A Unique Cellular Organization of Human Distal Airways and Its Disarray in Chronic Obstructive Pulmonary Disease.

Rationale: Remodeling and loss of distal conducting airways, including preterminal and terminal bronchioles (pre-TBs/TBs), underlie progressive airflow limitation in chronic obstructive pulmonary disease (COPD). The cellular basis of these structural changes remains unknown. Objectives: To identify biological changes in pre-TBs/TBs in COPD at single-cell resolution and determine their cellular origin. Methods: We established a novel method of distal airway dissection and performed single-cell transcriptomic profiling of 111,412 cells isolated from different airway regions of 12 healthy lung donors and pre-TBs of 5 patients with COPD. Imaging CyTOF and immunofluorescence analysis of pre-TBs/TBs from 24 healthy lung donors and 11 subjects with COPD were performed to characterize cellular phenotypes at a tissue level. Region-specific differentiation of basal cells isolated from proximal and distal airways was studied using an air-liquid interface model. Measurements and Main Results: The atlas of cellular heterogeneity along the proximal-distal axis of the human lung was assembled and identified region-specific cellular states, including SCGB3A2+ SFTPB+ terminal airway-enriched secretory cells (TASCs) unique to distal airways. TASCs were lost in COPD pre-TBs/TBs, paralleled by loss of region-specific endothelial capillary cells, increased frequency of CD8+ T cells normally enriched in proximal airways, and augmented IFN-γ signaling. Basal cells residing in pre-TBs/TBs were identified as a cellular origin of TASCs. Regeneration of TASCs by these progenitors was suppressed by IFN-γ. Conclusions: Altered maintenance of the unique cellular organization of pre-TBs/TBs, including loss of the region-specific epithelial differentiation in these bronchioles, represents the cellular manifestation and likely the cellular basis of distal airway remodeling in COPD.

Adverse pulmonary effects after oral exposure to copper, manganese and mercury, alone and in mixtures, in a Spraque-Dawley rat model.

The rise in respiratory disease has been attributed to an increase in environmental pollution. Heavy metals contribute to environmental contamination via air, water, soil and food. The effects of atmospheric exposure to heavy metals on pulmonary structure and function have been researched, but the effects through drinking water have been neglected. The aim of this study was to investigate the potential in vivo alterations in the pulmonary tissue of male Sprague-Dawley rats after a 28-day oral exposure to copper (Cu), manganese (Mn) and mercury (Hg), alone and in mixtures, at 100 times the World Health Organization's (WHO) safety limit for each heavy metal in drinking water. Forty-eight male Sprague-Dawley rats were randomly divided into eight groups (n = 6): control, Cu, Mn, Hg, Cu + Mn, Cu + Hg, Mn + Hg and Cu, Mn + Hg. The morphology of lung tissue and the bronchioles were evaluated using light- and transmission electron microscopy. For all exposed groups, morphological changes included thickened inter- and intra-alveolar spaces, stratified epithelium, disrupted smooth muscle and early fibrosis and desquamation of the epithelia of the bronchioles to varying degrees. In all exposed groups, ultrastructurally, an increase in disarranged collagen and elastin fibers, nuclear membrane detachment, chromatin condensation, indistinct nucleoli and an increase in collagen fiber disarrangement was observed. This study has identified that oral exposure to Cu, Mn and Hg and as part of mixtures caused pathogenesis due to inflammation, cellular damage and fibrosis with Mn + Hg being the most potent heavy metal group.

Pathological Comparisons of Paraseptal and Centrilobular Emphysema in Chronic Obstructive Pulmonary Disease.

