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The reader will come to appreciate: • Post-infectious bronchiolitis obliterans is potentially devastating disease. • History of respiratory infection in healthy children, frequently during childhood. • Nonreversible airway obstruction. • Mosaic pattern on chest-computed tomography. • Exclusion of other chronic lung diseases such as severe asthma, cystic fibrosis or ciliary dyskinesia, bronchopulmonary dysplasia, immunodeficiency, and alpha-1-antitrypsin deficiency. • One hypothesis is it occurs as a result of damage to the respiratory epithelium, which provides professionals with a new therapeutic target on which to base their research. • Post-infectious bronchiolitis obliterans is potentially devastating disease. • PIBO criteria include appropriate history and radiological changes. • It is important to exclude other respiratory pathologies. • One hypothesis suggests that PIBO results from damage to the respiratory epithelium. • This may provide new therapeutic targets for research. Post infectious bronchiolitis obliterans (PIBO) is a rare but severe disease in children. Several respiratory pathogens are incriminated but adenovirus is still the most represented. Risk factors are well described: the male gender, hypoxemia at diagnosis and required mechanical ventilation. No risk factor is linked to the newborn period. The clinical spectrum of PIBO is broad, ranging from asymptomatic patients with fixed airflow obstruction to severe respiratory insufficiency requiring continuous oxygen supplementation. Diagnosis includes a combination of a clinical history, absence of reversible airflow obstructions and ground glass and gas trapping on high resolution computed tomography. PIBO is primarily a neutrophilic pathology of small bronchioles characterized by high levels of pro-inflammatory cytokines leading to tissue remodeling and fibrosis of the small airways. The difficulty is to discriminate between the host's normal response, an exaggerated inflammatory response and the potential iatrogenic consequences of the initial infection treatment, particularly prolonged mechanical ventilation. Damage to the respiratory epithelium with a possible link to viral infections are considered as potential mechanisms of PIBO. No specific management exists. Much remains to be done in this field to clarify the underlying mechanisms, identify biomarkers, and develop clear monitoring pathways and treatment protocols. [ABSTRACT FROM AUTHOR]

Background Lipoxins are biologically active eicosanoids with anti-inflammatory properties. Lipoxin A 4 (LXA 4 ) signaling blocks asthmatic responses in human and experimental model systems. There is evidence that patients with respiratory diseases, including severe asthma (SA), display defective generation of lipoxin signals despite glucocorticoid therapy. Objective We investigated airway levels of formyl peptide receptor 2–lipoxin receptor (FPR2/ALXR), LXA 4 , and its counterregulatory compound, leukotriene B 4 (LTB 4 ), in patients with childhood asthma. We addressed the potential interplay of the LXA 4 -FPR2/ALXR axis and glucocorticoids in the resolution of inflammation. Methods We examined LXA 4 and LTB 4 concentrations in induced sputum supernatants from children with intermittent asthma (IA), children with SA, and healthy control (HC) children. In addition, we investigated FPR2/ALXR expression in induced sputum cells obtained from the study groups. Finally, we evaluated in vitro the molecular interaction between LXA 4 and glucocorticoid receptor–based mechanisms. Results We found that children with SA have decreased LXA 4 concentrations in induced sputum supernatants in comparison with children with IA. In contrast to decreases in LXA 4 concentrations, LTB 4 concentrations were increased in children with asthma independent of severity. LXA 4 concentrations negatively correlated with LTB 4 concentrations and with exacerbation numbers in children with SA. FPR2/ALXR expression was reduced in induced sputum cells of children with SA compared with that seen in HC subjects and children with IA. Finally, we describe in vitro the existence of crosstalk between LXA 4 and glucocorticoid receptor at the cytosolic level mediated by G protein–coupled FPR2/ALXR in peripheral blood granulocytes isolated from HC subjects, children with IA, and children with SA. Conclusion Our findings provide evidence for defective LXA 4 generation and FPR2/ALXR expression that, associated with increased LTB 4 , might be involved in a reduction in the ability of inhaled corticosteroids to impair control of airway inflammation in children with SA. [ABSTRACT FROM AUTHOR]

