Quantitation of mast cells and eosinophils in the bronchial mucosa of symptomatic atopic asthmatics and healthy control subjects using immunohistochemistry

We have used fiberoptic bronchoscopy to obtain endobronchial biopsies in which mast cells and eosinophils were enumerated using monoclonal antibodies directed against mast cell tryptase (AA1) and the eosinophil cationic protein (EG2). Eleven symptomatic atopic asthmatics treated with beta 2-agonists alone and six normal subjects were studied. Over a period of 2 wk prior to bronchoscopy, patients recorded asthma symptom scores, bronchodilator usage, and twice-daily peak expiratory flow. Five days before bronchoscopy, methacholine responsiveness was assessed. Two biopsies were taken from the subcarinae, one of which was processed into araldite for immunostaining by the streptavidin biotin immunoperoxidase method and the other into Spurr resin for electron microscopy. The number of AA1 staining mast cells present in the bronchial mucosa was not significantly different in the epithelium or submucosa between the asthmatic and the normal subjects. However, in the biopsies from asthmatics, there were significantly greater numbers of EG2-staining eosinophils in the epithelium (median, 1.2/mm versus zero; p less than 0.005) and in the submucosa (median, 50/mm2 versus 1/mm2; p less than 0.001). Electron microscopy showed morphologic features of mast cell and eosinophil degranulation in the asthmatics. No correlation could be established between mast cell or eosinophil numbers and indices of disease activity of PC20 methacholine, which points to the complexity of mechanisms responsible for the symptoms and the airway hyperresponsiveness of asthma.     

Effect of an inhaled corticosteroid on airway inflammation and symptoms in asthma.

The effect of inhaled corticosteroid therapy on airway mucosal inflammation was investigated in 10 symptomatic atopic asthmatic patients treated with inhaled albuterol and whose disease severity required preventative antiinflammatory treatment. Endobronchial biopsies were obtained by fiberoptic bronchoscopy before and after 6 wk of therapy with inhaled beclomethasone dipropionate (2,000 micrograms/day for 2 wk followed by 1,000 micrograms/day for 4 wk). Following treatment, there was a significant increase in mean morning peak expiratory flow (p less than 0.05) and baseline FEV1 measured on the day of methacholine challenge (p less than 0.05) and a decrease in asthma symptoms (p less than 0.01), peak expiratory flow variation (p less than 0.05), and albuterol usage (p less than 0.05). This was accompanied by a sevenfold decrease in airway responsiveness (p = 0.001). The clinical improvement in asthma was associated with a significant (p less than 0.05) reduction in epithelial and mucosal mast cells and eosinophils and submucosal T lymphocytes, but electron microscopy did not identify any changes in the extent of mast cell and eosinophil degranulation following treatment. Because of the association between the decrease in inflammatory cell numbers and the improvement in all the measured clinical and physiologic indices of asthma, we suggest that the beneficial effect of inhaled corticosteroids in asthma may be attributed to their antiinflammatory action in the bronchial mucosa.     

Identification of T lymphocytes, macrophages, and activated eosinophils in the bronchial mucosa in intrinsic asthma. Relationship to symptoms and bronchial responsiveness.

Using immunohistochemistry and a panel of monoclonal antibodies, we have compared T-lymphocyte, eosinophil, macrophage, and neutrophil infiltration in bronchial biopsies from 10 intrinsic (nonallergic) asthmatics (IA) and seven extrinsic (allergic) asthmatic (EA), with similar degrees of disease severity. The results were compared with 12 normal healthy nonatopic controls (NC). All subjects were nonsmokers and were not taking oral or inhaled corticosteroids. An intense mononuclear cell infiltrate was identified in IA with an increase in the number of CD45+ cells (total leukocytes), CD3+ and CD4+ lymphocytes, and CD68+ macrophages (p < 0.03, p < 0.01, p < 0.03, and p < 0.03, respectively), compared with NC. Increases were also found in CD4+ (p < 0.05) and CD68+ (p < 0.05) cell numbers between IA and EA. IL-2 receptor-bearing cells (CD25+) and the number of total (MBP+) and actively secreting (EG2+) eosinophils, were also increased in IA compared with NC (p < 0.01, p < 0.01, and p < 0.01, respectively). Similar increases in EG2+ eosinophils and CD25+ (IL-2 receptor-positive) cells were observed in EA (p < 0.01 and p < 0.02, respectively). No differences were detected in the three groups for the number of elastase-positive cells (neutrophils). EG2+ numbers in IA correlated with the Aas asthma symptoms score (r = 0.65, p < 0.05), whereas EG2+ cell numbers in all asthmatics (IA + EA) correlated with airway methacholine responsiveness (r = -0.55, p < 0.03) and with the Aas asthma symptom score (r = 0.54, p < 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)     