Rationale: Although centrilobular emphysema (CLE) and paraseptal emphysema (PSE) are commonly identified on multidetector computed tomography (MDCT), little is known about the pathology associated with PSE compared with that of CLE.Objectives: To assess the pathological differences between PSE and CLE in chronic obstructive pulmonary disease (COPD).Methods: Air-inflated frozen lung specimens (n = 6) obtained from patients with severe COPD treated by lung transplantation were scanned with MDCT. Frozen tissue cores were taken from central (n = 8) and peripheral (n = 8) regions of each lung, scanned with micro-computed tomography (microCT), and processed for histology. The core locations were registered to the MDCT, and a percentage of PSE or CLE was assigned by radiologists to each of the regions. MicroCT scans were used to measure number and structural change of terminal bronchioles. Furthermore, microCT-based volume fractions of CLE and PSE allowed classifying cores into mild emphysema, CLE-dominant, and PSE-dominant.Measurements and Main Results: The percentages of PSE measured on MDCT and microCT were positively associated (P = 0.015). The number of terminal bronchioles per milliliter of lung and cross-sectional lumen area were significantly lower and wall area percentage was significantly higher in CLE-dominant regions compared with mild emphysema and PSE-dominant regions (all P < 0.05), whereas no difference was found between PSE-dominant and mild emphysema samples (all P > 0.5). Immunohistochemistry showed significantly higher infiltration of neutrophils (P = 0.002), but not of macrophages, CD4, CD8, or B cells, in PSE compared with CLE regions.Conclusions: The terminal bronchioles are relatively preserved, whereas neutrophilic inflammation is increased in PSE-dominant regions compared with CLE-dominant regions in patients with COPD.

Heart of glass: fatal hematemesis caused by bronchiole-cardiac fistula.

A 58-year old woman presented for autopsy after having been found unresponsive in a public bathroom surrounded by a pool of blood. During attempts at resuscitation, blood was noted in her airway. She had a past medical history that included surgical repair of Tetralogy of Fallot as a child. At autopsy, a shard of glass was identified projecting from the surface of the left lung, having formed densely fibrotic adhesions at the pleural surface. The glass also penetrated through a bronchiole lumen and into a previously surgically repaired bulging right ventricular outflow tract, forming a bronchiole-cardiac fistula, allowing for the massive hemoptysis that led to her death. After further inquiry, it was discovered that the decedent also had a history of seizure disorder and had fallen through a glass door during a seizure many years ago, requiring several shards of glass to be removed from her chest wall.

Bicarbonate transport of airway surface epithelia in luminally perfused mice bronchioles.

HCO3- secretion in distal airways is critical for airway mucosal defense. HCO3-/H+ transport across the apical membrane of airway surface epithelial cells was studied by measuring intracellular pH in luminally microperfused freshly dissected mice bronchioles. Functional studies demonstrated that CFTR, ENaC, Cl--HCO3- exchange, Na+-H+ exchange, and Na+-HCO3- cotransport are involved in apical HCO3-/H+ transport. RT-PCR of isolated bronchioles detected fragments from Cftr, α, ß, γ subunits of ENaC, Ae2, Ae3, NBCe1, NBCe2, NBCn1, NDCBE, NBCn2, Nhe1, Nhe2, Nhe4, Nhe5, Slc26a4, Slc26a6, and Slc26a9. We assume that continuous decline of intracellular pH following alkaline load demonstrates time course of HCO3- secretion into the lumen which is perfused with a HCO3--free solution. Forskolin-stimulated HCO3- secretion was substantially inhibited by luminal application of CFTRinh-172 (5 µM), H2DIDS (200 µM), and amiloride (1 µM). In bronchioles from a cystic fibrosis mouse model, basal and acetylcholine-stimulated HCO3- secretion was substantially impaired, but forskolin transiently accelerated HCO3- secretion of which the magnitude was comparable to wild-type bronchioles. In conclusion, we have characterized apical HCO3-/H+ transport in native bronchioles. We have demonstrated that cAMP-mediated and Ca2+-mediated pathways are involved in HCO3- secretion and that apical HCO3- secretion is largely mediated by CFTR and H2DIDS-sensitive Cl--HCO3- exchanger, most likely Slc26a9. The impairment of HCO3- secretion in bronchioles from a cystic fibrosis mouse model may be related to the pathogenesis of early lung disease in cystic fibrosis.

Bronchopulmonary Penetration of Isavuconazole in Pulmonary Transplant Recipients (PBISA01): Protocol for a Phase IV Clinical Trial With a Single Treatment Arm.

