Yuan-jue Zhu

Effect of TGF-β/Smad signaling pathway on lung myofibroblast differentiation

AbstractAim:Myofibroblasts play important roles in the pathogenesis of lung fibrosis. Transforming growth factor (TGF)-β1 has been widely recognized as a key fibrogenic cytokine. The major signaling pathway of TGF-β1 is through cytoplasmic Smad proteins. Our study investigated the role of individual TGF-β1/Smad signal proteins in mediating α-smooth muscle actin (α-SMA) gene expression, which is a well-known key marker of myofibroblast differentiation.Methods:We transiently cotransfected α-SMA promoter-luciferase fusion plasmid (p895-Luc) and Smad expression plasmids and measured Luc activity in TGF-β1-treated human fetal lung fibroblasts. We induced Smad3 knockout mice lung fibrosis by bleomycin. α-SMA protein expression was assessed by Western blotting. Collagen protein was analyzed by measuring hydroxyprolin. Myofibroblast morphology was assessed by immunohistochemistry.Results:We found that the overexpression of Smad3, not Smad2 markedly increased TGF-β1-induced α-SMA promoter activity and α-SMA protein expression in vitro, whereas the over-expression of dominant negative mutant Smad3 and Smad7 repressed TGF-β1 induced α-SMA gene expression. Compared to wild-type mice, Smad3 knockout mice showed attenuated lung fibrosis after bleomycin treatment, manifested by lower collagen production and myofibroblast differentiation.Conclusion:Our study suggested TGF-β1/Smad3 is a major pathway which regulated the myofibroblast differentiation. This result indicates a potential significance for future attempts of attenuating the progression of human lung fibrosis by the inhibition of the Smad3 cascade.

Effect of Supplementing a High-Fat, Low-Carbohydrate Enteral Formula in COPD Patients

OBJECTIVEnOne of the goals in treating patients with chronic obstructive pulmonary disease (COPD) who suffer from hypoxemia, hypercapnia, and malnutrition is to correct the malnutrition without increasing the respiratory quotient and minimize the production of carbon dioxide. This 3-wk study evaluated the efficacy of feeding a high-fat, low-carbohydrate (CHO) nutritional supplement as opposed to a high-carbohydrate diet in COPD patients on parameters of pulmonary function.S METHODS: Sixty COPD patients with low body weight (<90% ideal body weight) were randomized to the control group, which received dietary counseling for a high-CHO diet (15% protein, 20% to 30% fat, and 60% to 70% CHO), or the experimental group, which received two to three cans (237 mL/can) of a high-fat, low-CHO oral supplement (16.7% protein, 55.1% fat, and 28.2% CHO) in the evening as part of the diet. Measurements of lung function (forced expiratory volume in 1 s or volume of air exhaled in 1 s of maximal expiration, minute ventilation, oxygen consumption per unit time, carbon dioxide production in unit time, and respiratory quotient) and blood gases (pH, arterial carbon dioxide tension, and arterial oxygen tension) were taken at baseline and after 3 wk.nnnRESULTSnLung function measurements decreased significantly and forced expiratory volume increased significantly in the experimental group.nnnCONCLUSIONnThis study demonstrates that pulmonary function in COPD patients can be significantly improved with a high-fat, low-CHO oral supplement as compared with the traditional high-CHO diet.

Pulmonary Manifestations of Sjögren’s Syndrome

Background: Primary Sjögren’s syndrome (PSS) is associated with various histological patterns of interstitial lung disease. Although chest images and lung function studies showed that lung involvement predominantly occurs in small airways, pathological findings were not consistent with the results of high-resolution CT (HRCT) and lung function tests. Objectives: To investigate the pathological characteristics of PSS-associated interstitial lung disease (PSS-ILD) and their relationship with HRCT lung function tests. Methods: Fourteen patients diagnosed as PSS who underwent surgical lung biopsy in Peking Union Medical College Hospital from October 2000 to October 2006 were reviewed. Histopathologic findings, radiologic findings and lung function tests were analyzed. Results:The study included 13 women. The median age was 46 years. Most patients presented with dyspnea and cough. CT scans revealed bilateral ground-glass, consolidative, reticular and nodular opacities and cyst lesions. The histological patterns included nonspecific interstitial pneumonia (NSIP) cellular pattern associated with organizing pneumonia (OP), NSIP mixed pattern associated with OP, noncaseating granulomas, chronic bronchiolitis, follicular bronchiolitis, constrictive bronchiolitis, lymphocytic interstitial pneumonia associated with follicular bronchiolitis, NSIP mixed pattern associated with follicular bronchiolitis, NSIP mixed pattern coexisting with chronic bronchiolitis, OP associated with chronic bronchiolitis, and noncaseating granulomas coexisting with OP. Treatment included prednisone and cyclophosphamide. During the follow-up period (median 38 months), most patients improved or remained stable. The patient with constrictive bronchiolitis died from progression of primary disease. Conclusions: The histopathologic patterns of PSS-ILD included lung interstitial involvement and small airway involvement or both. Corticosteroid therapy combined with cyclophosphamide was administered with a favorable response in the majority of patients.

