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Asthma is characterised by chronic airway inflammation and remodelling, which can be (partially) suppressed by inhaled corticosteroids (ICSs). Plasminogen activator inhibitor-1, encoded by the SERPINE1 gene, is the key inhibitor of the plasminogen activator system, which affects tissue repair and remodelling.We studied associations between a functional SERPINE1 -675 4G/5G promoter polymorphism and asthma development, severity and response to ICSs.Longitudinal cohorts of 281 asthmatics and their nonasthmatic spouses, and the general population (n=1,390) were studied. No significant associations were found with asthma development and immunoglobulin (Ig) E levels, or with forced expiratory volume in 1 s (FEV(1)) in nonasthmatic controls. Asthmatic subjects carrying the SERPINE1 5G allele had higher IgE and lower lung function levels at follow-up, lower maximally attained lung function levels, and faster lung function decline compared with individuals with the 4G/4G genotype. ICS treatment showed an immediate improvement in FEV(1) in asthmatics carrying the 5G allele. However, these asthmatics still had the fastest rate of FEV(1) decline after initiating ICS treatment. Finally, the 5G allele was associated with a lower prevalence of complete asthma remission at follow-up.These findings suggest that SERPINE1 is not an asthma susceptibility gene, but rather affects the severity, progression and long-term ICS response in asthma.

Rationale Individuals with asthma may outgrow symptoms despite not using treatment, whereas others reach complete remission (CoR) with absence of airway obstruction and bronchial hyper-responsiveness. It is uncertain whether this associates with remission of all inflammatory and remodeling asthma features.Objectives: To compare the pathologic phenotype of individuals with asthma with CoR and clinical remission (ClinR) and those with active asthma, with and without the use of inhaled corticosteroids (ICS).Methods: We investigated 165 individuals known with active asthma, on reexamination having CoR (n = 18), ClinR (n = 44), and current asthma (CuA, n = 103, 64 with and 39 without ICS).Measurements Main Results: Inflammatory cells were measured in blood, induced sputum, and bronchial biopsies; histamine and ECP in sputum; and eosinophilic peroxidase (EPX) immunopositivity and remodeling (epithelial changes, E-cadherin expression, basement membrane [BM] thickening, collagen deposition) in bronchial biopsies. Median (range) blood eosinophils from CoR were significantly lower than those from CuA (0.10 [0.04-0.24] vs. 0.18 [0.02-1.16] x 10(9)/L). Bronchial EPX immunopositivity was lower in CoR than in both ClinR and CuA (67 [0.5-462] vs. 95 [8-5329] and 172 [6-5313] pixels). Other inflammatory findings were comparable. BM thickness was lowest in CuA, caused by lower BM thickness in those using ICS (CoR, 6.3 [4.7-8.4]; ClinR, 6.5 [3.8-11.7]; CuA, 5.7 [2.8-12.6]; and ICS using CuA, 5.3 [2.8-8.2] mu m).Conclusions: CoR is still accompanied by airway abnormalities because BM thickness is similar in individuals with asthma with CoR, ClinR, and CuA without ICS. Airway eosinophilic activation best differentiates these three groups, signifying their importance in the clinical expression and severity of bronchial hyper-responsiveness in asthma.

Background: As it is unknown whether complete asthma remission or progression of asthma is associated with airway inflammation and remodeling, we assessed these characteristics in bronchial biopsies of relevant subsets of asthma patients.Methods: Sputum and bronchial biopsies were obtained from asthma patients in remission (PC20 histamine > 32 mg/ml, PC20 AMP > 320 mg/ml) and from those with either a slow FEV1 decline (30 ml/year). Inflammatory cells and mediators were determined in sputum, inflammatory cells and aspects of airway remodeling in bronchial biopsies.Results: Asthmatics in remission and asthma patients with a slow FEV1 decline had a similar extent of airway inflammation and remodeling in sputum and bronchial biopsies. Asthma patients with a fast FEV1 decline had high sputum eosinophil numbers. Moreover, FEV1 decline (ml/year) correlated with sputum eosinophil numbers (Rs = 0.51, p = 0.003) and ECP levels (Rs = 0.57, p = 0.001). Airway remodeling, i.e. basement membrane thickness, correlated with sputum eosinophils (Rs = 0.69, p Conclusions: Asthma, even when in remission, is accompanied by airway inflammation and remodeling. Data suggest that eosinophils are important in a subset of asthma patients by association to accelerated FEV1 decline and change of basement membrane thickness. (C) 2010 Elsevier Ltd. All rights reserved.

Background The definition of "clinical asthma remission" is based on absence of symptoms and use of medication. However, in the majority of these subjects airway inflammation is still present when measured. In the present study we investigated whether "complete asthma remission", additionally defined by the absence of bronchial hyperresponsiveness (BHR) and the presence of a normal lung function, is associated with the absence of airway inflammation. Methods Patients with a former diagnosis of asthma and a positive histamine provocation test were re-examined to identify subjects with complete asthma remission (no asthma symptoms or medication, PC20 histamine > 32 mg/ml, FEV1 > 90% predicted). Patients with PC20 histamine ≤ 32 mg/ml were defined as current asthmatics and were divided in two groups, i.e. asthmatics with and without BHR to adenosine 5'monophoshate (AMP). Sputum induction was performed 1 week before and 1 hour after AMP provocation. Sputum induction and AMP provocation were previously shown to be sensitive markers of airway inflammation. Results Seven patients met criteria for complete asthma remission. Twenty-three were current asthmatics, including twelve without hyperresponsiveness to AMP. Subjects with complete asthma remission showed no AMP-induced sputum eosinophilia (median (range) 0.2 (0 - 4.6)% at baseline and 0.2 (0 - 2.6)% after AMP). After AMP, current asthmatics had a significant increase in sputum eosinophils (0.5 (0 - 26.0)% at baseline and 2.6 (0 - 32.0) % after AMP), as had the subgroup of current asthmatics without hyperresponsiveness to AMP (0.2 (0 - 1.8)% at baseline and 1.3 (0 - 6.3)% after AMP). Conclusions Subjects with complete asthma remission, in contrast to subjects with current asthma, do not respond with eosinophilic inflammation in sputum after AMP provocations. These data lend support to the usefulness of the definition of complete asthma remission.