Notch signaling in the mammalian respiratory system, specifically the trachea and lungs, in development, homeostasis, regeneration, and disease.

The respiratory system has ideal tissue structure and cell types for efficient gas exchange to intake oxygen and release carbon dioxide. This complex system develops through orchestrated intercellular signaling among various cell types, such as club, ciliated, basal, neuroendocrine, AT1, AT2, endothelial, and smooth muscle cells. Notch signaling is a highly conserved cell-cell signaling pathway ideally suited for very short-range cellular communication because Notch signals are transmitted by direct contact with an adjacent cell. Enthusiastic efforts by Notch researchers over the last two decades have led to the identification of critical roles of this signaling pathway during development, homeostasis, and regeneration of the respiratory system. The dysregulation of Notch signaling results in a wide range of respiratory diseases such as pulmonary artery hypertension (PAH), chronic obstructive pulmonary disease (COPD), interstitial pulmonary fibrosis (IPF), and lung cancer. Thus, a deep understanding of the biological functions of Notch signaling will help identify novel treatment targets in various respiratory diseases.

Asociación de bronquio traqueal y drenaje venoso pulmonar anómalo parcial en paciente con neurofibromatosis tipo 1 y neurofibroma del nervio vago ipsilateral / Combination of tracheal bronchus and partial anomalous pulmonary venous return in a patient with type 1 neurofibromatosis and ipsilateral vagal nerve neurofibroma

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[Primary sinus histiocytosis of the trachea: a case report and review of literature].

OBJECTIVE: To study the clinicopathological features, diagnosis and prognosis of primary sinus histiocytosis (Rosai-Dorfman disease, RDD) of the trachea by case report and review of the literature. METHODS: A 63 year old man with a space-occupying lesion of the trachea firstly diagnosed as a malignant tumor was admitted to this hospital for further evaluation and treatment. The lesion was removed by surgery and the final diagnosis was primary RDD. The clinical data of the case was analyzed and the related literatures were reviewed. The literature review was carried out respectively with"Rosai-Dorfman disease" and "sinus histiocytosis"as the key words in Wanfang Med Online and with"Rosai-Dorfman disease","sinus histiocytosis","trachea or lung"as the key words in PubMed database by July 2012. RESULTS: The chest computerized tomography of the case showed that the mass was located at the right side of the trachea with heterogeneous density and contrast enhancement. Bronchoscopy revealed a neoplasma occluding the distal trachea. The lesion was excised by surgery. Microscopic histology showed that in the dark-staining area a large number of lymphocytes and plasma cells were noted while the light-staining area was formed by giant histiocytes. The pathological changes invaded the tracheal wall and eroded the cartilages. Intact lymphocytes and plasma cells were observed within the eosinophilic cytoplasm of the histiocytes. Immunohistochemistry showed that the giant histiocytes were strongly positive for S-100 protein and CD68 protein. Primary RDD of trachea was confirmed. The patient remained well without any other treatment or evidence of progression for 11 months. A total of 13 literatures and 26 cases were retrieved from Wanfang Med Online and Pubmed, including 21 cases of primary RDD of the upper respiratory tract and 4 cases of primary RDD of the lung. A total of 5 literatures and 5 cases of RDD affecting the trachea were retrieved from Wanfang Med Online and Pubmed. There was only one case of primary RDD of the trachea in Pubmed. A 39-year-old female patient with 1 month of dyspnea was misdiagnosed as having bronchial asthma and was unresponsive to empirical corticosteroid and bronchodilator therapy. The chest computerized tomography revealed an ill-defined irregular soft tissue in the trachea. A tracheal ring sleeve resection and reanastomosis was performed to prevent asphyxia. The mass was confirmed to be primary RDD of the trachea according to histopathology and immunohistochemistry. The patient was well without any treatment for 12 months. CONCLUSIONS: Primary RDD of the trachea is an extremely rare disease, with dyspnoea as a feature of the disease. When it is completely removed, the prognosis is good. Typical histopathology and immunohistochemistry are needed to make a definite diagnosis. The positive immunohistochemistry staining for S-100 and CD68 protein in giant histiocytes and lymphocyteemperipolesis are essential for the diagnosis. The differential diagnosis includes other benign or malignant space-occupying lesions of the trachea.