BACKGROUND: Aspergillosis is the most frequently observed invasive fungal disease (IFD) in lung transplant recipients. Isavuconazole (ISA) has shown a better safety profile and noninferiority to voriconazole in the treatment of patients with IFD. OBJECTIVE: The aim of this study is to describe the bronchopulmonary pharmacokinetic profile of oral ISA by analyzing the degree of penetration in the epithelial lining fluid and alveolar macrophages in patients receiving lung transplantation with a diagnosis of IFD. METHODS: A total of 12 patients aged ≥18 years receiving a lung transplant with an IFD diagnosis and indication for ISA treatment and follow-up bronchoscopy will be included in the study. After 5 days of treatment with ISA and before the treatment is discontinued, the patients will be randomized (1:1:1:1) to perform the scheduled bronchoscopy at various times after the administration of ISA (2, 4, 8, and 12 hours). In total, 4 blood samples will be obtained per patient: at 72 hours after treatment initiation, on the day of the bronchoscopy, at the time of the bronchoalveolar lavage (simultaneously), and at 7 days after treatment initiation, to analyze tacrolimus and ISA plasma levels. ISA concentrations will be measured in plasma, epithelial lining fluid, and alveolar macrophages by a high-performance liquid chromatography/UV coupled to fluorescence method. RESULTS: Enrollment for the PBISA01 trial began in October 2020 and was completed in October 2021. All samples will be analyzed once recruitment is complete, and the results are expected to be published in October 2022. CONCLUSIONS: There are no clinical studies that analyze the bronchopulmonary penetration of ISA. Bronchoalveolar lavage performed routinely in the follow-up of lung transplant recipients constitutes an opportunity to analyze the bronchopulmonary penetration of ISA. TRIAL REGISTRATION: European Clinical Trials Register 2019-004240-30; www.clinicaltrialsregister.eu/ctr-search/trial/2019-004240-30/ES. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/37275.

Pathological and clinical relevance of selective recruitment of Langerhans cells in the respiratory bronchioles of smokers.

BACKGROUND: Smoking causes an influx of inflammatory cells including Langerhans cells (LCs) into the airways and lung parenchyma, thus inducing histological changes, such as emphysema and fibrosis. We examined the distribution and quantity of Langerhans cells in relation to clinical and pathological findings and explored the association between smoking and accumulation of Langerhans cells in the respiratory bronchioles. METHODS: Fifty-three patients who underwent lung resection for primary diseases, including lung cancer, were recruited. Histological and immunohistochemistry analyses were utilized to identify CD1a-positive Langerhans cells in peripheral lung specimens separated from primary lesions. Clinical characteristics, pathological changes, and distribution of CD1a-positive Langerhans cells distribution were assessed. RESULTS: Of the 53 patients, 35 were smokers and 18 were non-smokers. The number of Langerhans cells in the respiratory bronchioles was significantly increased in smokers as compared to that in non-smokers (p < 0.001). The number of Langerhans cells in smokers was significantly higher in patients with mild emphysema than in those without emphysema (p < 0.01). The high-LC group showed more frequent smoking-related histological changes, such as respiratory bronchiolitis, parenchymal fibrosis, accumulation of macrophages, and smoking-related interstitial fibrosis, than the low-LC group. However, there were no differences in the smoking indices and pulmonary functions of the groups. CONCLUSIONS: Selective accumulation of Langerhans cells in the respiratory bronchioles of smokers may lead to the development of smoking-related pathological changes.

Application of an evidence-based, out-patient treatment strategy for COVID-19: Multidisciplinary medical practice principles to prevent severe disease.

The COVID-19 pandemic has devastated individuals, families, and institutions throughout the world. Despite the breakneck speed of vaccine development, the human population remains at risk of further devastation. The decision to not become vaccinated, the protracted rollout of available vaccine, vaccine failure, mutational forms of the SARS virus, which may exhibit mounting resistance to our molecular strike at only one form of the viral family, and the rapid ability of the virus(es) to hitch a ride on our global transportation systems, means that we are will likely continue to confront an invisible, yet devastating foe. The enemy targets one of our human physiology's most important and vulnerable life-preserving body tissues, our broncho-alveolar gas exchange apparatus. Notwithstanding the fear and the fury of this microbe's potential to raise existential questions across the entire spectrum of human endeavor, the application of an early treatment intervention initiative may represent a crucial tool in our defensive strategy. This strategy is driven by evidence-based medical practice principles, those not likely to become antiquated, given the molecular diversity and mutational evolution of this very clever "world traveler".

