Congenital high airway obstruction syndrome due to complete tracheal agenesis: an accident of nature with clues for tracheal development and lessons in management.

Congenital high airway obstruction syndrome (CHAOS) is a life-threatening condition characterized by complete blockage of the fetal airways associated with hydrops. We present a case of CHAOS due to the rare cause of complete tracheal agenesis. The ex utero intrapartum therapy (EXIT) strategy was employed to allow for neck and mediastinal exploration. Thymectomy allowed dissection to the level of the carina demonstrating the confluence of dilated mainstem bronchi but no trachea and no connection to the esophagus. A 2.5 endotracheal tube was inserted into the right mainstem bronchus and secured to the left clavicle. At 3 months of age, the infant succumbed to sepsis from Enterobacter mediastinitis due to friction between the tracheostomy tube and the nasogastric tube resulting in erosion of the esophagus. Complete tracheal agenesis, as seen in this case, is consistent with the failure of normal tracheal elongation as suggested by newer theories of foregut development. This case illustrates the most severe form of tracheal atresia causing CHAOS ever salvaged by the EXIT procedure at birth. The subsequent postnatal course highlights the need for early tracheal replacement in this particularly challenging form of CHAOS.

Bmp4 is required for tracheal formation: a novel mouse model for tracheal agenesis.

Tracheal agenesis/atresia (TA) is a rare but fatal congenital disease in which the breathing tube fails to grow. The etiology of this serious condition remains largely unknown. We found that Bmp signaling is prominently present in the anterior foregut where the tracheal primordium originates and targeted ablation of Bmp4 (Bmp4(cko)) resulted in a loss-of-trachea phenotype that closely resembles the Floyd type II pathology, the most common form of TA in humans. In Bmp4(cko) embryos, tracheal specification was not affected; however, its outgrowth was severely impaired due to reduced epithelial and mesenchymal proliferation. In agreement, we also observed significant reduction in the expression of Cyclin D1, a key cell cycle regulator associated with cellular proliferation. However, the proliferative effect of Bmp signaling appears to be independent of Wnt signaling. Interestingly, we found significantly reduced expression of activated extracellular signal-regulated kinase (Erk) in the Bmp4(cko) ventral foregut, suggesting that Bmp signaling promotes Erk phosphorylation which has been associated with cellular proliferation. This study provides the first evidence linking Bmp signaling to tracheal formation by regulating the proliferative response of the anterior ventral foregut. Our finding sheds light on human tracheal malformations by providing a novel mouse model implicating Bmp signaling, non-canonical Erk activation and cellular proliferation.

Adriamycin mouse model: a variable but reproducible model of tracheo-oesophageal malformations.

A spectrum of tracheo-oesophageal malformations is seen in humans: oesophageal atresia, tracheal agenesis and laryngotracheo-oesophageal clefts. They are thought to share a common but unknown aetiology. These birth defects are frequently associated with other VACTERL anomalies. The adriamycin rat model (ARM) has proved to be a valuable model of the VACTERL anomalies, illustrating the dysmorphogenesis of oesophageal atresia and tracheal agenesis. As organogenesis relies on temporaspatially co-ordinated signalling systems, the next step would be to study the molecular pathogenesis of tracheo-oesophageal malformations. However, the mouse is the foremost mammal studied by developmental biologists, offering an expanding wealth of knowledge and scientific research techniques with which to investigate these anomalies. A limited dose response analysis of the teratogenicity of adriamycin in the mouse has identified a dose and timing of injections that produced tracheo-oesophageal malformations and other VACTERL anomalies. A clear account of the types and variability of the tracheo-oesophageal malformations produced by this dose is essential in order to be able to plan and interpret any future investigations of early gestation fetuses. CBA/Ca mice were accurately time-mated (n = 10). Nine dams received intraperitoneal injections of adriamycin (6 mg/kg) and one control dam received saline injections, on days 7 and 8. Fetuses were harvested on day 18, near term. Tracheo-oesophageal malformations were examined by dissecting microscope and serial transverse sections. Results are reported in the standard teratological manner as mean percentage per litter (+/-SEM). The resorption rate of the adriamycin treated fetuses was 50.4%. There were 29 adriamycin treated fetuses for inspection. Tracheo-oesophageal malformations were found in 29.2% (+/-10.3), affecting five out of nine litters. Oesophageal atresia occurred in 15.6% (+/-8.1), laryngotracheo-oesophageal cleft in 10.4% (+/-7) and tracheal agenesis in 3.1% (+/-3.1). All of these malformations occurred with a tracheo-oesophageal fistula. Unlike the ARM, the AMM can produce fetuses with complete laryngotracheo-oesophageal cleft as well as oesophageal atresia or tracheal agenesis. Their occurrence was found to be reproducible but variable. These are important considerations when planning and interpreting experiments using this model.

