transforming-growth-factor-beta and Airway-Obstruction

Topics: Airway Obstruction; Airway Resistance; Animals; Antibodies; Asthma; CpG Islands; Humans; Immunotherapy; Interleukin-5; Respiratory System; Transforming Growth Factor beta

Topics: Airway Obstruction; Asthma; Humans; Myocytes, Smooth Muscle; Smad3 Protein; Transforming Growth Factor beta; Transforming Growth Factor beta1; Transforming Growth Factors

Survivors of severe congenital diaphragmatic hernia (CDH) present significant respiratory morbidity despite lung growth induced by fetal tracheal occlusion (TO). We hypothesized that the underlying mechanisms would involve changes in lung extracellular matrix and dysregulated transforming growth factor (TGF)-β pathway, a key player in lung development and repair. Pulmonary expression of TGF-β signaling components, downstream effectors, and extracellular matrix targets were evaluated in CDH neonates who died between birth and the first few weeks of life after prenatal conservative management or TO, and in rabbit pups that were prenatally randomized for surgical CDH and TO vs. sham operation. Before tissue harvesting, lung tissue mechanics in rabbits was measured using the constant-phase model during the first 30 min of life. Human CDH and control fetal lungs were also collected from midterm onwards. Human and experimental CDH did not affect TGF-β/Smad2/3 expression and activity. In human and rabbit CDH lungs, TO upregulated TGF-β transcripts. Analysis of downstream pathways indicated increased Rho-associated kinases to the detriment of Smad2/3 activation. After TO, subtle accumulation of collagen and α-smooth muscle actin within alveolar walls was detected in rabbit pups and human CDH lungs with short-term mechanical ventilation. Despite TO-induced lung growth, mediocre lung tissue mechanics in the rabbit model was associated with increased transcription of extracellular matrix components. These results suggest that prenatal TO increases TGF-β/Rho kinase pathway, myofibroblast differentiation, and matrix deposition in neonatal rabbit and human CDH lungs. Whether this might influence postnatal development of sustainably ventilated lungs remains to be determined.

Topics: Airway Obstruction; Animals; Fetus; Hernias, Diaphragmatic, Congenital; Humans; Lung; Pulmonary Alveoli; Rabbits; Respiration, Artificial; rho-Associated Kinases; Trachea; Transforming Growth Factor beta

Cardiac asthma describes symptoms of airflow obstruction due to heart failure. Chronic heart failure is associated with decreased FEV 1 , and FEV 1 improves after heart transplantation. Fibrotic remodeling of the heart and airways is mediated, in part, through transforming growth factor (TGF)- β . Blood TGF- b 1 concentration correlates with ventricular remodeling in cardiac disease, and TGF- β decreases after repair.. We established a coculture of normal human bronchial epithelial (NHBE) cells differentiated at air-liquid interface with submerged basal cardiomyoblasts. Airway cells were immunostained with cytokeratin, actin, and involucrin. TGF- β synthesis was assayed using enzyme-linked immunosorbent assay. Phosphorylation of Smad in NHBE cells was determined by Western blotting.Mice given doxorubicin developed cardiac failure, and their airways were histologically examined.. Coculture induced involucrin-positive squamous metaplasia of NHBE cells, and this was attenuated by TGF- β antibody. Total TGF- β 1 was increased in coculture conditioned medium( P < .001). After 14 days of exposure to recombinant TGF- β 1 , there was squamous transformation of NHBE cells. One week after removing cardiomyoblasts from culture, squamous metaplasia resolved into normal ciliated epithelia. Smad was phosphorylated in NHBE cells with cardiomyoblasts or with recombinant TGF- β 1 exposure. The airways of mice with heart failure also demonstrated involucrin-positive squamous transformation.. TGF- β from cardiomyoblasts or from the failing heart can cause airway squamous metaplasia via Smad signaling, and this is blocked by anti-TGF- b antibody and reversed when cardiac cells are removed from culture. This appears to be an important mechanism for airflow obstruction with heart failure, sometimes described as cardiac asthma.

