactivity were equally successful in separating the normal and asthmatic groups. The results indicate that cold air provocation may be reliably and reproducibly used to assess bronchial reactivity. The use of a naturally-occurring stimulus of asthma in all subjects has great potential as an investigational technique.     

Evidence of airway inflammation and remodeling in ski athletes with and without bronchial hyperresponsiveness to methacholine

Asthma-like symptoms, methacholine hyperresponsiveness, and use of asthma medication are prevalent in elite cross-country skiers. We quantitated mucosal inflammatory cell infiltration and tenascin expression in the subepithelial basement membrane in endobronchial biopsy specimens of the proximal airways from 40 elite, competitive skiers (mean: 17.5; range: 16 to 20 yr) without a diagnosis of asthma, in 12 subjects with mild asthma, and in 12 healthy controls, through immunohistochemistry and indirect immunofluorescence, respectively. All of the subjects were nonsmokers. T-lymphocyte, macrophage, and eosinophil counts were, respectively, greater by 43-fold (p < 0.001), 26-fold (p < 0.001), and twofold (p < 0.001) in skiers, and by 70-fold (p < 0.001), 63-fold (p < 0.001), and eightfold (p < 0.001) in asthmatic subjects than in controls. In skiers, neutrophil counts were more than twofold greater than in asthmatic subjects, and mast cell counts were not significantly different than in controls. Tenascin expression (as measured through the thickness of the tenascin-specific immunoreactivity band in the basement membrane) was increased in skiers (median: 6.7 microm; interquartile range [IQR]: 5.3 to 8.5 microm, p < 0.001) and asthmatic subjects (mean: 8.8 microm; IQR: 7.2 to 10.8 microm, p < 0. 001) compared with controls (mean: 0.8 microm; IQR: 0 to 3.1 microm) and did not correlate with inflammatory cell counts. Inflammatory changes were present irrespective of asthmalike symptoms, hyperresponsiveness, or atopy. Prolonged repeated exposure of the airways to inadequately conditioned air may induce inflammation and remodeling in competitive skiers.     

Evidence for elevated levels of histamine, prostaglandin D2, and other bronchoconstricting prostaglandins in the airways of subjects with mild asthma

Histamine and certain cyclooxygenase products of arachidonic acid have been implicated as mediators of inflammation and are potent constrictors of human airways. Because asthma may represent manifestations of chronic inflammation of the airways, the levels of histamine and six prostanoid mediators were measured in airway fluids obtained by bronchoalveolar lavage (BAL) of 12 normal, 11 allergic rhinitic, and 15 asymptomatic, allergic asthmatic subjects. Simultaneous profiling of prostanoid mediators in individual samples was performed using gas chromatography-mass spectrometry. Levels of PGD2, 9 alpha,11 beta-PGF2 and PGF2 alpha were 12 to 22 times higher in asthmatic than in normal subjects (p less than 0.01), with concentrations in airway fluids of asthmatic subjects after correction for dilution of 3.8, 0.5, and 1.4 nanomolar, respectively. Levels of PGD2 and 9 alpha,11 beta-PGF2 were increased nearly tenfold in asthmatic subjects compared with those in rhinitic subjects (p less than 0.01), distinguishing the subjects with lower airway disease from those with another atopic condition. Histamine levels were increased fourfold in asthmatic subjects compared with those in normal subjects (p less than 0.001); however, similar increases were found in rhinitic subjects. We conclude that elevated levels of multiple mediators with potent bronchoconstricting activity are present in the airways of subjects with mild asthma, indicating that even mild disease is associated with evidence of airway inflammation. The interactions of bronchoconstricting mediators and airway inflammation may play important roles in the pathogenesis of asthma.     

Perivascular fibrosis of muscular pulmonary arteries in chronic obstructive pulmonary disease.