The St. George's Respiratory Questionnaire in lymphangioleiomyomatosis.

OBJECTIVEnTo examine the correlation between the health-related quality of life measured by the St. Georges Respiratory Questionnaire (SGRQ) and the commonly used physiological measures in lymphangioleiomyomatosis (LAM).nnnMETHODSnThis study retrospectively analyzed the SGRQ scores and other measures (the Borg scale of breathlessness at rest, 6-minute walking distance, blood oxygen levels, and pulmonary function) of patients diagnosed and confirmed with LAM. Altogether 38 patients between June 2007 and November 2009 were included.nnnRESULTSnThe mean values of the SGRQ three components (symptoms, activity, and impacts) and total scores in the LAM patients were 46.95 +/- 28.90, 58.47 +/- 25.41, 47.89 +/- 29.66, and 51.11 +/- 26.35, respectively. The SGRQ total or component scores were correlated well with the Borg scale of breathlessness, 6-minute walking distance, partial pressure of oxygen in arterial blood, spirometry and diffusion capacity of lung. There were poor correlations between SGRQ score and residual volume or total lung capacity. In our preliminary observation, sirolimus improved the SGRQ total and three component scores and the Borg scale of breathlessness significantly after 101-200 days of treatment (n = 6).nnnCONCLUSIONSnThe SGRQ score in LAM is correlated well with physiological measures (Borg scale of breathlessness, 6-minute walking distance, blood oxygen levels, and pulmonary function tests). The SGRQ could therefore be recommended in baseline and follow-up evaluation of patients with LAM. Treatment with sirolimus, an inhibitor of mammalian target of rapamycin, may improve the quality of life and patients perception of breathlessness in LAM.

p.G970D is the most frequent CFTR mutation in Chinese patients with cystic fibrosis

Cystic fibrosis (CF), the most common life-threatening autosomal recessive disorder in Caucasians, is caused by mutations in CF transmembrane conductance regulator gene (CFTR). We and others previously identified CFTR mutations in 20 Chinese patients with CF. In this study, eight Chinese patients with a clinical diagnosis of suspected CF were newly collected and screened for CFTR mutations using a combination of conventional Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA) analysis. The CFTR mutations observed in Chinese CF patients, both reported previously and identified in the present study, were also summarized. In the newly collected patients, we identified 10 different CFTR mutations, including p.F508del, the most common CF-causing mutation in Caucasians, and three novel mutations (p.V1212Afs*15; p.L666* and p.A969A). Most notably, the previously reported p.G970D mutation was found in six patients, making it the most frequent CFTR mutation identified in Chinese CF patients thus far. In conclusion, we detected p.F508del for the first time, identified additional novel CFTR mutations and recorded the most frequent CF-causing mutation in Chinese CF patients.

Clinical Features and Prognosis in 21 Patients with Extrinsic Allergic Alveolitis

OBJECTIVEnTo assess the spectrum of causes, clinical features, differences between disease phases, and prognosis of extrinsic allergic alveolitis (EAA).nnnMETHODSnPatients with EAA diagnosed at Peking Union Medical College Hospital from August 1983 to May 2007 were analyzed retrospectively. Their medical records were examined to gather clinical, laboratorial, radiological, and histopathological data. Patients were divided to three phases (acute, subacute, and chronic) according to clinical presentations. Follow-up data regarding treatment response, subsequent radiological and pulmonary function studies, and clinical outcomes were collected.nnnRESULTSnA total of 21 cases were enrolled. Among them, 11 were subacute, 10 were chronic. The most common exposure was pet birds (6 cases, 28.6%). The primary abnormality of pulmonary function was restriction and/or reduction in diffusing capacity (12 cases, 63.2%). The most common findings on high-resolution computed tomography (HRCT) were ground-glass opacities (13 cases, 68.4%) and centrilobular nodules (8 cases, 42.1%). Airway obstruction in pulmonary function test, emphysema, lung cysts, and fibrosis on HRCT were more frequently seen in chronic than in subacute patients, though the differences were not statistically significant. Bronchoalveolar lavage fluid (BALF) showed lymphocytosis. The total cell count and the percentage of neutrophils were significantly higher in subacute than in chronic patients (P<0.05). Nonnecrotizing granulomas were seen in 8 (47.1%) cases. Improvement or normalization in symptoms, radiography, and pulmonary function test after treatment were seen in all 18 patients with available follow-up data. Five patients recurred.nnnCONCLUSIONSnThe characteristic abnormalities of pulmonary function, findings on HRCT, and pathology are essential for all phases of EAA, and the atypical manifestations such as obstruction and fibrosis can also be present frequently, particularly in chronic cases. Differential cell counts of BALF are related to the phase of the disease. The treatment response and prognosis of EAA are good.

