A neonate with tracheobronchial cobblestone mucosa presenting with acute severe hypercapnia.

Liu Y, Ly Li, Hu YL. A neonate with tracheobronchial cobblestone mucosa presenting with acute severe hypercapnia. Turk J Pediatr 2019; 61: 971-974. Here, we describe the case of a neonate suffering from respiratory distress complicated by pulmonary hemorrhage shortly after birth. The neonate experienced repeated dyspnea and acute severe hypercapnia (160-100 mmHg) that began on the 7th day after birth during invasive mechanical ventilation. Rescue high frequency oscillatory ventilation played a key role in maintaining gas exchange during these episodes. Subsequent bronchoscopy revealed tracheobronchial edematous mucosa with a cobblestone pattern, which we believe is the first report of this condition in neonates. Protrusion of the diffuse edematous mucosa led to airway stenosis and respiratory distress. Lesions of the tracheal mucosa should therefore be considered as one potential cause of neonatal respiratory distress.

Gastric Duplication Cyst with Respiratory Epithelium: a Rare Entity.

Gastric duplication cyst is an uncommon entity and management is principally surgical. Diagnosis is often delayed because of the non-specific nature of symptoms. The authors report one case of gastric duplication cyst incidentally diagnosed in a 23-year-old man. He had no specific symptoms but follow up of the unknown retro gastric mass showed an increase in size and cholelithiasis. Magnetic resonance imaging (MRI) was not useful for diagnosis but an endoscopic ultrasound suggested a GIST. The growing size of the mass led to a laparoscopic resection. Histopathology showed a gastric duplication cyst boarded with gastric and respiratory ciliated epithelium. This respiratory differenciation is extremely rare. Our patient is the 25th case reported in the literature. The embryologic origin, diagnosis tools and treatment of those rare cysts are briefly reviewed.

Relationships between the varied ciliated respiratory epithelium abnormalities and severity of Mycoplasma pneumoniae pneumonia.

BACKGROUND: The pathogenesis of Mycoplasma pneumoniae infection involves cytoadherence of M. pneumoniae to the ciliated respiratory epithelium (CRE), followed by CRE injury caused by the M. pneumoniae. However, whether CRE abnormalities are related to the severity of M. pneumoniae pneumonia (MP) remains to be determined. METHODS: Thirty-eight patients with MP and 8 controls who underwent fiber-optic bronchoscopy with bronchial biopsy were included in this study. Patients with MP were divided into 2 groups: a mild disease group (12 patients) and a severe disease group (26 patients). The clinical features, laboratory findings, chest radiographic findings, and CRE abnormalities were characterized. RESULTS: Patients with severe pneumonia had a higher epithelial integrity score than those with mild pneumonia (5.1 ± 0.76 vs 3.8 ± 0.75; p < 0.01). Patients with severe CRE abnormalities had a longer duration of fever (p < 0.01), higher C-reactive protein (p < 0.01), and lower proportion of blood lymphocytes (p < 0.05) compared to those with mild abnormalities. Patients with a positive bacteria culture had a higher epithelial integrity score compared to those with a negative culture (6.0 ± 0.44 vs 4.8 ± 0.71; p < 0.01). CONCLUSIONS: CRE abnormalities are closely related to the severity of MP. These findings extend our current knowledge of MP.

Foxm1 mediates cross talk between Kras/mitogen-activated protein kinase and canonical Wnt pathways during development of respiratory epithelium.

While Kras/mitogen-activated protein kinase (MAPK) and canonical Wnt/ß-catenin are critical for lung morphogenesis, mechanisms integrating these important signaling pathways during lung development are unknown. Herein, we demonstrate that the Foxm1 transcription factor is a key downstream target of activated Kras(G12D). Deletion of Foxm1 from respiratory epithelial cells during lung formation prevented structural abnormalities caused by activated Kras(G12D). Kras/Foxm1 signaling inhibited the activity of canonical Wnt signaling in the developing lung in vivo. Foxm1 decreased T-cell factor (TCF) transcriptional activity induced by activated ß-catenin in vitro. Depletion of Foxm1 by short interfering RNA (siRNA) increased nuclear localization of ß-catenin, increased expression of ß-catenin target genes, and decreased mRNA and protein levels of the ß-catenin inhibitor Axin2. Axin2 mRNA was reduced in distal lung epithelium of Foxm1-deficient mice. Foxm1 directly bound to and increased transcriptional activity of the Axin2 promoter region. Foxm1 is required for Kras signaling in distal lung epithelium and provides a mechanism integrating Kras and canonical Wnt/ß-catenin signaling during lung development.

