Pulmonary emphysema is characterized by alveolar wall destruction and airspace enlargement. Recent evidence indicates that epithelial or endothelial apoptosis may be involved in the pathogenesis of emphysema. Here, we describe the induction of emphysematous changes, including airspace enlargement, alveolar wall destruction, and enhanced lung distensibility, in mice receiving a single intratracheal injection of active caspase-3 and Chariot, a newly developed protein transfection reagent. Epithelial apoptosis and enhanced elastolytic activity (optimal at pH 5.5) in bronchoalveolar lavage were noted. Emphysematous changes were also generated in mice receiving an intratracheal injection of nodularin, a proapoptotic serine/threonine kinase inhibitor. This murine model provides direct evidence that confirms that alveolar wall apoptosis causes emphysematous changes. Furthermore, this simple technique for protein transfection of lung tissue can be used in a variety of future applications.

No abstract

Cigarette smoking generates an oxidative stress in the lung, which may contribute to the pathogenesis of chronic obstructive pulmonary disease. We performed an immunohistochemical study to evaluate oxidative stress in the lung after acute cigarette smoke (CS) exposure in mice. Paraffin-embedded lung tissue sections were prepared from mice exposed and unexposed to CS for 1 h. The sections were immunostained with antibodies against 8-hydroxy-2'-deoxyguanosine (8-OHdG), an oxidative DNA adduct, and 4-hydroxy-2-nonenal (4-HNE), a lipid peroxidation product. The bronchiolar and alveolar epithelium of mice unexposed to CS exhibited weak signals for 8-OHdG and 4-HNE, whereas by 1 h after CS exposure the signals in the bronchiolar epithelial cells and the alveolar epithelial cells, particularly type II cells, had increased dramatically. The increases in both were associated with increased 8-OHdG levels in bronchoalveolar lavage fluid as determined by enzyme-linked immunoassay. These results suggest that acute CS exposure imposes oxidative stress predominantly on bronchiolar epithelial and alveolar type II cells, confirming that cigarette smoking causes oxidative damage to the respiratory epithelium.

Cigarette smoking generates an oxidative stress in the lung, which may contribute to the pathogenesis of chronic obstructive pulmonary disease. We performed an immunohistochemical study to evaluate oxidative stress in the lung after acute cigarette smoke (CS) exposure in mice. Paraffin-embedded lung tissue sections were prepared from mice exposed and unexposed to CS for 1 h. The sections were immunostained with antibodies against 8-hydroxy-2'-deoxyguanosine (8-OHdG), an oxidative DNA adduct, and 4-hydroxy-2-nonenal (4-HNE), a lipid peroxidation product. The bronchiolar and alveolar epithelium of mice unexposed to CS exhibited weak signals for 8-OHdG and 4-HNE, whereas by 1 h after CS exposure the signals in the bronchiolar epithelial cells and the alveolar epithelial cells, particularly type II cells, had increased dramatically. The increases in both were associated with increased 8-OHdG levels in bronchoalveolar lavage fluid as determined by enzyme-linked immunoassay. These results suggest that acute CS exposure imposes oxidative stress predominantly on bronchiolar epithelial and alveolar type II cells, confirming that cigarette smoking causes oxidative damage to the respiratory epithelium.

Cough variant asthma (CVA) is a common cause of chronic persistent cough, in which allergic airway inflammation may play a role. Although current guidelines recommend bronchodilators and anti-inflammatory drugs for the treatment, comparison of the efficacy of these medications has not been investigated. This study was designed to evaluate the effectiveness of pranlukast, a leukotriene receptor antagonist, and salmeterol, a long-acting beta₂-adrenergic agonist, in the treatment of CVA. The study was a randomized, controlled, parallel-group, multicenter trial. After a 4-week run-in period, 49 patients with newly diagnosed CVA were assigned to receive oral pranlukast (225 mg, b.i.d.) or inhaled salmeterol (100 μg, b.i.d.) for 4 weeks. Primary outcome measure was cough symptom and secondary outcome measures were pulmonary function and eosinophilic airway inflammation. Treatment with pranlukast and salmeterol each decreased cough symptom scores, where the changes from baseline values were significantly greater in the pranlukast group than in the salmeterol group. Forced expiratory volume in 1 second and peak expiratory flow (PEF) increased in the two treatment groups with the same magnitudes, but significant decreases in diurnal variation of PEF and eosinophil counts and eosinophil cationic protein contents in the peripheral blood and induced sputum were observed only in the pranlukast group. In view of antitussive and anti-inflammatory actions, the leukotriene receptor antagonist pranlukast seems to be more effective than the long-acting beta₂-adrenergic agonist salmeterol in the treatment of CVA.