Topics: Airway Obstruction; Analysis of Variance; Animals; Blotting, Western; Bronchi; Coculture Techniques; DNA Primers; Doxorubicin; Enzyme-Linked Immunosorbent Assay; Glyceraldehyde 3-Phosphate Dehydrogenase (NADP+); Heart Failure; Humans; Immunohistochemistry; Lung; Male; Mice; Mice, Inbred C57BL; Myocytes, Cardiac; Phosphorylation; Protein Precursors; Rats; Real-Time Polymerase Chain Reaction; Signal Transduction; Smad Proteins; Transforming Growth Factor beta

Distraction osteogenesis of the mandible has become an alternative to tracheostomy in infants and children who present with upper airway obstruction due to micrognathia. To avoid prolonged intubation during distraction, we have implemented a protocol of immediate distraction at the time of distractor placement, which results in acute airway improvement. Over 2 years, 22 patients with micrognathia and severe airway obstruction have undergone mandibular distractor placement. Indications for surgery were apnea and desaturations with feeding. Resorbable distraction devices were placed bilaterally and activated to 5 to 8 mm. Recombinant human bone morphogenetic protein 2 was placed in the gap. Distraction was implemented at postoperative day 2 at 2 mm/d. Forty-four distraction devices were placed in 22 patients (68% male, 32% female) with a mean age of 24.1 months (range, 3 days to 5.5 years). The average distance of distraction performed in the operating room was 5 mm. The average total distraction was 24 mm performed over 12 days. Overall, 89% of patients were extubated after distractor placement in the operating room. Two patients with difficult intubations were extubated 7 days later in the operating room with otolaryngology. Of the 4 tracheostomy patients, 1 patient was decannulated, whereas 3 patients are pending postoperative sleep studies. One patient had a minor wound complication. Tracheostomy and prolonged intubation in patients with mandibular hypoplasia have significant morbidity and mortality. We have implemented a successful protocol of immediate distraction in the operating room with placement of bone morphogenetic protein. Immediate distraction appears to be an effective method of avoiding postoperative intubation and tracheostomy.

Topics: Absorbable Implants; Airway Obstruction; Apnea; Bone Morphogenetic Protein 2; Child, Preschool; Female; Goldenhar Syndrome; Humans; Infant; Infant, Newborn; Internal Fixators; Intubation, Intratracheal; Laryngoscopy; Male; Mandible; Mandibulofacial Dysostosis; Micrognathism; Osteogenesis, Distraction; Pierre Robin Syndrome; Recombinant Proteins; Time Factors; Tracheostomy; Transforming Growth Factor beta

Long-term success in lung transplantation is limited by obliterative bronchiolitis (OB). Presently, complete understanding of the mechanisms of OB has been elusive. Bone marrow-derived mesenchymal stem cells (MSC) have been shown to modulate repair of the injured lung in multiple disease models. We hypothesized that the injection of MSC would prevent development of early airway obstruction (AO) in the heterotopic tracheal transplant model.. Forty-four tracheas from BALB/c and C57BL/6 donors were transplanted into 22 C57BL/6 recipients. At the time of transplant, 13 of the allogeneic recipient mice were injected with 5 × 10(5) MSC from various murine sources. To confirm the role of the immune response in the generation of AO we used a permeable inhibitor of nuclear factor-kappaB (NF-κB) in 11 recipients after transplantation with 22 BALB/c tracheas.. After transplantation, administration of MSC inhibited intraluminal obstruction by collagen in 98% of the mice and transforming factor-beta (TGF-β) expression decreased to levels similar to those observed in isograft controls. These effects were associated with a significant (p < 0.05) increase in expression of the anti-inflammatory cytokine interleukin-10 (IL-10). NF-κB inhibitor showed decreased expression of transforming growth factor-beta (TGF-β) in the Day 7 and Day 14 groups, resulting in a 60% reduction of luminal obstruction as well as a decrease in inflammatory cells to the airway.. Our observations suggest that administration of MSC prevents development of airway occlusion in a mouse model, probably through the modulated immune response altering TGF-β expression.