Aggregations of lymphoid cells in the airways of nonsmokers, smokers, and subjects with asthma

Persistent airway inflammation is present in cases with asthma and in smokers with airflow obstruction. Isolated aggregations of lymphoid cells (IALC) may be sites of localized inflammatory cell activation. Their distribution and characteristics in cartilaginous airways were assessed in postmortem tissue from nonsmokers (n=10), smokers (n=9), and cases of nonfatal (n=10) and fatal asthma (n=10). IALC were present in 70-100% of cases, were more often in proximal than distal airways, and 80% were confined to the outer airway wall. IALC with area greater than 0.1 mm2 were more frequent in both asthma groups (p<0.001). Airways with IALC had increased airway dimensions and greater numbers of eosinophils and lymphomononuclear cells. Within IALC, T and B lymphocytes were segregated and comprised more than 90% of all cells. Proliferating, apoptotic, and antigen-presenting cells (Rel B+ and HLA-DR+) were less than 5%, 30-40%, and less than 1% of all cells, respectively, and were similar in each case group. Vascular structures were increased (p < 0.01) in cases of fatal asthma. These findings show that, even in nonsmoking cases and cases without asthma, IALC are common, show cellular organization, and are associated with airway wall inflammation and remodeling. It remains to be determined if IALC contribute to or result from persistent airway inflammation in asthma.     

Small bowel of patients with asthma and allergic rhinitis: absence of inflammation despite the presence of major cellular components of allergic inflammation.

Eosinophils participate in the pathogenesis of inflammatory diseases of the respiratory tract and the gut. We investigated the constitutive presence of eosinophils and mononuclear cells in the macroscopically normal duodenal mucosa of patients with asthma and allergic rhinitis. Macroscopically normal duodenal specimens were obtained at routine endoscopy for upper gastrointestinal symptoms from 16 patients with asthma and 13 patients with allergic rhinitis. Twelve nonatopic patients with irritable bowel syndrome were studied as controls. Specimens were analyzed by immunohistochemistry using a panel of antibodies to human eosinophil cationic protein clone EG1 (EG1) and clone EG2 (EG2), anti-human interleukin (anti-hIL)-5, anti-hIL-4, anti-CD4, and anti-CD68. Significantly increased numbers of eosinophils stained with EG1 and EG2 were found in the duodenum of patients with asthma and allergic rhinitis compared with controls. IL-5+ cells and IL-4+ cells were detected in significantly increased numbers in the duodenal mucosa of patients with asthma and rhinitis compared with controls. Mononuclear cells expressing CD4 (helper T cells) and CD68 (macrophages) also were significantly increased in the duodenal mucosa of asthma and rhinitis compared with controls. Accumulation of eosinophils in conjunction with IL-4+ cells and IL-5+ cells in the noninflamed duodenal mucosa may reflect a predominant T helper cell subset 2 systemic immune response in patients with asthma and allergic rhinitis. The absence of intestinal inflammation despite the marked presence of cells implicated in the allergic inflammation suggests that local mechanisms might determine the state of nonresponsiveness in the gut mucosa of patients with asthma and allergic rhinitis.     