We performed a morphometric analysis of peribronchiolar and perivascular fibrosis in lungs obtained at autopsy from six patients with chronic bronchitis, six with pulmonary emphysema, and four normal control subjects. The areas of fibrosis outside the smooth muscle layer of bronchioles and outside the external elastic lamina of muscular pulmonary arteries were measured and their thickness was then calculated by assuming a round airway or artery. Patients with chronic bronchitis had significantly thicker peribronchiolar fibrosis in bronchioles of 1 mm or less in diameter and also thicker perivascular fibrosis of the adjacent muscular pulmonary arteries than the other two groups. The extent of perivascular fibrosis was significantly correlated with peribronchiolar fibrosis only in the muscular pulmonary arteries adjacent to the bronchioles but not in those away from the bronchioles. These findings suggest direct extension of chronic inflammation from bronchioles to the adjacent muscular pulmonary arteries in chronic bronchitis but not in pulmonary emphysema. Such perivascular fibrosis might lead to sustained pulmonary hypertension.     

Pulmonary vascular damage and the development of cor pulmonale following hyaline membrane disease

Light microscopic morphometric techniques have been used to study the lungs in 17 infants and young children aged 2 weeks to 3.5 years who were born prematurely, developed hyaline membrane disease (HMD), and died with chronic lung disease. They were divided into three groups. In group 1 the babies died without recovering from their initial illness at age 2-13 weeks. In group 2 they died, aged 4-15 months, having recovered from the neonatal illness. Neither group showed clinical or pathological evidence of cor pulmonale (CP). In group 3 children died aged 6 months to 3.5 years with CP. None of the 17 patients had classical fibrotic bronchopulmonary dysplasia (BPD) but all had a reduced alveolar number and an increase in bronchial smooth muscle in small airways. All three groups showed an increase in pulmonary arterial medial thickness (P less than 0.001). In group 1 the appearance of the arteries suggested persistance of the fetal state. In group 2 and 3 the vessels had a more mature structure; in group 3 a marked secondary increase in muscularity was found, approaching the thickness seen in fetal life. In groups 2 and 3 muscle extended into smaller arteries than normal. Vein wall thickness was increased. The alveolar to arterial ratio was normal, the alveolar number was reduced, therefore the total number of arteries was reduced in all three groups. Thus, babies who recover from HMD may have significant vascular abnormalities in the absence of CP; conversely, CP if present, does not mean advanced obliterative pulmonary vascular disease. Thus, pulmonary vascular morphology does not correlate with the presence or absence of CP.     

Site of airflow obstruction during early and late phase asthmatic responses to allergen bronchoprovocation

Chronic asthma and late asthmatic responses (LAR) are associated with local inflammation which might be expected to produce airflow obstruction in small airways and to increase nonspecific airway reactivity. In contrast, early asthmatic responses (EAR) are primarily bronchospastic and probably involve more central airways. We challenged 17 nonsmoking, mildly asthmatic atopic subjects with allergen bronchoprovocation and measured changes in spirometry (FEV1) over the next 24 hours. Each subject also performed a helium-oxygen (He-O2) flow-volume loop before challenge (baseline), during the EAR, and six hours and 24 hours after challenge to measure the effect of gas density on flow rates at midvital capacity. Twelve subjects had both an EAR and a LAR; five subjects had only a LAR. Of these 17 subjects, 15 were initially density dependent, while only two were density independent. During the EAR, 13 percent of the density dependent population had significant decreases in delta Vmax 50 percent; 47 percent had significant decreases during LAR. The He-O2 flow data analyzed at specified time points after challenge revealed significant decreases in the mean delta Vmax 50 percent at six hours in those who had only a LAR (p less than 0.01). In those who had a dual airway response, density dependence increased during the EAR, but decreased at six and significantly at 24 hours (p less than 0.05) postchallenge. There was a strong trend for the severity of the LAR (measured by changes in FEV1) to be directly related to the total decrease in delta Vmax 50 percent during the LAR. We conclude that late asthmatic responses occur frequently after a single antigenic bronchial challenge and can be associated with persistent symptoms. The LAR were often associated with a decrease in density dependence of maximal expiratory airflow, and therefore, may involve small airways.     