Topics: Airway Obstruction; Animals; Disease Models, Animal; Female; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Trachea; Transforming Growth Factor beta; Transplantation, Heterotopic; Transplantation, Homologous

Mandibular distraction is recognized as a treatment of respiratory distress in neonates with microretrognathia as seen in the Pierre Robin syndrome. However, mandibular distraction is a complex and lengthy treatment involving 2 to 4 weeks of distraction and another 4 to 12 weeks for bone consolidation. This study was performed to establish the safety and effectiveness of rapid protocol distraction osteogenesis with recombinant human bone morphogenetic protein 2 (rhBMP-2) in neonates with the Pierre Robin syndrome.. A retrospective review of all patients treated in our department between February 2003 and February 2008 was performed. Three patients with the Pierre Robin syndrome who underwent distraction osteogenesis with rhBMP-2 were identified. Inpatient and outpatient charts were reviewed for time to completion of distraction, age at distraction, need for tracheostomy, and complications of the mandibular distraction.. Three patients (6 hemimandibles) with Pierre Robin syndrome underwent rapid protocol distraction with rhBMP-2. Mean age at initial distraction was 17.3 days. Mean time from device placement to removal was 89.3 days. The complication rate was 16%, with 1 case of nonunion that required subsequent operative intervention. No patient required tracheostomy.. Rapid protocol distraction with rhBMP-2 allows distraction of the hypoplastic mandible to class III occlusion during the initial operation and avoids the latency and distraction phases of standard mandibular distraction. This case series demonstrates the safety and effectiveness of rapid distraction in neonates with Pierre Robin syndrome. Larger studies and long-term follow-up are necessary; however, this study suggests that rapid protocol distraction with rhBMP-2 is effective in neonates with Pierre Robin syndrome.

Topics: Airway Obstruction; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Female; Humans; Infant, Newborn; Intubation, Intratracheal; Male; Mandibular Advancement; Osteogenesis, Distraction; Pierre Robin Syndrome; Postoperative Complications; Recombinant Proteins; Retrognathia; Retrospective Studies; Transforming Growth Factor beta; Treatment Outcome

Endobronchial tuberculosis (EBTB) has been shown to frequently complicate bronchial stenosis, a condition which can induce dyspnea as a result of airway obstruction, and is also frequently misdiagnosed as either bronchial asthma or lung cancer.. This study attempted to determine whether there was a correlation between interferon-gamma (IFN-gamma) and transforming growth factor-beta (TGF-beta) levels in the serum and bronchial washing fluid (BWF), and the results of the treatment of EBTB patients.. Thirty patients, all of whom were diagnosed as EBTB, were enrolled, as were 10 healthy control subjects. IFN-gamma and TGF-beta levels were measured by the ELISA method in the serum and BWF of these 30 EBTB patients before and after treatment. The EBTB patients were divided into two groups: those who exhibited bronchial stenosis after treatment and those who did not. Chest computed tomography (CT) and pulmonary function test (PFT) were performed in 16 and 25 patients, respectively, at initial bronchoscopy.. IFN-gamma and TGF-beta levels in the BWF of the EBTB patients were elevated compared to the controls (p < 0.05). After 2 months of treatment, 13 of the 30 EBTB patients exhibited bronchial fibrostenosis and the other 17 cases had recovered without sequelae. In the bronchial stenosis group, the initial serum TGF-beta levels were lower than in the patients without bronchial stenosis (p < 0.05). Moreover, the levels of serum TGF-beta after treatment were shown to have decreased more than in the patients without bronchial stenosis (p < 0.05). On chest CT findings of 16 EBTB patients, bronchial narrowing was suspected except in 2 cases (1 edematous-hyperemic type, 1 actively caseating type of segmental bronchus). The common features of PFT in EBTB at the initial diagnosis were a restrictive pattern and normal ventilatory function.. Elevated IFN-gamma and TGF-beta levels in the BWF of the EBTB patients may be related to EBTB pathogenesis. Lowered initial serum TGF-beta levels as well as the observed changes in the levels of TGF-beta in the serum after treatment have been implicated in bronchial fibrostenosis during the course of the disease.

Topics: Adult; Aged; Airway Obstruction; Antitubercular Agents; Biomarkers; Bronchial Diseases; Bronchoalveolar Lavage Fluid; Bronchoscopy; Female; Follow-Up Studies; Humans; Interferon-gamma; Male; Middle Aged; Mycobacterium tuberculosis; Prognosis; Severity of Illness Index; Tomography, X-Ray Computed; Transforming Growth Factor beta; Tuberculosis