Background: Recent studies have shown that T cells are the predominant cells infiltrating the alveolar wall of patients with emphysema. Since CD4+ and CD8+ cells have dissimilar function, they may have different distributions in emphysematous lungs. Objectives: The aim of this study was to investigate whether CD4+ and CD8+ are differently distributed in the lungs of patients with emphysema. Methods: We evaluated CD4+ and CD8+ cell infiltration in lung tissue sections obtained from smokers with pulmonary emphysema who had undergone lung volume reduction surgery (n = 10). Paraffin-embedded lung tissue sections were immunostained using antibodies against CD4+ or CD8+, and distributions of CD4+ and CD8+ cells were evaluated using a morphometric analysis. We determined the degree of emphysema using the area fraction of the alveolar wall (A_A,aw) and examined its relation to the number of cells per unit area of the alveolar wall (N_A). Results: The majority of CD4+ cells were located in the lung parenchyma of severe emphysematous lesions characterized by the lowest alveolar wall fraction (A_A,aw). In contrast, more CD8+ cells were located in mild emphysematous lesions than in severe lesions. Conclusions: These results suggest that CD4+ and CD8+ cells are differently distributed according to the severity of emphysema. CD4+ T cells are located preferentially in severe emphysematous lesions whereas CD8+ T cells occur preferentially in mild emphysematous lesions.

Common variable immunodeficiency (CVID) is a heterogeneous subset of immunodeficiency disorders. Recurrent bacterial infection is the main feature of CVID, but various non-infectious complications can occur. A 42-year-old woman presented with cough and abnormal chest X-ray shadows. Laboratory tests showed remarkable hypogammaglobulinemia. Computed tomography revealed multiple consolidation and nodules on the bilateral lung fields, systemic lymphadenopathy, and splenomegaly. A surgical lung biopsy specimen provided the final diagnosis of lymphoproliferative disease in CVID, which was grouped under the term granulomatous lymphocytic interstitial lung disease. Interestingly, the lung lesions of this case resolved immediately after the initiation of intravenous immunoglobulin monotherapy.

Background: Lung regeneration is an innovative strategy that may cure pulmonary emphysema. The bone marrow (BM) harbors pulmonary stem cells. Hematopoietic cytokine-driven mobilization of BM cells may thus support lung regeneration. Objectives: The aim of this study was to determine whether systemic administration of macrophage colony-stimulating factor (M-CSF) leads to the regeneration of lungs in a murine model of elastase-induced emphysema. Methods: C57BL/6J mice were administered elastase intratracheally. Four weeks later, in the absence or presence of elastase treatment, mice were intraperitoneally given either M-CSF or saline on days 1–5 each week for 3 weeks. Lung tissue was harvested 24 h after the last injection. Results: M-CSF administration without prior elastase did not affect the mean linear intercept, surface area, or surface area/lung volume. In contrast, M-CSF administration following elastase injury caused a greater increase in the mean linear intercept and greater decreases in surface area and surface area/lung volume than saline administration following elastase, indicating that M-CSF aggravated emphysema. This aggravation of emphysema was accompanied by accumulation of pulmonary alveolar macrophages (AMs) expressing metalloproteinase (MMP)-9 and MMP-12. M-CSF stimulated AMs to express MMPs in vitro. Conclusions: These results suggest that M-CSF administration does not support lung regeneration but rather aggravates the lung destruction associated with elastase injury.