Aberrant Epithelial Cell Proliferation in Peripheral Airways in Bronchiectasis.

Dilation of bronchi and bronchioles caused by destruction and excessive epithelial remodeling is a characteristic feature of bronchiectasis. It is not known how epithelial progenitor cells contribute to these pathologic conditions in peripheral airways (bronchioles) in bronchiectasis. We aimed to explore the expression levels of signature airway progenitor cells in the dilated bronchioles in patients with bronchiectasis. We obtained the surgically resected peripheral lung tissues from 43 patients with bronchiectasis and 33 control subjects. Immunostaining was performed to determine the expression patterns of thyroid transcription factor-1 (TTF-1, for labeling progenitor cells in distal airways), P63 (basal cells), club cell 10 kDa protein (CC10, club cells), and surfactant protein C (SPC, alveolar type II epithelial cells) in epithelium or sub-epithelium. Here, we reported significantly lower percentage of TTF-1+ cells and CC10+ cells, and higher percentage of P63+ cells within the epithelium of dilated bronchioles compared with control bronchioles. In airway sub-epithelium of the dilated bronchioles, epithelial hyperplasia with disarrangement of TTF-1+ cells yielded cuboidal (100%) and columnar (93.0%) type among bronchiectasis patients. Most progenitor cell markers co-localized with TTF-1. The median (the 1st, 3rd quartile) percentage of P63+TTF-1+, CC10+TTF-1+, and SPC+TTF-1+ cells was 16.0% (8.9, 24.0%), 14.5% (7.1, 20.8%), and 52% (40.3, 64.4%), respectively. For cuboidal epithelial hyperplasia, 91.0% (86.5, 94.0%) of areas co-stained with SPC and TTF-1. Columnar epithelial hyperplasia was characterized by TTF-1 co-staining with P63+TTF-1+ and CC10+TTF-1+ cells. Taken together, aberrant proliferation of airway progenitor cells in both epithelium and sub-epithelium are implicated in bronchiectasis.

Recent advances in the understanding of bronchiolitis in adults.

Bronchiolitis is injury to the bronchioles (small airways with a diameter of 2 mm or less) resulting in inflammation and/or fibrosis. Bronchioles can be involved in pathologic processes that involve predominantly the lung parenchyma or large airways, but, in some diseases, bronchioles are the main site of injury ("primary bronchiolitis"). Acute bronchiolitis caused by viruses is responsible for most cases of bronchiolitis in infants and children. In adults, however, there is a wide spectrum of bronchiolar disorders and most are chronic. Many forms of bronchiolitis have been described in the literature, and the terminology in this regard remains confusing. In clinical practice, a classification scheme based on the underlying histopathologic pattern (correlates with presenting radiologic abnormalities) facilitates the recognition of bronchiolitis and the search for the inciting cause of the lung injury. Respiratory bronchiolitis is the most common form of bronchiolitis in adults and is usually related to cigarette smoking. Currently, the diagnosis of respiratory bronchiolitis is generally achieved based on the clinical context (smoking history) and chest CT findings. Constrictive (obliterative) bronchiolitis is associated with airflow obstruction and is seen in various clinical contexts including environmental/occupational inhalation exposures, transplant recipients (bronchiolitis obliterans syndrome), and many others. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is increasingly recognized and can be associated with progressive airflow obstruction related to constrictive bronchiolitis ("DIPNECH syndrome"). Diffuse aspiration bronchiolitis is a form of aspiration-related lung disease that is often unsuspected and confused for interstitial lung disease. Novel forms of bronchiolitis have been described, including lymphocytic bronchiolitis and alveolar ductitis with emphysema recently described in employees at a manufacturing facility for industrial machines. Bronchiolitis is also a component of vaping-related lung injury encountered in the recent outbreak.

Relationship Between Expression of Interleukin-5 and Interleukin-13 by Epithelial Cells and Bronchiolar Changes in Pigs Infected with Mycoplasma hyopneumoniae.