The effect of pranlukast on allergen-induced bone marrow eosinophilopoiesis in subjects with asthma

We investigated the mechanisms by which leukotriene receptor antagonists decrease airway eosinophil number. In a randomized, double-blind crossover study, we examined the effects of 2 weeks of treatment with pranlukast 300 mg twice a day or placebo on allergen-induced changes in airway eosinophil number and bone marrow eosinophil progenitors in 15 subjects with mild asthma. Pranlukast treatment for 2 weeks decreased mean sputum eosinophil count from 0.15 x 10(6)/g (5.3% of cells) before treatment to 0.02 x 10(6)/g (0.7% of cells) after treatment (p < 0.05), whereas placebo did not. Pranlukast also decreased the eosinophil count (5.6% at 7 hours and 7.5% at 24 hours) (p < 0.05) after allergen inhalation compared with placebo (13.8% at 7 hours and 15.3% at 24 hours). There was a similar trend for sputum cells immunostaining for EG2, eotaxin, interleukin-5, and regulated upon activation, normal T cell expressed and secreted. Pranlukast also significantly attenuated the allergen-induced increase in the number of bone marrow eosinophil/basophil cfu (mean 0.3) at 24 hours compared with placebo (mean 6.2). The proportion of CD34(+) cells expressing the eotaxin receptor CC chemokine receptor 3, 24 hours after allergen inhalation, was also reduced by pranlukast. We conclude that, the cysteinyl leukotriene receptor antagonist, pranlukast, attenuates allergen-induced increase in airway eosinophils by decreasing bone marrow eosinophilopoiesis and airway chemotactic and eosinophilopoietic cytokines.     

Empiric treatment with amiodarone in patients with sustained ventricular tachyarrhythmia. Results of a long-term follow-up

The long-term follow-up of 52 pts (36 M, 16 F, mean age: 62 years) with sustained ventricular tachyarrhythmias (SVT) was analyzed to assess the efficacy and feasibility of empiric amiodarone treatment. Forty-five pts had organic heart disease (mean EF: 38.3%) and 7 pts no overt heart disease. Twenty pts suffered from syncope or cardiac arrest secondary to sustained ventricular tachyarrhythmias (mean: 2.35 episodes) and 32 did not. All pts were given amiodarone empirically (mean dose: 390 mg) and followed-up for a mean period of 29.5 months (range 1-137). Two pts (3.8%) died of non cardiac causes, 5 (9.6%) of non sudden cardiac death and 7 (13.4%) of sudden death. Fifteen pts (28.8%) experienced non fatal arrhythmic recurrences. Four out of 7 pts who died suddenly experienced non fatal arrhythmic recurrence before death. The actuarial incidence of cardiac death was 10.8, 22.7, 31.5, 31.5% at 1, 2, 3 and 5 years; the actuarial incidence of sudden death was 8.9, 12, 22.1, 22.1% at 1, 2, 3 and 5 years; the actuarial incidence of non fatal arrhythmic recurrences was 17.4, 26.3, 26.3, 26.3, 44.7% at 1, 2, 3, 4 and 5 years. Univariate analysis identified recent myocardial infarction, NYHA functional class, detection of frequent and/or repetitive premature ventricular contractions on Holter monitoring and non fatal arrhythmic recurrences as predictors of cardiac death (p less than 0.05), while only non fatal arrhythmic recurrences were associated with sudden death (p less than 0.05). Twenty-two pts (42.3%) developed side effects. Nine (17.3%) discontinued amiodarone: 6 pts (11.5%) because of side effects and 3 inadvertently.(ABSTRACT TRUNCATED AT 250 WORDS)     