Summary: Background: Epidemics of asthma and overweight have been linked recently. They might be associated with systemic inflammation. In asthma hyperresponsiveness to adenosine (AMP) is more closely related to inflammation than to methacholine (MCh). The aim of the study was to determine responsiveness to AMP and MCh in overweight compared with normal weight asthmatics. Methods: Thirty women were enrolled (19 overweight) with mild controlled asthma according to GINA. A Body Mass Index (BMI) less than 25kg/m2 was considered as normal and a BMI above 25kg/m2 as overweight. We assessed the recent control of asthma (ACQ), pulmonary function tests, bronchial responsiveness to MCh and AMP (PC20 and O''Connor two-point dose–response slope), perception of symptoms (Borg scale), and blood inflammatory markers (leptin and hs-CRP by ELISA). Results: Overweight had a significant lower dose-response slope of the MCh challenge (p =0.009) as compared to normal weight patients, whereas no significant difference was observed for AMP challenge (p =0.27). Overweight patients had higher intercepts of the Borg scale measured before the MCh and AMP challenge tests (p =0.01 and p =0.03). Plasma leptin (p =0.001) and hs-CRP (p =0.05) concentrations were higher in overweight than normal weight patients. There was no correlation between challenges and inflammatory markers. Conclusions: Overweight asthmatic women have more pronounced systemic inflammation, but are less responsive to MCh. AMP responsiveness appeared to be comparable between both groups. Our findings suggest that overweight asthmatic women do not feature increased airway inflammation, but do represent a distinct phenotype as compared to normal weight patients. [Copyright &y& Elsevier]

Background: Structural changes to the airways are features of severe asthma. The bronchial epithelium facilitates this remodeling process. Learning about the changes that develop in the airway epithelium could improve our understanding of asthma pathogenesis and lead to new therapeutic approaches. Objective: We sought to determine the feasibility and relevance of air-liquid interface cultures of bronchial epithelium derived from endobronchial biopsy specimens of patients with different severities of asthma for studying the airway epithelium. Methods: Human bronchial epithelial cells derived from endobronchial biopsy specimens of patients with mild and severe asthma were maintained in culture for 21 days in an air-liquid interface to reproduce a fully differentiated airway epithelium. Initially, features of remodeling that included epithelial and subepithelial layers, as well as mucus production, were assessed in paraffin-embedded endobronchial biopsy specimens to evaluate morphologic characteristics of asthmatic patients’ epithelia. Ex vivo differentiated epithelia were then analyzed for morphology and function based on ultrastructural analysis, IL-8 release, lipoxin A4 generation, mucin production, and lipoxygenase gene expression. Results: Morphologic and inflammatory imbalances initially observed in endobronchial biopsy specimens obtained from patients with severe or mild asthma persisted in the air-liquid interface reconstituted epithelium throughout the differentiation process to 21 days. Epithelium from patients with severe asthma produced greater levels of mucin, released more IL-8, and produced lower levels of lipoxin A4 than that from patients with mild asthma. Expression of 15-lipoxygenase 2 was increased in epithelium from patients with severe asthma, whereas expression levels of MUC5AC, MUC5B, 5-lipoxygenase, and 15-lipoxygeanse 1 were similar to those of patients with mild asthma. Conclusion: Ex vivo cultures of fully differentiated bronchial epithelium from endobronchial biopsy specimens maintain inherent phenotypic differences specifically related to the severity of asthma. [Copyright &y& Elsevier]

Background: The adipokine leptin is a potential new mediator for bronchial epithelial homeostasis. Asthma is a chronic inflammatory disease characterized by airway remodeling that might affect disease chronicity and severity. TGF-β is a tissue growth factor the dysregulation of which is associated with airway remodeling. Objective: We sought to determine whether a bronchial epithelial dysfunction of the leptin/leptin receptor pathway contributes to asthma pathogenesis and severity. Methods: We investigated in vitro the presence of leptin/leptin receptor on human bronchial epithelial cells. Then we studied the effect of TGF-β and fluticasone propionate on leptin receptor expression. Finally, the role of leptin on TGF-β release and cell proliferation was analyzed. Ex vivo we investigated the presence of leptin/leptin receptor in the epithelium of bronchial biopsy specimens from subjects with asthma of various severities and from healthy volunteers, and some features of airway remodeling, such as reticular basement membrane (RBM) thickness and TGF-β expression in the epithelium, were assessed. Results: In vitro bronchial epithelial cells express leptin/leptin receptor. TGF-β decreased and fluticasone propionate increased leptin receptor expression, and leptin decreased the spontaneous release of TGF-β and increased cell proliferation. Ex vivo the bronchial epithelium of subjects with mild, uncontrolled, untreated asthma showed a decrease expression of leptin and its receptor and an increased RBM thickness and TGF-β expression when compared with values seen in healthy volunteers. Furthermore, severe asthma was associated with a reduced expression of leptin and its receptor and an increased RBM thickness with unaltered TGF-β expression. Conclusions: Decreased expression of leptin/leptin receptor characterizes severe asthma and is associated with airway remodeling features. [Copyright &y& Elsevier]