Mycoplasma hyopneumoniae (Mh) is a bacterium that specifically infects the surface of bronchi and bronchioles of pigs without invading the host cells, and it is considered to be the primary agent of porcine enzootic pneumonia (PEN). The present study investigates the morphological and immunohistological changes induced in bronchiolar epithelium by Mh infection. Lungs from 20 pigs with naturally occurring Mh pneumonia were compared with those from 10 uninfected controls. Bronchiolar epithelial height, inflammatory infiltration, hyperplasia of bronchus-associated lymphoid tissue (BALT) and mucin subtype MUC5AC-producing cells significantly increased in all infected animals. Mh antigen was detected in association with the cilia of the bronchial and bronchiolar epithelium. Interleukin (IL)-5 and IL-13 were expressed consistently by epithelial and mononuclear cells of the airways of infected animals. The expression of these cytokines in the bronchial and bronchiolar tissues is related to the histological changes of PEN.

Small bronchiolar histopathological changes related to prolonged diabetes / Pequeños cambios histopatológicos bronquiolares relacionados con la diabetes prolongada

SUMMARY: Diabetes mellitus increases the risk of developing chronic obstructive pulmonary disease (COPD). The small bronchiole is a prominent site of airflow obstruction that causes increased airway resistance in patients with the COPD. Therefore, the histological and ultrastructural changes in small bronchioles in streptozotocin (STZ)-induced chronic diabetes were determined. Twenty-four weeks after STZ induction, rats were sacrificed, and the right and left lungs were collected for examination by light and electron microscopy. The alterations to the small bronchioles were the same in both lungs of these diabetic rats. The bronchiolar epithelial cells, both ciliated and secretory club cells, showed pyknotic nuclei and damaged cytoplasmic organelles. Increased thickening of the bronchiolar wall occurred in diabetic rats due to smooth muscle layer thickening, inflammatory cell infiltration, and increased numbers of myofibroblasts with collagen deposition.These results indicated that chronic diabetes caused extreme damage to small bronchioles, which may lead to chronic small airway obstruction and ultimately increase the likelihood of COPD progression. This basic knowledge provides a better understanding of the progression of pathogenesis in the small airways of patients with prolonged diabetes.

RESUMEN: La diabetes mellitus aumenta el riesgo de desarrollar enfermedad pulmonar obstructiva crónica (EPOC). El bronquiolo es un sitio prominente de obstrucción del flujo de aire que causa una mayor resistencia de las vías respiratorias en pacientes con EPOC. Por lo tanto, se determinaron los cambios histológicos y ultraestructurales en los bronquiolos en la diabetes crónica inducida por estreptozotocina (STZ). 24 semanas después de la inducción de STZ, se sacrificaron las ratas y se analizaron los pulmones derecho e izquierdo por microscopía óptica y electrónica. Las alteraciones de los pequeños bronquiolos fueron las mismas en ambos pulmones de estas ratas diabéticas. Las células epiteliales bronquiolares, tanto ciliadas como secretoras, mostraban núcleos picnóticos y orgánelos citoplasmáticos dañados. Se produjo un aumento del engrosamiento de la pared bronquiolar en ratas diabéticas debido al engrosamiento de la capa de músculo liso, infiltración de células inflamatorias y un mayor número de miofibroblastos con colágeno. Estos resultados indicaron que la diabetes crónica causaba daño extremo a los pequeños bronquiolos, lo que puede conducir a una obstrucción crónica de las vías respiratorias pequeñas y además aumentar la probabilidad de progresión de la EPOC. Esta información proporcionará un mejor conocimiento de la patogénesis en las vías respiratorias pequeñas de los pacientes con diabetes prolongada.

Target cell types with stem/progenitor function to isolate for in vitro reconstruction of human bronchiolar epithelia.