A prospective study of asthma in a rural community

Changes in symptoms and pulmonary function among asthmatic subjects in the general population remain poorly characterized. We studied 1,303 white residents aged seven years and older in Lebanon, Conn, a rural community largely unaffected by air pollution or major occupational exposures. These residents were examined in 1972 and again in 1978. There were 73 asthmatic subjects seen in 1972 who were followed. In addition, we identified 278 persons in 1972 who complained of wheezing who were also seen in 1978. Of the original asthmatic subjects, 50 (68 percent) were in remission; and from the original nonasthmatic population, 19 (1.4 percent) new asthmatic subjects were identified. Similarly, the condition of 215 (77 percent) of those who initially complained of wheeze had improved, whereas 56 (4.6 percent) of those initially studied either developed new wheeze or saw their wheezing worsen. When the groups of persons complaining of wheeze and the asthmatic subjects were analyzed for the presence of chronic bronchitis, we found a significant correlation between wheeze and chronic bronchitis in individuals aged 18 years and older (p less than 0.001) for both men and women, and a significant correlation (p less than 0.001) between asthma and chronic bronchitis in women aged 18 years and older. Loss of pulmonary function over time measured in terms of the forced expiratory volume in one second and the forced expiratory flow at 50 percent of total lung capacity was consistently greater for asthmatic adults than for nonasthmatic adults. Furthermore, when individuals were studied by the severity and duration of their asthmatic symptoms, a trend of worse pulmonary function was seen in those individuals with chronic asthma. We conclude that remission rates among asthmatic subjects and persons with wheeze are high in individuals aged seven years and older, that chronic bronchitis is frequently associated with wheezing and a history of asthma in adults, and that significant abnormalities in pulmonary function as well as accelerated loss of pulmonary function are associated with asthma.     

CD8+ve cells in the lungs of smokers with chronic obstructive pulmonary disease.

Previous studies have shown an increased number of inflammatory cells and, in particular, CD8+ve cells in the airways of smokers with chronic obstructive pulmonary disease (COPD). In this study we investigated whether a similar inflammatory process is also present in the lungs, and particularly in lung parenchyma and pulmonary arteries. We examined surgical specimens from three groups of subjects undergoing lung resection for localized pulmonary lesions: nonsmokers (n = 8), asymptomatic smokers with normal lung function (n = 6), and smokers with COPD (n = 10). Alveolar walls and pulmonary arteries were examined with immunohistochemical methods to identify neutrophils, eosinophils, mast cells, macrophages, and CD4+ve and CD8+ve cells. Smokers with COPD had an increased number of CD8+ve cells in both lung parenchyma (p < 0.05) and pulmonary arteries (p < 0.001) as compared with nonsmokers. CD8+ve cells were also increased in pulmonary arteries of smokers with COPD as compared with smokers with normal lung function (p < 0.01). Other inflammatory cells were no different among the three groups. The number of CD8+ve cells in both lung parenchyma and pulmonary arteries was significantly correlated with the degree of airflow limitation in smokers. These results show that an inflammatory process similar to that present in the conducting airways is also present in lung parenchyma and pulmonary arteries of smokers with COPD.     

Inflammation and remodeling of the distal airways: studies in humans and experimental models

Asthma is characterized by inflammation and remodeling of the airways, giving rise to airway obstruction and symptoms of wheezing, chest tightness, cough and dyspnea. Most of these observations arise from the study of samples obtained from the central airways by distinct methods. However, it is currently accepted that this inflammatory process occurs not only in the central airway but also in the small airway and even in the pulmonary parenchyma of all asthmatic patients, even those with mild asthma. CD4+ lymphocytes, activated eosinophils and IL-5 mRNA expression are present in a greater quantity in the small airways. Also present is remodeling, with an increase in submucosal thickness, the muscular layer and adventitia. This inflammatory process causes a disconnection between the pulmonary parenchyma and the airway, giving rise to obstruction of the small airway, which is currently considered to be predominant in asthmatic patients. Likewise, studies of experimental asthma in animals support the substantial role of the distal airway. Recognition that asthma affects the entire airway could be clinically important and lead to the distal lung being considered as a target in any effective therapeutic strategy. However, longitudinal studies are required to evaluate the impact of distal airway inflammation and its treatment in asthma.     

