New insights on congenital pulmonary airways malformations revealed by proteomic analyses.

BACKGROUND: Congenital Pulmonary Airway Malformation (CPAM) has an estimated prevalence between 0.87 and 1.02/10,000 live births and little is know about their pathogenesis. To improve our knowledge on these rare malformations, we analyzed the cellular origin of the two most frequent CPAM, CPAM types 1 and 2, and compared these malformations with adjacent healthy lung and human fetal lungs. METHODS: We prospectively enrolled 21 infants undergoing surgical resection for CPAM. Human fetal lung samples were collected after termination of pregnancy. Immunohistochemistry and proteomic analysis were performed on laser microdissected samples. RESULTS: CPAM 1 and 2 express mostly bronchial markers, such as cytokeratin 17 (Krt17) or α-smooth muscle actin (ACTA 2). CPAM 1 also expresses alveolar type II epithelial cell markers (SPC). Proteomic analysis on microlaser dissected epithelium confirmed these results and showed distinct protein profiles, CPAM 1 being more heterogeneous and displaying some similarities with fetal bronchi. CONCLUSION: This study provides new insights in CPAM etiology, showing clear distinction between CPAM types 1 and 2, by immunohistochemistry and proteomics. This suggests that CPAM 1 and CPAM 2 might occur at different stages of lung branching. Finally, the comparison between fetal lung structures and CPAMs shows clearly different protein profiles, thereby arguing against a developmental arrest in a localized part of the lung.

[Childrens' chronic cough revisited]. / La toux chronique de l'enfant revisitée.

Chronic cough is a common symptom in childhood and very often the expression of a cold like respiratory tract infection. Chronic cough may follow an acute cough lasting more than 4-8 weeks or may be the primary symptom of an underlying severe respiratory disease. It is important to find out the exact origin of chronic cough to allow accurate investigation steps and treatment. In childhood, adults like diagnostic approach is not appropriate and differential diagnosis must encompass children specific age dependent diagnosis. This article aims to stress a specific paediatric approach in prolonged or chronic cough and emphasizes the role of protracted bacterial bronchitis, a form of airway disease newly described. This entity should be diagnosed and treated adequately to avoid recurrence and development of bronchiectasis.

Bronchoalveolar cytology for diagnosing pulmonary GVHD after bone marrow transplant in children.

BACKGROUND: Cytological composition of bronchoalveolar lavage (BAL) fluid in pediatric bone marrow transplant (BMT) recipients with pulmonary complications has not been comprehensively described and BAL specific markers of pulmonary GVHD are lacking. The aim of this retrospective study was to assess the role of BAL in the diagnosis of pulmonary GVHD by comparing BAL cytological findings between pediatric allogenic BMT patients with pulmonary complications and oncology children receiving chemotherapy alone. METHODS: Retrospective analysis of BAL specimens for cytology, total and differential cell counts and presence of infections. RESULTS: Seventeen BMT and 13 chemotherapy BAL were analyzed. BAL total cell count was increased but similar between groups (96.9 x 10(4) vs. 98.2 x 10(4), P = NS). BAL cellular composition differed considerably between groups with a significantly higher number of lymphocytes (18% vs. 6.25%, P = 0.03) and a significantly lower number of neutrophils (25.9% vs. 58%, P = 0.02) in BMT BAL specimens. Atypical epithelial cells were significantly more frequent (75% vs. 30.8%, P = 0.027), and significantly more severe (P = 0.01) in BMT patients. The presence and severity of atypia was not associated with infection or pneumotoxic drug exposure (P = NS). CONCLUSION: BAL cytology differs significantly between BMT and chemotherapy patients. The presence BAL lymphocytosis and severe epithelial cell atypia concomitantly to respiratory symptoms and GVHD in other organs may suggest the diagnosis of pulmonary GHVD. Prospective studies assessing the reliability of this finding combined with markers such as epithelial cell apoptosis and increased cytokines are needed.

[Recurrent lower respiratory tract infection in children: when and how should they be investigated?]. / Infections récurrentes des voies respiratoires inférieures de l'enfant: quand et comment les investiguer?

Children with recurrent lower respiratory tract infections are often a challenge for their physicians. This article reviews the differential diagnosis of recurrent cough, bronchopneumonia and/or pneumonia in children and emphasizes on the necessity of preventing long-term complications of these infections. It also suggests a step-wise immunological work-up, which includes investigating a possible immune maturation delay or deficiency which could explain these symptoms. This work-up focuses on measuring antibody responses to pneumococci, followed by immunization when necessary, to rule out B cell dysfunction. Finally, this article also describes an upcoming study in Switzerland which will evaluate in 2005 the clinical and immunological outcome of these young patients.