Recent advancement in research on stem/progenitor cells of respiratory organs is breathtaking, benefiting from the rapid development of technology to create transgenic mice. There is now a great deal of knowledge capable of direct translation from mice to humans. Nevertheless, one has to be careful, since there may be unexpected pitfalls. First of all, there are differences anatomically, histologically and ultrastructurally in the airway epithelia of the two species. In parallel with these structural differences, regionally specific cell types behave and function, particularly in regenerative instances, differently between the two species, at least to some extent. From the viewpoint of important human respiratory diseases, one of the most susceptible regions of the respiratory tract is the bronchiole. In our approach to develop in vitro systems utilizing human bronchiolar epithelial cells, we are currently leaning on the data obtained from mouse studies in spite of the above-mentioned species differences. With the help of such in vitro systems we should be able to investigate the damaging effects and mechanisms of environmental pollutants in the human respiratory epithelium and consequently achieve results useful for quantitative analyses of the impact on human respiratory health. While pursuing this goal, the mouse data have suggested that it should be worthwhile to pay close attention to the stem/progenitor cells contained in the human bronchiolar epithelia and eventually make use of them. The mouse data have further shown that these stem/progenitor cells possess a very close association with the immature and variant club cells and the neuroendocrine cells, and our own unpublished preliminary data with human cells are, apparently, at least partly consistent with what the mouse data are telling us.

Ozone-induced injury and oxidative stress in bronchiolar epithelium are associated with altered pulmonary mechanics.

In these studies, we analyzed the effects of ozone on bronchiolar epithelium. Exposure of rats to ozone (2 ppm, 3 h) resulted in rapid (within 3 h) and persistent (up to 72 h) histological changes in the bronchiolar epithelium, including hypercellularity, loss of cilia, and necrotizing bronchiolitis. Perivascular edema and vascular congestion were also evident, along with a decrease in Clara cell secretory protein in bronchoalveolar lavage, which was maximal 24 h post-exposure. Ozone also induced the appearance of 8-hydroxy-2'-deoxyguanosine, Ym1, and heme oxygenase-1 in the bronchiolar epithelium. This was associated with increased expression of cleaved caspase-9 and beclin-1, indicating initiation of apoptosis and autophagy. A rapid and persistent increase in galectin-3, a regulator of epithelial cell apoptosis, was also observed. Following ozone exposure (3-24 h), increased expression of cyclooxygenase-2, inducible nitric oxide synthase, and arginase-1 was noted in bronchiolar epithelium. Ozone-induced injury and oxidative stress in bronchiolar epithelium were linked to methacholine-induced alterations in pulmonary mechanics. Thus, significant increases in lung resistance and elastance, along with decreases in lung compliance and end tidal volume, were observed at higher doses of methacholine. This indicates that ozone causes an increase in effective stiffness of the lung as a consequence of changes in the conducting airways. Collectively, these studies demonstrate that bronchiolar epithelium is highly susceptible to injury and oxidative stress induced by acute exposure to ozone; moreover, this is accompanied by altered lung functioning.

Cigarette Smoke Extract-induced Reduction in Migration and Contraction in Normal Human Bronchial Smooth Muscle Cells.

The proliferation, migration, cytokine release, and contraction of airway smooth muscle cells are key events in the airway remodeling process that occur in lung disease such as asthma, chronic obstruction pulmonary disease, and cancer. These events can be modulated by a number of factors, including cigarette smoke extract (CSE). CSE-induced alterations in the viability, migration, and contractile abilities of normal human airway cells remain unclear. This study investigated the effect of CSE on cell viability, migration, tumor necrosis factor (TNF)-α secretion, and contraction in normal human bronchial smooth muscle cells (HBSMCs). Treatment of HBSMCs with 10% CSE induced cell death, and the death was accompanied by the generation of reactive oxygen species (ROS). CSE-induced cell death was reduced by N-acetyl-l-cysteine (NAC), an ROS scavenger. In addition, CSE reduced the migration ability of HBSMCs by 75%. The combination of NAC with CSE blocked the CSE-induced reduction of cell migration. However, CSE had no effect on TNF-α secretion and NF-κB activation. CSE induced an increase in intracellular Ca(2+) concentration in 64% of HBSMCs. CSE reduced the contractile ability of HBSMCs, and the ability was enhanced by NAC treatment. These results demonstrate that CSE treatment induces cell death and reduces migration and contraction by increasing ROS generation in normal HBSMCs. These results suggest that CSE may induce airway change through cell death and reduction in migration and contraction of normal HBSMCs.