The mechanics of airway narrowing in asthma

This study was designed to determine the potential importance of airway wall thickening in the pathogenesis of the excess airways narrowing of asthma. The airways in postmortem specimens of lung obtained from 18 patients who suffered from asthma were compared to similar airways from 23 patients without asthma. Each airway was projected onto a digitizing board of a microcomputer to trace the internal and external perimeter of the airway and to calculate the submucosal and mucosal thicknesses. The relaxed length of the airway smooth muscle and the shortening required to occlude the airway lumen were calculated. These data show that the wall area was greater (p less than 0.001) in the membranous and cartilaginous airways of asthmatic patients and the airway smooth muscle shortening required to occlude the lumen was less in asthmatic than nonasthmatic airways (p less than 0.001). The increased wall area was due to increased areas of epithelium, muscle, and submucosa. We conclude that the walls of the airways of patients with asthma are thickened by chronic inflammation and that this thickening could be as important as smooth muscle shortening in determining the airway responsiveness of these patients.     

Mortality and decline in lung function in 213 adults with bronchial asthma: a ten-year follow up.

The purpose of this longitudinal study was to describe mortality and change in lung function in adults with bronchial asthma, and furthermore to investigate a potential difference in the prognosis for patients with intrinsic and extrinsic asthma. Out of 213 asthmatics admitted to our hospital, 170 (82%) participated in a 10-year follow-up examination; according to the tests for extrinsic asthma at the first examination, the patients were divided into 117 patients with intrinsic asthma and 53 subjects with extrinsic asthma. Twenty-seven (13%) patients, 23 with intrinsic and 4 with extrinsic asthma, died during the observation period, which was almost twice the number expected in both intrinsic and extrinsic asthmatics, but because of the small number of patients with extrinsic asthma, the findings were statistically significant for the intrinsic asthmatics only (p less than 0.05). Seventeen (8.2%) died of pulmonary diseases, of whom 9 (6 patients with intrinsic asthma) died in an acute attack of bronchial asthma. After a questionnaire concerning respiratory symptoms had been answered, a lung function test was performed in all subjects in both 1976-1979 and 1988. A histamine challenge test was performed at the examination in 1988. Of the 143 subjects who were re-examined in 1988, 96% still had respiratory symptoms. The first lung function test in 1976-1979 showed no difference in FEV1 (% predicted) between the two groups, whereas the annual mean loss of FEV1 during the observation period for the intrinsic and extrinsic asthmatics was 50 ml and 22.5 ml, respectively (p less than 0.0001). Decline in FEV1 was found to be independent of smoking habits in both patient groups. We found that the decline in lung function increased with increasing age in both intrinsic and extrinsic asthmatics (p less than 0.001 and p less than 0.05, respectively). The so-called "horse-racing effect" could be demonstrated for the patients with extrinsic asthma (p less than 0.003); whereas no significant relation was found between FEV1 at the time of enrollment and decline of FEV1 for the intrinsic asthmatics. We conclude that asthmatic subjects have an excess mortality and that the prognosis for intrinsic asthma is worse than that of extrinsic asthma with regard to rate of decline in lung function.     

Effect of cessation of exposure to toluene diisocyanate (TDI) on bronchial mucosa of subjects with TDI-induced asthma.

