Recurrent idiopathic pulmonary hemosiderosis after long-term remission presented with Sjogren's syndrome: Idiopathic no more?

We report a case of recurrent idiopathic pulmonary hemosiderosis after a long-term remission presented with Sjögren's syndrome. The patient was diagnosed with IPH due to repeated pneumonia and blood sputum in his childhood. He was admitted to our hospital due to exertional dyspnea and dry cough with bilateral ground-glass opacity in chest computed tomography at the age of 32. Video-assisted thoracoscopic surgery was performed and the specimens showed nonspecific interstitial pneumonia pattern with diffuse, chronic alveolar hemorrhage, suggesting recurrence of IPH. He was also diagnosed with Sjögren's syndrome. Further immunological studies will reveal the pathogenesis of IPH. Keywords: Idiopathic pulmonary hemosiderosis, Sjögren's syndrom

Depletion of club cells attenuates bleomycin-induced lung injury and fibrosis in mice

Abstract Background The role of bronchiolar epithelial cells in the pathogenesis of pulmonary fibrosis has not been clarified. We previously demonstrated DNA damage in murine bronchioles in the early stages of bleomycin-induced pulmonary fibrosis that subsequently extended to alveolar cells at the advanced stages of the disease. Club cells are progenitor cells for bronchioles and are known to play protective roles against lung inflammation and damage. The aim of the present study was to elucidate the role of club cells in the development of pulmonary fibrosis. Methods C57BL/6 J mice received naphthalene intraperitoneally on day −2 to deplete club cells and were given intratracheal bleomycin or a vehicle on day 0. Lung tissues were obtained on days 1, 7, and 14, and bronchoalveolar lavage was performed on day 14. Bronchiolar epithelial cells sampled by laser capture microdissection were analyzed by gene expression microarray analysis on day 14. Results Club cell depletion induced by naphthalene protected mice from bleomycin-induced lung injury and fibrosis. Bleomycin-triggered bronchiolar TGF-β1 expression was reduced. Gene expression microarray analysis revealed that genes associated with inflammatory response and chemokine activity were downregulated in the bleomycin-injured bronchiolar epithelium with club cell injury compared to that in bronchiolar epithelium without cell injury. Conclusions Club cells are involved in the development of lung injury and fibrosis

Bax-inhibiting peptide attenuates bleomycin-induced lung injury in mice

Bax is a pro-apoptotic member of the Bcl-2 family of proteins, and plays a central role in mitochondria-dependent apoptosis. Several lines of evidence have implied that Bax is involved in both epithelial apoptosis and fibroblast proliferation in idiopathic pulmonary fibrosis; however, the mechanisms remain unknown. Bax-inhibiting peptide V5 (BIP-V5) exhibits membrane permeability and inhibits the activation of Bax. The purpose of this study was to investigate whether the control of Bax activity by BIP-V5 reduces the degree of bleomycin-induced lung injury. C57BL/6J mice were administered bleomycin and BIP-V5 intratracheally on day 0. Bronchoalveolar lavage fluid and lung tissue were obtained on day 7. Human pulmonary alveolar epithelial cells (A549 cells) and mouse pulmonary alveolar epithelial cells (LA-4 cells) were stimulated with bleomycin to induce apoptosis. Administration of BIP-V5 improved the survival rate and degree of bleomycin-induced lung injury by suppressing Bax activation in mice. BIP-V5 treatment decreased bleomycin-induced apoptosis of alveolar epithelial cell lines (A549 cells and LA-4 cells) by suppressing Bax activation. These results indicate that administration of BIP-V5 may constitute a novel therapeutic strategy against lung injury