[Air-filled cysts of tracheal origin: nosological problems and actual frequency]. / Kystes aériens d'origine trachéale: problèmes nosologiques et fréquence réelle.

Air-filled paratracheal bronchogenic cysts are extremely rare. They are lined by respiratory epithelium. We have operated on 2 patients whose cysts were diagnosed by CT scan: one presenting with bloody sputum and the other with dysphagia. Both patients had a history of neck surgery. Because such cases are rare in the literature, their exact origin, whether tracheocele, diverticulum or other form of air-filled cyst, remains a matter of debate. However, their frequency is probably underestimated because most cause few symptoms and are well tolerated. In a recent radiologic study their prevalence was found to be 2% in patients undergoing CT scan.

Tracheal dyskinesia associated with midline abnormality: embryological hypotheses and therapeutic implications.

Abnormalities of tracheal rigidity, which may lead to the collapse of the airway during expiration and consequent complications, characterize two groups of disorders: tracheomalacia (weakness of the anterior cartilaginous arc of the trachea) and tracheal dyskinesia (dysfunction of the posterior membranous trachea). Tracheal dyskinesia can either be isolated or associated with a more complex syndrome of malformations: esophageal atresia, tracheoesophageal fistula and laryngotracheal cleft. Although our knowledge of the embryological development of the tracheoesophageal axis remains limited, the existence of these associations suggests that tracheal dyskinesia is of congenital origin. The presentation of three clinical cases demonstrates that the coexistence of a midline malformation and of tracheal dyskinesia complicates the therapeutic management of the first malformation. In particular, the postoperative follow-up is often more difficult, and a long-term tracheostomy is often required (sometimes for several years). However, it must be pointed out that tracheal dyskinesia, even in the associated forms, has a good long-term prognosis, since spontaneous resolution as the child grows up is the rule.

Increased lung expansion alters the proportions of type I and type II alveolar epithelial cells in fetal sheep.

Type I and type II alveolar epithelial cells (AECs) are derived from the same progenitor cell, but little is known about the factors that regulate their differentiation into separate phenotypes. An alteration in lung expansion alters the proportion type II AECs in the fetal lung, indicating that this may be a regulatory factor. Our aim was to quantify the changes in the proportion of type I and type II AECs caused by increased fetal lung expansion and to provide evidence for transdifferentiation of type II into type I cells. Lung tissue samples were collected from ovine fetuses exposed to increased lung expansion induced by 2, 4, or 10 days of tracheal obstruction (TO). The identities and proportions of AEC types were determined with electron microscopy. The proportion of type II cells was reduced from 28.5 +/- 2.2% in control fetuses to 9.4 +/- 2.3% at 2 days of TO and then to 1.9 +/- 0.8% at 10 days. The proportion of type I AECs was not altered at 2 days of TO (63.1 +/- 2.3%) compared with that of control cells (64.8 +/- 0.5%) but was markedly elevated (to 89.4 +/- 0.9%) at 10 days of TO. The proportion of an intermediate AEC type, which displayed characteristics of both type I and type II cells, increased from 5.7 +/- 1.3% in control fetuses to 23.8 +/- 5.1% by 2 days of TO and was similar to control values at 10 days of TO (7.7 +/- 0.9%). Our data show that increases in fetal lung expansion cause time-dependent changes in the proportion of AEC types, including a transient increase in an intermediate cell type. These data provide the first evidence to support the hypothesis that increases in fetal lung expansion induce differentiation of type II into type I AECs via an intermediate cell type.