The effect of cessation of exposure to toluene diisocyanate (TDI) was studied in six patients with TDI-induced asthma, proved by a positive inhalation challenge with TDI. Bronchial challenges with TDI and methacholine were performed, and lobar bronchial biopsies were taken at diagnosis and 6 months later, after cessation of exposure. Biopsies from four nonasthmatic control subjects were also examined. At diagnosis, asthmatic subjects had thickened reticular basement membrane (p less than 0.05) and increased numbers of mononuclear cells (p less than 0.05) and eosinophils (p less than 0.05) in the lamina propria when compared with control subjects. Electron microscopy showed degranulation of eosinophils and mast cells in asthmatics. Six months after cessation of exposure, the thickness of reticular basement membrane was significantly reduced compared with that at diagnosis (p less than 0.05), and it decreased to values similar to those of control biopsies. Inflammatory cell numbers in bronchial mucosa of asthmatic subjects did not change significantly 6 months after removal from exposure, and degranulation of eosinophils and mast cells was still present. At the end of the study, airway hyperresponsiveness to methacholine and/or sensitivity to TDI persisted in most of the asthmatic patients despite the cessation of exposure and the disappearance of asthmatic symptoms. In conclusion, in patients with occupational asthma induced by TDI, the avoidance of exposure to the sensitizing agent for 6 months is able to reverse the reticular basement membrane thickening in the bronchial mucosa, but the inflammatory cell infiltrate, the specific sensitivity to TDI, and the nonspecific airway hyperreactivity may persist.     

Rhinovirus-16 colds in healthy and in asthmatic subjects: similar changes in upper and lower airways.

Rhinovirus (RV) infections appear to precipitate most asthma exacerbations. To investigate whether RV-16 induces different inflammatory changes in upper and lower airways of asthmatic and healthy subjects, we inoculated 10 nonatopic healthy and 11 atopic asthmatic adults with 2,000 TCID50 RV-16. Subjects recorded symptoms and peak flow daily; and they underwent spirometry, methacholine challenge (PC20), nasal lavage, and sputum induction at baseline and on Days 2, 4, 15, and 29 d after inoculation. One asthmatic subject developed an exacerbation requiring prednisone treatment 5 d after inoculation. The cold symptom severity (Jackson score) did not differ between groups. During the cold, asthma symptoms increased slightly from baseline in the asthmatic group; and PC20 decreased in the healthy group. However, peak flow, bronchodilator use, and spirometry did not change in either group. At baseline, asthmatics had higher neutrophils, eosinophils, and interleukin (IL)-6 in nasal lavage. After inoculation, both groups developed significant increases in nasal neutrophils, IL-6 and IL-8, and modest increases in sputum neutrophils and IL-6, but not IL-8. However, these changes did not differ between groups. IL-5, interferon-gamma, and RANTES were detected only in nasal lavages from two asthmatic subjects, who had the most severe colds. IL-11 was not detected in any sample. We conclude that inflammatory responses of upper and lower airways during RV-16 colds are similar in asthmatic and healthy subjects, and that RV-16 infection is not by itself sufficient to provoke clinical worsening of asthma.     

Increased expression of the chemoattractant cytokines eotaxin, monocyte chemotactic protein-4, and interleukin-16 in induced sputum in asthmatic patients

BACKGROUND: Induced sputum from asthmatic patients has been recently used to assess inflammatory cells. We have previously reported an increased expression of Th-2-type cytokines in induced sputum of asthmatic patients. C-C chemokines, particularly eotaxin and monocyte chemotactic protein (MCP)-4, are associated with eosinophilic infiltration. Interleukin (IL)-16 is associated with chemotactic activity for CD4+ cells. Chemokine expression in BAL and bronchial biopsy specimens has been demonstrated in asthmatic airways, but not in induced sputum. METHODS: We examined whether eotaxin, MCP-4, and IL-16 expression could be detected in induced sputum of asthmatic patients (n = 10), and whether the expression was increased compared to normal control subjects (n = 9). Eotaxin, MCP-4, and IL-16 immunoreactivity were determined by immunocytochemistry. In addition, inflammatory cells were investigated using markers for T cells (CD3), eosinophils (major basic protein [MBP]), macrophages (CD68), neutrophils (elastase), and epithelial cells (cytokeratin). RESULTS: Our results showed that there was a significant difference in the percentages of MBP-positive and epithelial cells between asthmatic patients and normal control subjects (p < 0.05). However, there was no difference between these two groups in the percentage of CD3-, elastase-, and CD68-positive cells. Immunoreactivity for eotaxin, MCP-4, and IL-16 was expressed in the induced sputum of all asthmatic patients, and expression of these chemotactic cytokines was significantly greater than in control subjects (p < 0.001, p < 0.005, and p < 0.001, respectively). CONCLUSIONS: This study showed that induced sputum could be used to detect chemokines in patients with bronchial asthma, and that the upregulation of chemotactic cytokines in the airways can be seen using noninvasive techniques.     