Effects of volatile anaesthetic agents on enhanced airway tone in sensitized guinea pigs.

BACKGROUND: Although volatile anaesthetics afford protection against bronchospasm, their potential to reverse a sustained constriction of hyperreactive airways has not been characterized. Accordingly, we investigated the ability of halothane, isoflurane, sevoflurane and desflurane to reverse lung constriction induced by prolonged stimulation of the muscarinic receptors in guinea pigs sensitized to ovalbumin. METHODS: Pulmonary input impedance (ZL) was measured using forced oscillations in five groups of ovalbumin-sensitized, mechanically ventilated guinea pigs. ZL was measured under baseline conditions, during steady-state bronchoconstriction induced by an i.v. infusion of methacholine (MCh), and after administration of one of the volatile agents at 1 MAC after the induction of a steady-state bronchoconstriction. Airway resistance (Raw), and parenchymal tissue resistive and elastic coefficients were extracted from ZL by model fitting. RESULTS: All four volatile agents exhibited an initial relaxation of the MCh-induced airway constriction followed by gradual increases in Raw. The bronchodilatory effect of isoflurane was the most potent (-28.9 (SE 5.5)% at 2 min, P<0.05) and lasted longest (7 min); sevoflurane and halothane had shorter and more moderate effects (-21.1 (3.9)%, P<0.05, and -6.1 (1.7)%, P<0.05, respectively, at 1 min). Desflurane caused highly variable changes in Raw, with a tendency to enhance airway tone. CONCLUSIONS: Volatile agents can reverse sustained MCh-induced airway constriction only transiently in sensitized guinea pigs. Isoflurane proved most beneficial in temporally improving lung function in the presence of a severe constriction of allergic inflamed airways. Desflurane displayed potential to induce further airway constriction.

Hyperoxia increases leptin production: a mechanism mediated through endogenous elevation of corticosterone.

Leptin, a cytokine involved in the regulation of food intake, has been reported to be decreased in lung diseases such as chronic obstructive pulmonary disease and cystic fibrosis and increased in critically ill patients with sepsis. We investigated the role of leptin during hyperoxia in mice, which results in alveolar edema, severe weight loss, and death within 3-4 days. In oxygen-breathing mice, serum leptin was increased six- to sevenfold and its mRNA was upregulated in white adipose tissue. Leptin elevation could not be attributed to changes in circulating tumor necrosis factor-alpha but was completely dependent on endogenous corticosterone elevation because adrenalectomized mice did not exhibit any increase in leptin levels. Using leptin-deficient mice and wild-type mice treated with anti-leptin antibody, we demonstrate that weight loss was leptin independent. Lung damage was moderately attenuated in leptin-deficient mice but was not modified by anti-leptin antibody or leptin administration, suggesting that leptin does not play an essential role in the direct and short-term effects of oxygen-induced injury.

Hyperoxia-induced changes in mouse lung mechanics: forced oscillations vs. barometric plethysmography.

Hyperoxia-induced lung damage was investigated via airway and respiratory tissue mechanics measurements with low-frequency forced oscillations (LFOT) and analysis of spontaneous breathing indexes by barometric whole body plethysmography (WBP). WBP was performed in the unrestrained awake mice kept in room air (n = 12) or in 100% oxygen for 24 (n = 9), 48 (n = 8), or 60 (n = 9) h, and the indexes, including enhanced pause (Penh) and peak inspiratory and expiratory flows, were determined. The mice were then anesthetized, paralyzed, and mechanically ventilated. Airway resistance, respiratory system resistance at breathing frequency, and tissue damping and elastance were identified from the LFOT impedance data by model fitting. The monotonous decrease in airway resistance during hyperoxia correlated best with the increasing peak expiratory flow. Respiratory system resistance and tissue damping and elastance were unchanged up to 48 h of exposure but were markedly elevated at 60 h, with associated decreases in peak inspiratory flow. Penh was increased at 24 h and sharply elevated at 60 h. These results indicate no adverse effect of hyperoxia on the airway mechanics in mice, whereas marked parenchymal damage develops by 60 h. The inconsistent relationships between LFOT parameters and WBP indexes suggest that the changes in the latter reflect alterations in the breathing pattern rather than in the mechanical properties. It is concluded that, in the presence of diffuse lung disease, Penh is inadequate for characterization of the mechanical status of the respiratory system.