Temporal pattern of accelerated lung growth after tracheal occlusion in the fetal rabbit.

Tracheal occlusion in utero is a potent stimulus of fetal lung growth. We describe the early growth mechanics of fetal lungs and type II pneumocytes after tracheal ligation (TL). Fetal rabbits underwent TL at 24 days gestational age (DGA; late pseudoglandular stage; term = 31 to 33 days) and were sacrificed at time intervals ranging from 1 to 5 days after TL. Lung growth was measured by stereological volumetry and bromodeoxyuridine (BrdU) pulse labeling. Pneumocyte II population kinetics were analyzed using a combination of anti-surfactant protein A and BrdU immunohistochemistry and computer-assisted morphometry. Nonoperated littermates served as controls. TL resulted in dramatically enhanced lung growth (lung weight/body weight was 5.00 +/- 0.81% in TL versus 2.52 +/- 0.13% in controls at 29 DGA; P < 0.001, unpaired Student's t-test). Post-TL lung growth was characterized by a 3-day lag-phase typified by relative stagnation of growth, followed by distension of airspaces, increased cell proliferation, and accelerated architectural and cellular maturation by postligation days 4 and 5. During the proliferation phase, the replicative activity of type II cells was markedly increased (type II cell BrdU labeling index was 10.0 +/- 4.1% in TL versus 1.1 +/- 0.3% for controls at 29 DGA; P < 0.02), but their numerical density decreased (3.0 +/- 0.5 x 10(-3)/microm2 in TL versus 4.5 +/- 0.3 x 10(-3)/microm2 in controls at 29 DGA; P < 0.02), suggesting accelerated terminal differentiation to type I cells. In conclusion, post-TL lung development is characterized by a well defined temporal pattern of lung growth and maturation. The rabbit model lends itself well to study the regulatory mechanisms underlying accelerated fetal lung growth after TL.

Effect of gestational age on the increase in fetal lung growth following tracheal obstruction.

The growth response of the fetal lung to increased expansion was compared at two gestational ages. In fetal sheep, lung expansion was increased by occluding the trachea for 48 h at either 112-114 days (younger fetuses) or 125-127 days (older fetuses) of gestation (term is approximately 145 days). After 24 h of tracheal occlusion, the volumes of liquid that could be drained from the lungs were increased by 64.7 and 158% above control in younger and older fetuses respectively; the volumes were not increased further after 48 h. In younger fetuses, 48 h of tracheal occlusion increased (p < .05) fetal lung wet weights (21% above control) and protein contents (43% above control) but not DNA contents. In older fetuses, 48 h of tracheal occlusion increased (p < .05) fetal lung wet weights (61% above control), protein contents (41% above control), and DNA contents (22% above control). However, 48 h of tracheal occlusion did not alter total lung hydroxyproline content at either age, resulting in a reduction in the hydroxyproline/protein ratio of the fetal lungs. The results suggest that the lung growth response to tracheal occlusion is greater at 125-127 days of gestation than at 112-114 days of gestation, probably due to a greater accumulation of lung liquid and hence a greater increase in lung expansion, in older fetuses.

[Tracheal diverticuli: apropos of a case: malformation etiopathogenesis?]. / Diverticules tracheaux: à propos d'une observation, ét iopathogénie malformative?

A case of 3 contiguous diverticula of the right posterior wall of the upper trachea is reported. The earlier literature on this subject and the different classifications described are studied. Congenital genesis of the tracheal diverticula is suggested by their localisation and histologic bronchial elements, and by embryogenesis and anomalies of the trachea. They are presumed to correspond to a rudimentary, extra, apical bronchis.