Tracheobronchial amyloidosis and confocal endomicroscopy.

Tracheobronchial amyloidosis is one of many causes of endobronchial stenosis and nodularity, the concrete diagnosis of which currently requires the finding of apple-green birefringence from endobronchial biopsies. Bronchoscopic probe-based confocal endomicroscopy (pCLE) is a novel optical biopsy technique which provides real-time images of the lattice structure of the bronchial basement membrane - a finding lost in malignancy. This case study outlines the imperfect, essentially palliative management of this rare disease, and shows for the first time the unusual dappled in vivo pCLE images of amyloid-affected endobronchium.

Unusual life-threatening Rosai-Dorfman disease of the trachea: role of NF-κB.

Rosai-Dorfman disease (RDD) is a rare non-neoplastic histioproliferative disorder characterised by painless lymphadenopathy, low fever, high erythrocyte sedimentation rate, leucocytosis and hypergammaglobulinaemia. Overactivity of nuclear factor κB (NF-κB) is linked with inflammatory, cancerous and autoimmune diseases. The first case is described of an unusual life-threatening RDD of the trachea with no lymphadenopathy at risk of suffocation in a 39-year-old Chinese woman. A diagnosis of RDD was made following CT scans, thoracotomy and histological examination. Gel shift assay revealed an essential role for NF-κB overactivity in RDD. The patient remains well with no evidence of progression without treatment. Histological confirmation should be sought in all cases as the clinical manifestation of RDD is similar to asthma or lung carcinoma.

The transmembrane protein TMEM16A is required for normal development of the murine trachea.

Pathological collapsibility of the upper airways, caused by many different genetic and environmental insults, is known as tracheomalacia in humans. We determined that Tmem16a, a member of an evolutionarily conserved family of predicted transmembrane proteins, is expressed in the developing trachea. We report that all mice homozygous for a null allele of Tmem16a died within one month of birth and exhibited severe tracheomalacia with gaps in the tracheal cartilage rings along the entire length of the trachea. In addition, the development of the trachealis muscle that spans the dorsal aspect of the trachea was abnormal in Tmem16a mutants. Since the chondrogenic mesenchyme does not express Tmem16a at any time, we propose that the cartilage ring defect observed in Tmem16a mutants is secondary to an expansion of the embryonic trachea that might result from improper stratification of the embryonic tracheal epithelium or the abnormal trachealis muscle. Our data identify Tmem16a as a novel regulator of epithelial and smooth muscle cell organization in murine development. This mutant, the first knockout of a vertebrate TMEM16 family member, provides a mouse model of tracheomalacia.

Single-dose versus two-dose dexamethasone effects on lung inflammation and airway reactivity in meconium-instilled rabbits.

Two doses of the corticosteroid dexamethasone may alleviate meconium-induced acute lung injury more effectively than a single dose. Meconium-instilled rabbits intravenously received dexamethasone (0.5 mg/kg) at one dose 0.5 hours after meconium instillation or at two doses 0.5 hours and 2.5 hours after meconium instillation or were left without treatment, and were oxygen-ventilated for additional 5 hours. At the end of experiment, lungs and trachea were excised. Two doses of dexamethasone effectively diminished meconium-induced lung edema, tracheal hyperreactivity to histamine, neutrophil count in bronchoalveolar lavage fluid, and decreased oxidative modifications of proteins and lipids in lung homogenate compared with the non-treated group. Single-dose dexamethasone also reduced lung edema, lung neutrophils, and tracheal hyperreactivity to histamine, but these effects were weaker than those after two-dose dexamethasone. We conclude that two-dose dexamethasone is superior to single-dose dexamethasone in prevention lung injury in meconium-instilled rabbits.