Circulating adhesion molecules in sera of asthmatic children

Infiltration of cells into the lung in asthma is regulated by several expressions of cell adhesion molecules (CAMs) on cells present in the airways, and may play a role in the pathogenesis of bronchial asthma. We sought to evaluate the role of serum concentrations of the soluble forms of intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), and E-selectin (sE-selectin) in the control of disease activity in acute asthma. Circulating levels of sICAM-1, sVCAM-1, and sE-selectin in sera from 15 normal control subjects and from 20 allergic asthmatic children with acute exacerbations who had returned to stable condition were determined by using commercially available enzyme-linked immunosorbent assay kits. The mean concentration of serum sICAM-1 levels was significantly higher during an acute exacerbation of asthmatic children than in those with stable asthma (19.41 +/- 10.65 ng/mL vs. 13.46 +/- 5.44 ng/mL; P < 0.001) or in control subjects (9.83 +/- 2.02 ng/mL; P < 0.001). For sVCAM-1 and sE-selectin, the mean serum concentration of sVCAM-1 was slightly higher in children during an acute exacerbation asthma than when stable. However, the differences did not reach statistical significance. The mean serum concentrations of sVCAM-1 and sE-selectin in acute asthma or stable asthma were significantly higher than in control subjects. This study provides further evidence that serum concentrations of sICAM-1, sVCAM-1, and sE-selectin are increased in acute asthma. These findings further confirm that leukocyte endothelial adhesion plays a role in inflammatory airway disease.     

Allergen-induced asthmatic responses. Relationship between increases in airway responsiveness and increases in circulating eosinophils, basophils, and their progenitors

The inflammatory response during allergen-induced asthma was assessed using serial measures of peripheral blood eosinophils (Eo), basophils (B), and Eo/B progenitor cells (Eo/B-CFU). A group of 14 stable asthmatic individuals (beta 2-agonists only as needed) had inhalation provocation tests with allergen (18 tests in total) and with diluent. Serial blood samples were taken before and 1 and 24 h after the tests; methylcellulose cultures for Eo/B-CFU and granulocyte-macrophage (GM-CFU) were scored at 14 days. Circulating Eo, B, and Eo/B-CFU were increased at 24 h after allergen inhalation when this resulted in increased histamine airway responsiveness (n = 13). In the 5 subjects with isolated early asthmatic responses the Eo, B, and Eo/B-CFU counts did not change. There was no change in the GM-CFU after allergen. The ratio change in circulating Eo/B-CFU was negatively correlated with baseline histamine airway responsiveness (r = -0.8, p less than 0.05). Four subjects who had an isolated early response and no blood changes to one allergen developed an increase in histamine airway responsiveness and an increase in Eo, B, and Eo/B progenitors after inhalation of a second different allergen. The results indicate that in subjects with an allergen-induced increase in histamine airway responsiveness, an inflammatory response occurs that includes an increase in the number of Eo/B progenitors. This response, possibly mediated by Eo/B growth and differentiation factors, could lead to the accumulation of these cells in the airway and contribute to the airways inflammation present in asthma.     