Lung fibroblasts play a key role in the pathogenesis of airway inflammation and remodeling through the release of mediators and the expression of surface molecules connected with cell-cell and cell-extracellular matrix interaction. The aim of the study was to evaluate the inhibitory effect of two corticosteroids, mometasone furoate (MOM) and dexamethasone (DEX), respectively, on a variety of fibroblast functions: DNA synthesis and proliferation, expression of adhesion molecules [intercellular adhesion molecule-1 (ICAM-1, CD54) and hyaluronic cellular adhesion molecule (HCAM, CD44)] and release of chemokines/cytokines [monocyte chemoattractant protein (MCP)-1, eotaxin, interleukin (IL)-6 and transforming growth factor (TGF)-beta]. Cells from a human foetal lung fibroblast cell line (GM 06114) were stimulated with basic fibroblast growth factor (bFGF) or tumour necrosis factor (TNF)-alpha in the presence of different concentrations (0.01-100.0nM) of MOM or DEX. A significant increase in fibroblast DNA synthesis and proliferation was observed when the cells were stimulated with bFGF (p<0.05), whereas TNF-alpha induced a significant upregulation in ICAM-1 expression and in MCP-1, eotaxin and IL-6 release (p<0.05, each comparison). No changes in HCAM expression and in TGF-beta release were observed (p>0.05, each comparison). The addition of MOM or DEX at the beginning of the cell cultures induced a significant downregulation in fibroblast DNA synthesis and proliferation, ICAM-1 and HCAM expression and chemokine/cytokine release (p<0.05, each comparison). At all the concentrations tested, MOM was more effective than DEX in inhibiting ICAM-1 expression and MCP-1 release (p<0.05, each comparison), whereas no potency advantage for MOM was detected in DNA synthesis, cell proliferation, HCAM expression and in eotaxin, IL-6 and TGF-beta release (p>0.05, each comparisons). These results extend the profile of the anti-inflammatory activity of mometasone furoate to lung fibroblast functions involved in airway inflammation and remodeling.

Topics: Airway Obstruction; Cell Adhesion Molecules; Cell Line; Chemokine CCL11; Chemokine CCL2; Chemokines, CC; Dexamethasone; DNA; Dose-Response Relationship, Drug; Fibroblasts; Humans; Hyaluronan Receptors; Intercellular Adhesion Molecule-1; Interleukin-6; Lung; Mometasone Furoate; Pregnadienediols; Transforming Growth Factor beta

Exposure to mineral dusts is associated with the development of chronic airflow obstruction, probably mediated in part by dust-induced fibrosis of the small airways. To investigate the mechanism of fibrosis, we exposed rat tracheal explants to amosite asbestos, iron oxide, or titanium dioxide. Explants were then maintained in air organ culture, and the expression of genes encoding for various mediators and matrix components assessed by reverse transcriptase-polymerase chain reaction (RT-PCR). At 7 d, all dusts produced significant increases in platelet-derived growth factor-A (PDGF-A) and transforming growth factor-beta1 (TGF-beta1) gene expression compared with control; asbestos and titanium dioxide produced increases in PDGF-B, and titanium dioxide increased TGF-alpha expression. Only asbestos caused increases in procollagen expression. No dust increased expression of tumor necrosis factor-alpha (TNF-alpha), fibronectin, or tropoelastin. Elevations in these factors coincided temporally with transport of particles into the epithelium and then to the subepithelial space. By in situ hybridization, TGF-beta gene expression was found in both the epithelium and subepithelial (interstitial) space, and PDGF-B and procollagen gene expression in the subepithelial space. Chemical analysis showed a small increase in hydroxyproline, a measure of collagen content, in asbestos-treated explants. We conclude that mineral dusts can induce airway wall fibrosis by directly upregulating proliferative and fibrogenic mediators as well as matrix components in the airway epithelium and interstitium, and that neither airspace nor circulating inflammatory cells are required for these effects. Different mineral dusts produce different patterns of reaction.

Topics: Airway Obstruction; Animals; Asbestos, Amosite; Culture Techniques; Dust; Epithelium; Extracellular Matrix Proteins; Ferric Compounds; Fibronectins; Gene Expression Regulation; Hydroxyproline; Inflammation Mediators; Irritants; Lung; Male; Mineral Fibers; Minerals; Platelet-Derived Growth Factor; Procollagen; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-sis; Pulmonary Fibrosis; Rats; Rats, Sprague-Dawley; Titanium; Transforming Growth Factor beta; Tropoelastin; Tumor Necrosis Factor-alpha; Up-Regulation