Evidence for neutrophil activation in occupational asthma

In order to evaluate the role of neutrophils in the pathogenesis of occupational asthma (OA), 15 toluene diisocyanate (TDI)-asthma and six grain dust-asthma patients were recruited. Controls were the same number of subjects showing negative bronchoprovocation test (BPT) and six house dust mite-sensitive asthma. Bronchoscopic biopsy specimens were stained with monoclonal antibodies to mast cell (AA1), eosinophil (EG2), pan T cell (CD3) and neutrophil (NE). Serum neutrophil chemotactic activity (NCA) was measured before and 10-420 min after BPT. Sputum interleukin-8 (IL-8) and myeloperoxidase (MPO) were also measured. There was a significant increase of NE+ cells as well as AA1+ and EG2+ cells in grain dust- and TDI-asthma compared with house dust-sensitive asthma (P < 0.05). Neutrophil+ cells and AA1+ cells showed a significant correlation in TDI-asthma (r = 0.73, P = 0.02). Serum NCA was significantly increased at 10 min after BPT and decreased at 60 min in subjects with TDI-asthma. In grain dust-asthma, serum NCA increased at 30 min and decreased at 240 min after BPT (P < 0.05). Sputum IL-8 and MPO were significantly increased after BPT in both TDI- and grain dust-asthma (P < 0.05). These findings suggested that neutrophils in the lungs might contribute to bronchoconstriction induced by either TDI or grain dust. The possible involvement of IL-8 in activation of neutrophils was also suggested.     

T-lymphocyte activation and the levels of eosinophilic cationic protein and interleukin-5 in asthmatic children with acute exacerbation and effect of glucocorticoid treatment.

The aim of this study was to evaluate the immunologic parameters and the effects of glucocorticoid treatment, the absolute numbers of CD4+/CD25+ T lymphocytes, eosinophil counts, levels of eosinophilic cationic protein (ECP), and interleukin (IL)-5 in peripheral blood of patients having acute asthma exacerbations and healthy children were investigated. Samples for the absolute numbers CD4+/CD25+ T lymphocyte and eosinophil count, ECP, and IL-5 were obtained before (day 1) and after (day 5) glucocorticoid treatment. Forced expiratory volume in 1 second and peak expiratory flow rate were measured on days 1 and 5 in asthma patients (n = 25) and in the control group (n = 15). The absolute numbers of CD4+/CD25+ T lymphocyte and eosinophils, levels of ECP, and IL-5 were significantly greater, while forced expiratory volume in 1 second and peak expiratory flow rate were significantly less in the patients with asthma than in the control subjects on day 1. These parameters normalized after glucocorticoid treatment with clinical improvement by day 5. Glucocorticoid treatment is associated with clinical and laboratory improvement achieved in patients with acute asthma exacerbations.     

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.     

Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics.

The mechanisms associated with the development of severe, corticosteroid (CS)-dependent asthma are poorly understood, but likely heterogenous. It was hypothesized that severe asthma could be divided pathologically into two inflammatory groups based on the presence or absence of eosinophils, and that the inflammatory subtype would be associated with distinct structural, physiologic, and clinical characteristics. Thirty-four severe, refractory CS-dependent asthmatics were evaluated with endobronchial biopsy, pulmonary function, allergy testing, and clinical history. Milder asthmatic and normal control subjects were also evaluated. Tissue cell types and subbasement membrane (SBM) thickness were evaluated immunohistochemically. Fourteen severe asthmatics [eosinophil (-)] had nearly absent eosinophils (< 2 SD from the normal mean). The remaining 20 severe asthmatics were categorized as eosinophil (+). Eosinophil (+) severe asthmatics had associated increases (p < 0.05) in lymphocytes (CD3+, CD4+, CD8+), mast cells, and macrophages. Neutrophils were increased in severe asthmatics and not different between the groups. The SBM was significantly thicker in eosinophil (+) severe asthmatics than eosinophil (-) severe asthmatics and correlated with eosinophil numbers (r = 0.50). Despite the absence of eosinophils and the thinner SBM, the FEV(1) was marginally lower in eosinophil (-) asthmatics (p = 0.05) with no difference in bronchodilator response. The eosinophil (+) group (with a thicker SBM) had more intubations than the eosinophil (-) group (p = 0.0004). Interestingly, this group also had a decreased FVC/slow vital capacity (SVC). These results suggest that two distinct pathologic, physiologic, and clinical subtypes of severe asthma exist, with implications for further research and treatment.     