Airways inflammation in nocturnal asthma

Nocturnal asthma is a frequent problem, but the mechanism is unclear. We investigated the possibility that airways inflammation occurred during the night. Bronchoalveolar lavage fluid was analyzed in asthmatic patients with (n = 7) and without nocturnal asthma (n = 7) at 1600 and 0400 h. The nocturnal asthma group had an increase in the total leukocyte count (24.0 +/- 7.0 to 41.1 +/- 9.9 x 10(4) cells/ml, p less than 0.05), neutrophils (1.1 +/- 0.6 to 3.7 +/- 1.5 x 10(4) cells/ml, p less than 0.05), and eosinophils (0.5 +/- 0.1 to 1.7 +/- 0.7 x 10(4) cells/ml, p less than 0.05) from 1600 to 0400 h. Cellular components for the non-nocturnal asthma group did not change. Between groups, the 1600-h cells were similar. At 0400 h the nocturnal asthma group had significantly higher total leukocyte, neutrophil, eosinophil, lymphocyte, and epithelial cell counts. For all subjects, the overnight fall in peak expiratory flow rates was correlated to the change in neutrophils (r = 0.54, p less than 0.05) and eosinophils (r = 0.77, p less than 0.05). We conclude that the nocturnal worsening of asthma has an associated cellular inflammatory response that is not seen in patients without overnight decrements in lung function. This inflammatory response together with epithelial damage may be important factors in the etiology of nocturnal asthma.     

The bronchoconstrictor properties of platelet-activating factor in humans

Platelet-activating factor (PAF) is an inflammatory mediator that causes bronchial smooth muscle contraction in vitro and in vivo in experimental animals. To characterize the effect of PAF on human airways, 6 normal subjects and 6 subjects with mild asthma inhaled PAF using a standard bronchoprovocation protocol and nebulizer concentrations ranging from 0.1 to 1000 micrograms/ml. Aerosolized PAF produced bronchoconstriction in 5 of 6 normal and 3 of 6 asthmatic subjects as defined by at least a 35% decrease in specific airway conductance (SGaw). However, in these same subjects, flow rates measured at 30% of vital capacity from a partial forced expiratory maneuver (V30P) did not decrease at least 30% nor did the FEV1 decrease by 20%. The 8 PAF responders were 5 to 836 times more sensitive to PAF than to methacholine when SGaw was used to assess the airway response. The relative airway sensitivity of the PAF nonresponders could not be assessed. Normal and asthmatic subjects could not be differentiated by their airway response to PAF, and there were no clinical features that differentiated PAF responders from nonresponders. The maximal airway response to PAF occurred within 2 to 3 min and lasted 15 to 45 min. There were no late reactions. Both normal (p less than 0.01) and asthmatic (p less than 0.05) subjects exhibited tachyphylaxis to PAF. Finally, PAF sensitized the airways of all normal subjects to methacholine, including the one PAF nonresponder (p less than 0.02), but it did not sensitize the airways of the asthmatic subjects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Asthma attack associated with oxidative stress by exposure to ETS and PAH.

Asthma is primarily an airways inflammatory disease, and the bronchial airways have been shown to be particularly susceptible to oxidant-induced tissue damage. OBJECTIVE: The purpose of this study was to investigate whether pulmonary inflammation in asthma is associated with exposure to environmental oxidants such as polycyclic aromatic hydrocarbon (PAH) and environmental tobacco smoke (ETS). METHOD: We assessed the exposure level of PAH and ETS by using urinary 1-hydroxypyrene glucuronide (1-OHPG) and cotinine. We estimated oxidative damage and inflammatory cytokine levels from 16 asthma patients and 16 patients in stable conditions 1 to 2 months later. RESULTS: Our study showed that the levels of oxidative damage, as measured by malondialdehyde (MDA), were significantly increased (p = 0.006) during the asthma attacks. Proinflammatory and anti-inflammatory cytokines were both increased during the asthma attacks compared to the stable conditions at follow-up. Interleukin (IL-6) and IL-10 were especially increased significantly (p = 0.015 and p < 0.001, respectively). Correlations were observed between inflammatory cytokines such as IL-6 and IL-1beta (p = 0.034). CONCLUSION: This study supports the results of in vitro studies that oxidative stress, specifically lipid peroxidation, contributes to the pathophysiology of asthma. Therefore, environmental interventions based on this better understanding are needed to significantly reduce oxidant stress and prevent or minimize the development of asthmatic symptoms.