Following damage, the majority of bone marrow-derived airway cells express an epithelial marker.

BACKGROUND: Adult-derived bone marrow stem cells are capable of reconstituting the haematopoietic system. However there is ongoing debate in the literature as to whether bone marrow derived cells have the ability to populate other tissues and express tissue specific markers. The airway has been an organ of major interest and was one of the first where this was demonstrated. We have previously demonstrated that the mouse airway can be repopulated by side population bone marrow transplanted cells. Here we investigate the frequency and phenotypic nature of these bone marrow derived cells. METHODS: Female mice were engrafted with male whole bone marrow or side population (SP) cells and subjected to detergent-induced damage after 3 months. Donor cells were identified by Y chromosome fluorescence in situ hybridisation and their phenotype was assessed by immunohistochemistry on the same sections. Slides were visualised by a combination of widefield and deconvolved microscopy and whole cells were analysed on cytospin preparations. RESULTS: The frequencies of engraftment of male cells in the airway of mice that show this (9/10), range from 1.0-1.6% with whole marrow and 0.6-1.5% with SP cells. Undamaged controls have only between 0.1 and 0.2% male cells in the trachea. By widefield microscopy analysis we find 60.2% (53/88) of male donor derived cells express cytokeratins as a marker of epithelial cells. These results were reinforced using deconvolved microscopy and scored by two independent investigators. In addition cytospin analysis of cells dissociated from the damaged trachea of engrafted mice also reveals donor derived Y chromosome positive cells that are immunopositive for cytokeratin. Using cytokeratin and the universal haematopoietic marker CD45 immunohistochemistry, we find the donor derived cells fall into four phenotypic classes. We do not detect cytokeratin positive cells in whole bone marrow using cytokeratin immunostaining and we do not detect any cytokeratin mRNA in SP or bone marrow samples by RT-PCR. CONCLUSION: The appearance of bone marrow derived cells in the tracheal epithelium is enriched by detergent-induced tissue damage and the majority of these cells express an epithelial marker. The cytokeratin positive donor derived cells in the tracheal epithelium are not present in the injected donor cells and must have acquired this novel phenotype in vivo.

Primary intratracheal neurilemmoma in children: case report and literature review.

A 9-year-old girl was admitted because of recurrent cough, dyspnea, and tachypnea for over 3 months, which had become worse for the preceding week. A chest X-ray revealed a mass in the lumen of the trachea. Fiberoptic bronchoscopy confirmed a polypoid mass in the upper trachea 3 cm under the vocal cords, with a 1.5-cm diameter that occluded approximately 70% of the lumen. Endoscopic excision of the neoplasm was performed with rigid bronchoscopy. Results of immunolabeling, which was positive for S-100 protein and vimentin, demonstrated a benign neurilemmoma. Clinical symptoms and signs improved after the tumor was removed. Intratracheal neurilemmoma is an extremely rare neoplasm, and only 34 cases were previously reported worldwide. The most common presentation is airway obstruction. Preoperative diagnosis is difficult, and radiographic techniques are helpful for diagnosis. Bronchoscopy is recommended for diagnosis, biopsy, and resection of the tumor. Long-term follow-up after simple enucleation is required.

Interferon-gamma knockout fails to confer protection against obliteration in heterotopic murine tracheal allografts.