Effects of acute and chronic ethanol administration on the gastrointestinal hormones gastrin, enteroglucagon, pancreatic glucagon and peptide YY in the rat

The effect of acute and chronic ethanol administration on the gastrointestinal hormones gastrin, enteroglucagon (EG), pancreatic glucagon (PG) and peptide YY (PYY) was studied in the rat alcohol model. Plasma levels of gastrin and PYY were not significantly changed under chronic and/or acute alcohol, while PG was stimulated by acute intraperitoneal ethanol injections in control animals as well as in chronically ethanol-fed rats (8 +/- 1 vs. 28 +/- 6 pmol/l, p less than or equal to 0.05, and 7 +/- 1 vs. 21 +/- 4 pmol/l, p less than or equal to 0.05). EG levels were significantly raised after chronic ethanol feeding (45 +/- 5 vs. 73 +/- 8 pmol/l, p less than or equal to 0.01) and even further elevated if an acute dose of alcohol was given to chronically ethanol-fed rats (73 +/- 8 vs. 168 +/- 29 pmol/l, p less than or equal to 0.05). The immunohistologically evaluated numbers of the respective hormone-producing cells were not significantly changed by alcohol feeding. The ethanol-dependent elevations of EG and PG may contribute, at least in part, to the intestinal hyper-regeneration, motility disturbances and altered glucose metabolism observed after alcohol consumption.     

Contribution of eotaxin-1 to eosinophil chemotactic activity of moderate and severe asthmatic sputum

The CC chemokine eotaxin-1 (CCL11) is chemotactic for eosinophils, basophils, and type 2 helper T cells and may play a role in allergic inflammation. We investigated its contribution as an eosinophil chemoattractant in asthmatic airway secretions (sampled as induced sputum), which possess chemotactic activity for eosinophils and T cells. Sputum samples collected from healthy subjects and subjects with mild, stable-moderate, unstable-moderate, and severe asthma were processed with phosphate-buffered saline and assayed for eotaxin by ELISA and for eosinophil chemotactic activity by fluorescence-based chemotaxis assay. The contribution of eotaxin to chemotactic activity was studied by using a high-affinity neutralizing human anti-eotaxin antibody, CAT-213. Sputum eotaxin concentration was significantly raised in moderate and severe asthma (p < 0.05 versus healthy control subjects) but not in mild asthma. Chemotactic activity was significantly increased in all asthmatic groups relative to healthy subjects (p < 0.05) and was significantly inhibited by CAT-213 (100 nM) in subjects with moderate and severe asthma, with median inhibition of 52% (p < 0.05), 78% (p < 0.0001), and 86% (p < 0.0001), respectively, in samples representing stable-moderate, unstable-moderate, and severe asthma. Eotaxin contributed to the eosinophil chemotactic activity of sputum from subjects with more severe forms of asthma but not mild asthma, suggesting that its contribution is more important in more severe disease. This activity is inhibited significantly by CAT-213.     

地塞米松对哮喘豚鼠气道炎症细胞凋亡的影响

目的 炎症细胞的清除是哮喘治疗效果的关键。探讨地塞米松治疗是否以凋亡形式清除哮喘粘膜组织中的炎症细胞。方法 采用卵蛋白诱导的豚鼠哮喘模型以地塞米松作治疗，用末端脱氧核苷酸转移酶（ＴｄＴ）倡导的脱氧三磷酸尿嘧啶（ｄＵＴＰ）末端标记（ＴＵＮＥＬ）法进行凋亡细胞的标记。以免疫组化标记活化的嗜酸性粒细胞蛋白（ＥＧ２）以及Ｔ淋巴细胞的ＣＤ３＾＋、ＣＤ４＾＋和ＣＤ８＾＋。对皮质激素组和对照组气道粘膜组织中的淋     

Activated, cytotoxic CD8(+) T lymphocytes contribute to the pathology of asthma death