Coxsackie-virus and adenovirus receptor expression in lung cancer bronchiole-alveolar carcinoma features and its significance / 中国肿瘤临床

Objective:This study aims to investigate the protein expression of coxsackie-virus and adenovirus receptor (CAR) in partial subtypes of pulmonary adeno-carcinoma, as well as its expression with clinico-pathological factors and prognosis. Methods:CAR expression was immunohistochemically assessed in 137 cases of lung cancer with bronchiole-alveolar carcinoma (PWBF) fea-tures, and analyzed in relation to various clinico-pathological parameters. All data were analyzed using SPSS statistics software, and Ka-plan-Meier survival curves were constructed. A Log-rank test was also conducted. Results: The CAR positive rates in PWBF, other types of lung cancer, and normal lung tissue were 71.5%, 50.0%, and 13.3%, respectively. The difference was statistically significant (P<0.05). In addition, a statistically significant difference was observed between the positive expression of CAR and other clini-co-pathologic parameters, such as pathological type and histological differentiation. No statistical significance was observed in other pa-rameters, such as gender, age, smoking, and tumor diameter. Patients with CAR positivity were characterized by longer survival times than the others;however, this difference did not reach statistical significance. Conclusion:CAR is related to the occurrence and devel-opment of lung cancer, especially PWBF. The higher expression of CAR in PWBF for gene therapy with adenovirus vectors opened a broader space. The conspicuous regulation of CAR may be reliable evidence and may bright future for the gene therapy of other types of lung cancer.

Cigarette Smoke Extract-induced Reduction in Migration and Contraction in Normal Human Bronchial Smooth Muscle Cells

The proliferation, migration, cytokine release, and contraction of airway smooth muscle cells are key events in the airway remodeling process that occur in lung disease such as asthma, chronic obstruction pulmonary disease, and cancer. These events can be modulated by a number of factors, including cigarette smoke extract (CSE). CSE-induced alterations in the viability, migration, and contractile abilities of normal human airway cells remain unclear. This study investigated the effect of CSE on cell viability, migration, tumor necrosis factor (TNF)-alpha secretion, and contraction in normal human bronchial smooth muscle cells (HBSMCs). Treatment of HBSMCs with 10% CSE induced cell death, and the death was accompanied by the generation of reactive oxygen species (ROS). CSE-induced cell death was reduced by N-acetyl-l-cysteine (NAC), an ROS scavenger. In addition, CSE reduced the migration ability of HBSMCs by 75%. The combination of NAC with CSE blocked the CSE-induced reduction of cell migration. However, CSE had no effect on TNF-alpha secretion and NF-kappaB activation. CSE induced an increase in intracellular Ca2+ concentration in 64% of HBSMCs. CSE reduced the contractile ability of HBSMCs, and the ability was enhanced by NAC treatment. These results demonstrate that CSE treatment induces cell death and reduces migration and contraction by increasing ROS generation in normal HBSMCs. These results suggest that CSE may induce airway change through cell death and reduction in migration and contraction of normal HBSMCs.

Bronchiole-alveolar Carcinoma-Analysis of 10 Autopsy Cases / 第三军医大学学报

Ten autopsy cases of bronchiole-alveolar carcinoma (BAC) were reported. Grossly, BAC may be divided into 3 types, i. e. finely nodular, coarsely nodular and diffuse type. Histologic pattern falls into 2 categories: ' (1) alveolar type, (2) papillary type. Metastasis is most frequently mediated through lymphatics, spreading to the regional lymph nodes. Next, they are spread by blood stream. Brain (meningeal carcinomatosis),bone and adrenal glands are the frequent metastasized sites. Pulmonary fibrosis and scar formation seem to be the predisposing factors to BAC.

Multiple Small Nodular Lung Lesions with Severe Dyspnea / 결핵

Diffuse panbronchiolitis is a chronic inflammatory lung disease of unknown etiology which is characterized by chronic airflow limitation and airway inflammation, predominantly localized in the respiratory bronchioles with infiltration of inflammatory cells, and has typical clinical, radiological and pathological features. Obstructive respiratory functional impairment, occasional symptoms of wheezing, and also cough and sputum resemble the feature of emphysema, bronchial asthma, or chronic bronchitis, respectively. We experienced a case of pathologically proven advanced diffuse panbronchiolitis in a 55-year-old man with productive cough and exertional dyspnea. The chest radiography showed multiple tiny nodular densities on whole lung fields. It was confirmed by thoracoscopy-guided lung biopsy and the patient was improved after initiation of treatment with low-dose erythromycin