BACKGROUND: Interferon-gamma, produced by T-helper cells, activates macrophages and increases expression of major histocompatibility complex (MHC) products in acute and chronic rejection. We investigated the role of interferon-gamma in murine heterotopic tracheal allografts. METHODS: Tracheas from BALB/c mice were heterotopically transplanted to BALB/c (12 isografts: 2 weeks [n = 6] and 4 weeks [n = 6], C57BL/6 (12 allografts: 2 weeks [n = 6] and 4 weeks [n = 6]) and C57BL/6 interferon-gamma knockout mice (12 interferon-gamma knockout allografts: 2 weeks [n = 4] and 4 weeks [n = 8]). BALB/c interferon-gamma knockout tracheas were transplanted to C57BL/6 mice (reverse knockout: 4 weeks [n = 6]) and BALB/c interferon-gamma knockout mice (4 weeks [n = 2]). C57BL/6 tracheas were transplanted to Bm12 mice (MHC Class II mismatch allografts: 4 weeks [n = 6]). Conventional histology and immunohistochemistry for CD4, CD8 and CD11b were performed. RESULTS: Minimal (<20%) obliteration was seen at 2 weeks in the allograft groups. No obliteration was seen in the isograft groups. However, all allografts were completely obliterated at 4 weeks. Interferon-gamma knockout allograft combinations displayed severe rejection characterized by intense intra- and extraluminal infiltration by CD4-, CD8- and CD11b-labeled cells. The MHC Class II mismatch allograft group showed normal epithelium and mild sub-epithelial infiltration by CD4+ cells at 4 weeks (CD8-, CD11b-). CONCLUSIONS: Absence of interferon-gamma does not protect the allograft from obliteration. Epithelial destruction by cytotoxic T cells appears to be an important mechanism in the development of obliteration in murine heterotopic tracheal allografts.

Primary diffuse tracheobronchial amyloidosis in a dog.

Primary diffuse tracheobronchial amyloidosis was diagnosed at necropsy in an intact male Akita dog aged 11 years, a non-productive chronic cough having been the only related clinical sign. Histologically, eosinophilic hyalinized deposits were found as a band in the lamina propria underneath the epithelium of the trachea and bronchi. When stained with Congo red, apple-green birefringence was observed in the deposits viewed with polarized light. The amyloid did not lose sensitivity to Congo red staining after incubation with potassium permanganate, indicating that it was of the AL (amyloid light chain) type. Ultrastructural features of the amyloid included a typical fibrillar meshwork with individual fibrils measuring 9.5 to 10.5 nm in diameter. This is the first report of primary diffuse tracheobronchial amyloidosis in the dog.

Re-expression of pulmonary surfactant proteins following tracheal obstruction in fetal sheep.

Increased fetal lung expansion, induced by tracheal obstruction (TO), is a potent stimulus for fetal lung growth, but rapidly reduces surfactant protein (SP) mRNA levels. Our aim was to determine the time course for the re-expression of the surfactant proteins in fetal lung tissue following the release of a TO and to relate these to the changes in lung liquid volume. Fetal sheep were exposed to either: (1) no treatment (controls); (2) 4 days of TO; (3) 4 days of TO, followed by release of the obstruction for 24 h; (4) 4 days of TO followed by release of the obstruction for 3 days. Four days of TO increased lung liquid volumes from 26.8 +/- 1.9 to 72.0 +/- 5.6 ml kg(-1) and reduced SP-A, SP-B and SP-C mRNA levels to 38.5 +/- 10.7, 56.8 +/- 10.3 and 18.3 +/- 5.3 % of control values, respectively. One day after TO release, lung liquid volumes were reduced to 17.4 +/- 5.3 ml kg(-1) (control 128 days, 31.0 +/- 3.8 ml kg(-1)) and SP-A and SP-B mRNA levels were not different from control levels. In contrast, SP-C mRNA levels only increased to 45.4 +/- 17.3 % of control. Three days after TO release, lung liquid volumes increased to 48.0 +/- 8.5 ml kg(-1) and SP-A and SP-B mRNA levels were reduced to 48.8 +/- 10.2 % and 71.5 +/- 19.8 % of control, respectively; SP-C mRNA levels remained at 35.3 +/- 12.3 % of control. Following the release of a TO, SP-A, SP-B and SP-C mRNA levels were closely and inversely related to the volume of lung liquid. Based on these relationships, the lung liquid volumes that equate to 100 % expression were considerably less than control lung volumes (< 10 vs. 30-40 ml kg(-1)) in fetuses of this age. Thus, the changes in fetal lung SP-A, SP-B and SP-C mRNA levels following the release of a TO are variable, differ between the proteins and are closely related to the changes in lung liquid volumes. We conclude that the re-expression of surfactant proteins following TO is variable and that the change in lung liquid volume is potentially a good indicator for surfactant protein re-expression. Experimental Physiology (2001) 86.1, 55-63.