[Tracheobronchial and pulmonary parenchymatous congenital abnormalities requiring surgical treatment in adults]. / Malformations trachéobronchiques et parenchymateuses pulmonaires de l'adulte relevant d'un traitement chirurgical.

Most tracheobronchial and parenchymatous congenital abnormalities of the respiratory system are diagnosed in early life. However, some lesions may be initially silent and diagnosed only in adulthood. These cases included congenital abnormalies of the tracheobronchial tract (tracheal and/or bronchial stenosis, bronchogenic cysts, bronchial atresia, oesotracheal fistula, oesobronchial fistula, and tracheal diverticulum), and lung parenchyma itself (pulmonary sequestration, congenital cystic adenomatoïd malformation, lobar emphysema, lobar or lung hypoplasia). To avoid dreadful complications, these rare cases deserve surgical management, and must be known by chest physicians and surgeons.

Bronchopulmonary foregut malformation.

Bronchopulmonary foregut malformation (BPFM) is a rare anomaly of accessory pulmonary tissue that usually arises from esophagus or stomach. We present a case of extralobar pulmonary sequestration (ELS) connecting with the esophagus by a cyst, the inner wall of which is lined with squamous epithelium or respiratory epithelium. BPFM is sometimes used to group a number of ventral anomalies of accessory pulmonary tissue. The term currently refers specifically to those lesions composed of sequestrations that retain communication with the gastrointestinal tract. Usually the communication is a well-formed muscular tube lined with stratified squamous or columnar epithelium. The presence of both epithelia in a communication that is a component of the BPFM suggests embryogenesis. We describe an adult with BPFM composed of ELS and a connecting stalk to the esophagus by a foregut cyst that contains both squamous epithelium and respiratory epithelium.

Loss of Rab27 function results in abnormal lung epithelium structure in mice.

Rab27 small GTPases regulate secretion and movement of lysosome-related organelles such as T cell cytolytic granules and platelet-dense granules. Previous studies indicated that Rab27a and Rab27b are expressed in the murine lung suggesting that they regulate secretory processes in the lung. Consistent with those studies, we found that Rab27a and Rab27b are expressed in cell types that contain secretory granules: alveolar epithelial type II (AEII) and Clara cells. We then used Rab27a/Rab27b double knockout (DKO) mice to examine the functional consequence of loss of Rab27 proteins in the murine lung. Light and electron microscopy revealed a number of morphological changes in lungs from DKO mice when compared with those in control animals. In aged DKO mice we observed atrophy of the bronchiolar and alveolar epithelium with reduction of cells numbers, thinning of the bronchiolar epithelium and alveolar walls, and enlargement of alveolar airspaces. In these samples we also observed increased numbers of activated foamy alveolar macrophages and granulocyte containing infiltrates together with reduction in the numbers of Clara cells and AEII cells compared with control. At the ultrastructural level we observed accumulation of cytoplasmic membranes and vesicles in Clara cells. Meanwhile, AEII cells in DKO accumulated large mature lamellar bodies and lacked immature/precursor lamellar bodies. We hypothesize that the morphological changes observed at the ultrastructural level in DKO samples result from secretory defects in AEII and Clara cells and that over time these defects lead to atrophy of the epithelium.

PPARgamma deficiency results in reduced lung elastic recoil and abnormalities in airspace distribution.