This study investigates the presence of CD8(+) T lymphocytes and their possible association with viral infection in bronchi of victims of fatal asthma. Postmortem samples from the peribronchial region of the lung were obtained from seven patients who died an asthma death (AD), seven asthmatic patients who died of unrelated causes (AUC), and seven postmortem cases with no history of lung disease (control subjects). Using immunohistochemical techniques, the CD8(+) cytotoxic T-cell population in peribronchial tissue was characterized in three patient groups. The percentage of CD8(+) cells expressing the activation marker CD25 was higher in the AD group than in both the AUC and control groups (11.91 +/- 1.92% versus 3.93 +/- 1.63% and 1.09 +/- 0.56%, respectively (p < 0.001). Perforin expression, a marker of cytotoxicity, was highest in the AD group (9.16 +/- 1.5%) compared with 1.39 +/- 0.9; 1.8 +/- 0.6% in the AUC and control groups respectively (p < 0.001). Expression of interleukin-4 (IL-4) and interferon gamma (IFN-gamma) by CD8(+) T cells was higher in the AD group than the control group (p < 0.05). Furthermore, the IFN-gamma/IL-4 ratio in the AD group was less than half that of the control group (1.46 +/- 0.2 versus 3.2 +/- 0.1; p = 0.02). Using polymerase chain reaction (PCR), viral genome for rhinovirus (RV) was detected in lung tissue from three of the seven cases in the AD group. Two of these cases also had detectable respiratory syncytial virus (RSV). Viral genome for RSV was detected in five of the AUC group and in one of these cases, RV was also detected. No viral genome was detected in the lungs of the control group. In conclusion, this study provides novel evidence of an aberrant CD8(+) T-cell population, possibly in response to viral infection in subjects who die of acute asthma.     

Eosinophil soluble protein levels, eosinophil peroxidase and eosinophil cationic protein in asthmatic patients.

Eosinophil granular proteins are useful eosinophil activation markers in asthmatic patients. In this study, eosinophil peroxidase (EPO) and eosinophil cationic protein (ECP) levels were assessed in different stages of bronchial asthma in 123 patients suffering from intrinsic (n = 42) and extrinsic (n = 81) asthma, with the aim of evaluating the difference in the protein levels between both types of asthma and their importance as a severity marker of the disease. The geometric mean serum level of EPO was 12.3 +/- 2.17 ng/ml (mean +/- SD) in controls, and 38.6 +/- 3.4 ng/ml in the asthmatic patients. Mean ECP levels were 13.22 +/- 1.11 ng/ml in controls and 30.5 +/- 2.38 ng/ml in patients. Depending on the asthma severity, the EPO levels were 30.4 +/- 4.35, 38.7 +/- 5.29, and 54.46 +/- 9.46 ng/ml in mild, moderate and severe asthmatics, respectively, with the differences being significant between the groups of patients with mild and severe asthma (p < 0.001). ECP levels were 24.23 +/- 3.37 in mild, 31.69 +/- 4.21 in moderate, and 37.61 +/- 4.52 ng/ml in severe asthma. There were significant differences in ECP levels between mild and moderate asthma (p < 0.001) and between mild and severe asthma (p < 0.001). Peripheral eosinophil count was 157 +/- 20 eosinophils/mm3 in controls, 334 +/- 35 eosinophils/mm3 in mild asthmatics, 510 +/- 87 eosinophils/mm3 in moderate asthmatics and 658 +/- 72 eosinophil/mm3 in severe asthmatics, with significant differences between all groups (p < 0.05-p < 0.001). Serum EPO and ECP levels and peripheral eosinophil count were significantly greater in patients with active asthma than in patients with silent asthma (p < 0.001). Significant negative correlations (p < 0.001) were found between serum EPO levels and FEV1 (rs = -0.30), MEF25-75 (rs = -0.33), MEF50 (rs = -0.34). There was also a significant (p < 0.001) and negative correlation between ECP levels and FEV1 (rs = -0.31), MEF25-75 (rs = -0.31), MEF50 (rs = -0.32). A good positive correlation was found between peripheral eosinophil count and EPO levels (rs = 0.80, p < 0.001), and ECP levels (rs = 0.67, p < 0.001). We also found a significant positive correlation between clinical score and peripheral eosinophil count (rs = 0.54, p < 0.001), EPO levels (rs = 0.46, p < 0.001) and ECP levels (rs = 0.52, p < 0.001).     

Time to death, airway wall inflammation and remodelling in fatal asthma.