Impaired lipid metabolism in idiopathic pulmonary alveolar proteinosis

BackgroundIt is well known that lipids abnormally accumulate in the alveoli during idiopathic pulmonary alveolar proteinosis (PAP). It is unclear, however, whether lipids also abnormally accumulate in serum. This study investigated the serum lipid panels in idiopathic PAP patients and explored the relationships between serum levels and the severity of idiopathic PAP.Methods and ResultsClinical data including the level of serum lipids were evaluated in 33 non-diabetic idiopathic PAP patients and 157 healthy volunteers. Serum levels of triglyceride were higher in PAP patients than in healthy subjects (median: 192.00 mg/dl (P25: 104.36, P75: 219.00) vs 119.56 mg/dl (P25: 78.81, P75: 193.03), P < 0.05), while high-density lipoprotein cholesterol (HDL-C) levels were lower in patients than in the control group (42.50 ± 10.30 vs 51.34 ± 12.06 mg/dl, P < 0.01). Forced expiratory volume in one second and forced vital capacity in hypertriglyceridemia patients were lower than those in patients with normal triglyceride. Serum LDL-C and HDL-C ratio correlated negatively with PaO2 (r = -0.403, P < 0.05) and positively with lactate dehydrogenase (r = 0.381, P < 0.05).ConclusionsPAP associates with high triglyceride and low HDL levels in the serum, and these lipids provide potential intervention strategy for treatment.

Pathological and High Resolution CT Findings in Churg-Strauss Syndrome

OBJECTIVEnTo investigate the Churg-Strauss syndrome (CSS) associated lung involvement, concentrating on clinical characteristics, pathological findings of lung involvements, response to treatment, and prognosis.nnnMETHODSnWe retrospectively analyzed the characters of the clinical manifestations, thin-section CT and pathological findings of CSS. The study involved 16 patients. Clinical data were obtained by chart review. All patients underwent transbronchial lung biopsy (TBLB). Six of them underwent surgical lung biopsy as well.nnnRESULTSnThe patients included 7 men and 9 women, aged from 14 to 61 years (median, 47.5 years). Extrathoracic organs involved included nervous system (7/16) and skin (5/16). Respiratory symptoms included cough (12/16), exertional dyspnea (11/16), hemoptysis (4/16), and chest pain (3/16). CT findings included bilateral ground-glass opacities (12/16), bilateral patchy opacities (12/16), and centrilobular nodules (6/16). The pathological findings of TBLB demonstrated increased eosinophils (3/16), vasculitis (3/16), and interstitial pneumonia (16/16). The pathological findings of surgical lung biopsy of 6 cases showed necrotizing vasculitis in 4 cases, capillaries in 5, eosinophilic pneumonia in 3, granulomas in 2, and airway abnormalities in 3. All patients improved in symptoms after therapy during the study period (range, 3 to 51 months; median, 15 months).nnnCONCLUSIONSnAsthma may be present in CSS patient when there is bronchial involvement. Ground-glass opacities and consolidation seen on high-resolution CT reflect the presence of eosinophilic pneumonia, vasculitis, and pulmonary alveolar hemorrhage. TBLB has significant limitations for the diagnosis of CSS. Early diagnosis and therapy can result in satisfactory prognosis.

Association between nonspecific interstitial pneumonia and presence of CD20+ B lymphocytes within pulmonary lymphoid follicles

Nonspecific interstitial pneumonia (NSIP) is characterised by interstitial infiltration of lymphocytes and varying amounts of interstitial fibrosis. B cells have been suggested to contribute to the pathogenesis of NSIP. However, the relationship between B-lymphocyte and the clinical outcomes of NSIP was unclear. In this study, 50 patients with histopathologically confirmed NSIP from Peking Union Medical College Hospital between April 2003 to December 2012 were retrospectively analyzed. Using immunohistochemical analyses, CD20+ B cells were counted in the lymphoid follicles, perivascular, interstitial, and peribronchiolar regions of lung tissure. The CD20+ lymphocytes were mainly present in the lymphoid follicles. The number of follicular CD20+ lymphocytes was higher in the fibrosing than cellular NSIP pattern [255.08 (132.92–449.71) vs. 121.33 (63.54–282.88)/0.1u2009mm2, pu2009=u20090.017]. After 1 year of therapy, the follicular CD20+ lymphocytes were significantly higher in patients whose forced vital capacity (FVC) worsened as compared to those who improved (pu2009=u20090.014). Additionally, follicular CD20+ lymphocytes were negatively correlated with the post-treatment percentage change in FVC (rhou2009=u2009−0.397, pu2009=u20090.004). However, follicular CD20+ lymphocytes were not correlated with survival. These results suggested that pulmonary follicular CD20+ lymphocytes were correlated with the fibrosing pattern of NSIP and predicted less clinical improvement after treatment.