BACKGROUND: Peroxisome proliferator-activated receptor (PPAR)-gamma is a nuclear hormone receptor that regulates gene expression, cell proliferation and differentiation. We previously described airway epithelial cell PPARgamma deficient mice that develop airspace enlargement with decreased tissue resistance and increased lung volumes. We sought to understand the impact of airspace enlargement in conditionally targeted mice upon the physio-mechanical properties of the lung. METHODS: We measured elastic recoil and its determinants, including tissue structure and surface forces. We measured alveolar number using radial alveolar counts, and airspace sizes and their distribution using computer-assisted morphometry. RESULTS: Air vs. saline-filled pressure volume profiles demonstrated loss of lung elastic recoil in targeted mice that was contributed by both tissue components and surface tension, but was proportional to lung volume. There were no significant differences in surfactant quantity/function nor in elastin and collagen content between targeted animals and littermate controls. Importantly, radial alveolar counts were significantly reduced in the targeted animals and at 8 weeks of age there were 18% fewer alveoli with 32% more alveolar ducts. Additionally, the alveolar ducts were 19% larger in the targeted animals. CONCLUSIONS: Our data suggest that the functional abnormalities, including loss of recoil are secondary to altered force transmission due to differences in the structure of alveolar ducts, rather than changes in surfactant function or elastin or collagen content. These data further define the nature of abnormal lung maturation in the absence of airway epithelial cell PPARgamma and identify a putative genetic determinant of dysanapsis, which may serve as a precursor to chronic lung disease.

Role for ephrinB2 in postnatal lung alveolar development and elastic matrix integrity.

Alveoli are formed in the lung by the insertion of secondary tissue folds, termed septa, which are subsequently remodeled to form the mature alveolar wall. Secondary septation requires interplay between three cell types: endothelial cells forming capillaries, contractile interstitial myofibroblasts, and epithelial cells. Here, we report that postnatal lung alveolization critically requires ephrinB2, a ligand for Eph receptor tyrosine kinases expressed by the microvasculature. Mice homozygous for the hypomorphic knockin allele ephrinB2DeltaV/DeltaV, encoding mutant ephrinB2 with a disrupted C-terminal PDZ interaction motif, show severe postnatal lung defects including an almost complete absence of lung alveoli and abnormal and disorganized elastic matrix. Lung alveolar formation is not sensitive to loss of ephrinB2 cytoplasmic tyrosine phosphorylation sites. Postnatal day 1 mutant lungs show extracellular matrix alterations without differences in proportions of major distal cell populations. We conclude that lung alveolar formation relies on endothelial ephrinB2 function.

Pten controls lung morphogenesis, bronchioalveolar stem cells, and onset of lung adenocarcinomas in mice.

PTEN is a tumor suppressor gene mutated in many human cancers. We generated a bronchioalveolar epithelium-specific null mutation of Pten in mice [SP-C-rtTA/(tetO)(7)-Cre/Pten(flox/flox) (SOPten(flox/flox)) mice] that was under the control of doxycycline. Ninety percent of SOPten(flox/flox) mice that received doxycycline in utero [SOPten(flox/flox)(E10-16) mice] died of hypoxia soon after birth. Surviving SOPten(flox/flox)(E10-16) mice and mice that received doxycycline postnatally [SOPten(flox/flox)(P21-27) mice] developed spontaneous lung adenocarcinomas. Urethane treatment accelerated number and size of lung tumors developing in SOPten(flox/flox) mice of both ages. Histological and biochemical examinations of the lungs of SOPten(flox/flox)(E10-16) mice revealed hyperplasia of bronchioalveolar epithelial cells and myofibroblast precursors, enlarged alveolar epithelial cells, and impaired production of surfactant proteins. Numbers of bronchioalveolar stem cells (BASCs), putative initiators of lung adenocarcinomas, were increased. Lungs of SOPten(flox/flox)(E10-16) mice showed increased expression of Spry2, which inhibits the maturation of alveolar epithelial cells. Levels of Akt, c-Myc, Bcl-2, and Shh were also elevated in SOPten(flox/flox)(E10-16) and SOPten(flox/flox)(P21-27) lungs. Furthermore, K-ras was frequently mutated in adenocarcinomas observed in SOPten(flox/flox)(P21-27) lungs. These results indicate that Pten is essential for both normal lung morphogenesis and the prevention of lung carcinogenesis, possibly because this tumor suppressor is required for BASC homeostasis.