Fatal asthma is characterised pathologically by airway wall remodelling, eosinophil and neutrophil infiltration, accumulation of mucus in the airway lumen and smooth muscle shortening. The durations of fatal attacks of asthma show a clear bimodal distribution. Airway smooth muscle contraction and the accumulation of luminal mucus may contribute to death from asthma and relate to time to death. The current authors have examined these two components in uninflated lung tissue in cases of fatal asthma from the second Victorian asthma mortality study. Based on time from onset of symptoms to death, cases fell into two distinct groups: short course <3 (1.5+/-0.6 mean+/-sd) h; and long course >8 (12.3+/-5.9) h. Short course cases had more muscle shortening, higher levels of salbutamol and higher ratios of neutrophils to eosinophils than long course cases, who tended to have more mucus in the lumen. In conclusion, this study confirms the dichotomy of both time to death and the eosinophil/neutrophil ratio in cases of fatal asthma. It suggests that in short course cases acute airway narrowing is due, predominantly, to bronchoconstriction despite higher blood levels of salbutamol. Mucus accumulation may be more important in long course cases.     

Airway hyperresponsiveness, increased intracellular spaces of bronchial epithelium, and increased infiltration of eosinophils and lymphocytes in bronchial mucosa in asthma.

Inflammation of the airway wall and airway hyperresponsiveness are consistent features of chronic asthma. We investigated how damage of the bronchial epithelium is related to airway hyperresponsiveness and how bronchial infiltration of eosinophils and lymphocytes is related to bronchial epithelial damage. We examined the biopsy specimens of bronchial mucosa taken from 19 patients with chronic asthma by electron microscopy. We also measured the incidence of opening of epithelial tight junctions, the widening of intercellular spaces in the epithelium, and the density of infiltrated eosinophils and lymphocytes in bronchial mucosa. Airway responsiveness was accessed by measuring PC20-acetylcholine (PC20-ACh). The inflammatory cells in the airway mucosa were counted by electron microscopy. Lymphocytes were most abundant, being 54.5% of the cells counted; eosinophils were 22.1%, neutrophils were 4.9%, and mast cells were 4.6%. A significant correlation was noted between the density of eosinophils and that of lymphocytes infiltrated in the airway mucosa (r = 0.80, p less than 0.01), suggesting that T cells may potentiate eosinophil infiltration. With increased density of eosinophils infiltrated in bronchial mucosa, both the incidence of opening of tight junctions of epithelial ciliary cells and the degree of widening of intercellular spaces in epithelium increased significantly (r = 0.51, p less than 0.05; r = 0.52, p less than 0.05), suggesting that eosinophils are related to damage of the bronchial epithelium. No correlation was observed between the density of lymphocyte infiltration and the degree of epithelial damage.(ABSTRACT TRUNCATED AT 250 WORDS)     

Airway remodeling: a comparison between fatal and nonfatal asthma.

BACKGROUND: Airway remodeling has been recently one of the main goals in asthma research because it has been implicated to influence airway behavior and evolution of asthma; hence, important in long-term followup of asthmatic patients. METHODS: Airways of fatal asthma (n=3), non-fatal asthma (n=3) and control cases (n=4) were studied using morphometry and immunohistochemical and H&E staining. RESULTS: The basement membrane was thicker in the cartilaginous and membranous airways of fatal and non-fatal asthma groups compared to the control group (p<0.05). Smooth muscle shortening was greater in airways of fatal asthma cases while submucosal gland area and mucus plug occupying ratio were greater in fatal asthma large airways compared to the two other groups (p<0.01). Increased intact and degranulated mast cells were observed in smooth muscle and in submucosal gland of fatal asthma airways (p<0.01) and were associated with greater degree of smooth muscle shortening and larger submucosal gland area, respectively. Eosinophil and EG2+ cell infiltrations were greatest in lamina propria of airways of fatal asthma than in nonfatal and control cases (p<0.01), but were not associated with any airway structural change. CONCLUSION: Increased infiltration of eosinophils in the lamina propria and mast cells in smooth muscle and submucosal glands may have a role in airway remodeling of fatal asthma airways but needs further investigation. Moreover, mast cells in cartilaginous airways may participate in the regulation of smooth muscle tone and mucous gland secretion and hyperplasia.