Immunohistochemical detection of bone morphogenetic protein-2 and transforming growth factor beta-1 in tracheopathia osteochondroplastica.

Tracheopathia osteochondroplastica (TO) is an unusual condition characterized by cartilaginous or bony submucosal nodules in the tracheobronchial tree. Bone morphogenetic protein-2 (BMP-2) and transforming growth factor beta-1 (TGF-beta 1) are potent inducers for new bone formation. We studied the precise localization of BMP-2 and TGF-beta 1 in two autopsied cases of TO, using immunohistochemical methods. Positive BMP-2 immunoreactivity was detected in numerous mesenchymal cells and chondroblasts lining the nodules in the tracheal submucosa. BMP-2 was not found in mature lamellar bony nodules. TGF-beta 1 was not seen in mesenchymal cells, though it did appear in chondrocytes and osteocytes in the nodules. These results suggest that BMP-2 plays an important role in nodule formation and acts synergistically with TGF-beta 1 to promote the nodules inductive cascade in the tracheal submucosa.

Tracheobronchial AL amyloidosis: histologic, immunohistochemical, ultrastructural, and immunoelectron microscopic observations.

We have studied three cases of localized amyloidosis in the lower respiratory tract. Amyloid was nodularly or diffusely deposited in the lamina propria of the tracheobronchial mucosa. Its nature was confirmed by Congo red staining with green birefringence on polarized microscopy. "Tracheobronchopathia osteoplastica" also was demonstrated. Plasma cells and lymphocytes were scant in the amyloid mass. Few fibroblasts and even fewer macrophages were seen. The number of plasma cells was not increased in the bone marrow in any of our cases. Amyloid fibrils were demonstrated by electron microscopic examination. The amyloid P component was detected by immunohistochemical methods. The precursor protein of amyloidosis was shown to be amyloid L protein by the postembedding protein-A gold technique with anti-light chain antisera. The role of the plasma cells in amyloid formation, however, could not be ascertained. Based on these observations, amyloid fibril formation in tracheobronchial amyloidosis appears to be related to light chains secreted by local plasma cells, combined with amyloid P, calcium, and other factors.

Effect of aerosol challenge with sensitising antigen on the permeability of the surface of the rat trachea in life.

A rat model of immediate pulmonary hypersensitivity was used to investigate the permeability changes in the tracheal epithelium produced by aerosol challenge with antigen. The rats were sensitised by the intraperitoneal injection of antigen (dinitrophenyl (DNP19) ovalbumin). Sensitised and control animals were then challenged for 60 minutes with an aerosol of the same antigen, which also contained the electron dense pore marker lanthanum. Histological examination and x ray probe microanalysis showed a greater intercellular concentration of lanthanum in the tracheal epithelium in sensitised than in control animals. The results show that in sensitised rats increased intercellular penetrance of antigen can occur after antigen challenge.

Amyloidosis localized to the lower respiratory tract: probable immunoamyloid nature of the tracheobronchial and nodular pulmonary forms.

Seven patients with localized nodular pulmonary amyloidosis and four with tracheobronchial amyloidosis are presented and the pathological features described. The congophilia of these forms of amyloid is resistant to potassium permanganate, compatible with it representing immunoamyloid. This, together with the associated intense lymphocytic and plasma cell infiltration suggests a local inflammatory aetiology.