Probucol attenuates hyperoxia-induced lung injury in mice

<div><p>Hyperoxic lung injury is pathologically characterized by alveolar edema, interlobular septal edema, hyaline membrane disease, lung inflammation, and alveolar hemorrhage. Although the precise mechanism by which hyperoxia causes lung injury is not well defined, oxidative stress, epithelial cell death, and proinflammatory cytokines are thought to be involved. Probucol—a commercially available drug for treating hypercholesterolemia—has been suggested to have antioxidant and antiapoptotic effects. This study aimed to assess whether probucol could attenuate hyperoxic lung injury in mice. Mice were exposed to 95% O₂ for 72 h, with or without pre-treatment with 130 μg/kg probucol intratracheally. Probucol treatment significantly decreased both the number of inflammatory cells in the bronchoalveolar lavage fluid and the degree of lung injury in hyperoxia-exposed mice. Probucol treatment reduced the number of cells positive for 8-hydroxyl-2′-deoxyguanosine or terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and suppressed NF-κB activation, Bax expression, and caspase-9 activation in lung tissues from hyperoxia-exposed mice. These results suggest that probucol can reduce oxidative DNA damage, apoptotic cell death, and inflammation in lung tissues. Intratracheal administration of probucol may be a novel treatment for lung diseases induced by oxidative stress, such as hyperoxic lung injury and acute respiratory distress syndrome.</p></div

Probucol ameliorates apoptosis in hyperoxic lung injury.

<p>(A-D) The effect of probucol on TUNEL staining. (A) No positive signals for TUNEL were observed in lung tissues of room-air-exposed mice treated with probucol. (B) There were some TUNEL-positive cells (arrows in F) in the lung tissues of hyperoxia-exposed mice. (C) Probucol treatment decreased the number of TUNEL-positive cells in hyperoxia-exposed mice. (D) Quantitative result of the number of TUNEL-positive cells in lung tissues. Original magnifications: ×200. Data are shown as the mean ± SEM from four mice in each group. **<i>p</i> < 0.01.</p

Effect of probucol on BALF and the histological findings in hyperoxic lung injury.

<p>(A) The results of cell count and level of IL-6 in BALF. Each bar shows mean ± SEM of the ten mice in each group. (B-E) Hematoxylin and eosin staining. In room-air-exposed mice without probucol treatment (B) and room-air-exposed mice treated with probucol (C), no abnormalities were observed. In the lung tissue of hyperoxia-exposed mice without probucol treatment (D), invasion of inflammatory cells, pulmonary edema, and alveolar hemorrhage were observed. In hyperoxia-exposed mice treated with probucol (E), those findings were improved. In the pathological grading, each circle corresponds to one mouse (F). Original magnifications: ×200. **<i>P</i> < 0.01, *<i>p</i> < 0.05.</p

Western blot analysis for p47^phox, phospho-ERK1/2, NF-κB (p65), Bcl-X_L, Bax (6A7), cleaved caspase-9, and β-tubulin.

<p>(A) Each lane corresponds to the data from one mouse. (B) Relative band intensities from western blot analysis. Optical density values for each individual band were normalized to β-tubulin expression from the same tissue. Data are means ± SEM from three mice. **<i>p</i> < 0.01.</p

Probucol treatment increases Bcl-X_L expression in the lung tissues.

<p>(A) There was no detectable expression of Bcl-X_L in room-air-exposed mice (A). In both room-air-exposed mice and hyperoxia-exposed mice, probucol treatment increased Bcl-X_L expression in lung epithelial cells (B, D). In hyperoxia-exposed mice without probucol treatment, there was a low-level expression of Bcl-X_L (C). Original magnifications: ×200.</p

Probucol ameliorates oxidative stress and apoptosis in hyperoxic lung injury.

<p>(A-D) The results of immunohistochemistry for 8-OHdG. (A) In room-air-exposed mice treated with probucol, expression of 8-OHdG was not detected. (B) In hyperoxia-exposed mice without probucol treatment, 8-OHdG was strongly expressed in nuclei of lung epithelial cells due to the tissue damage. (C) In hyperoxia-exposed mice treated with probucol, signal of 8-OHdG was decreased. (D) The immunostaining grade for 8-OHdG was significantly decreased by probucol treatment. Original magnifications: ×200. Data are shown as the mean ± SEM from four mice in each group. (E) Western blot analysis for p47^phox. Each lane corresponds to the data from one mouse. (F) Relative band intensities from western blot analysis. Optical density values for each individual band were normalized to β-tubulin expression from the same tissue. Data are means ± SEM from three mice. **<i>p</i> < 0.01.</p