Aging enhances susceptibility to cigarette smoke-induced inflammation through bronchiolar chemokines.

Cigarette smoking and aging are major risk factors for chronic obstructive pulmonary disease. An unsolved question is whether elderly lungs are particularly vulnerable to cigarette smoke (CS) exposure. In this study, we used a mouse model to test the hypothesis that aging increases the susceptibility to CS-induced pulmonary inflammation. We subjected 9-week-old and 69-week-old C57BL/6J mice to CS (whole-body exposure, 90 min/d), and evaluated neutrophil infiltration in the lungs, the levels of keratinocyte-derived chemokine (KC) and macrophage inflammatory protein (MIP)-2 in bronchoalveolar lavage fluid, and mRNA expression in bronchiolar epithelium retrieved by laser capture microdissection. The 69-week-old mice showed a greater number of neutrophils and higher levels of bronchiolar KC and MIP-2 expression than 9-week-old mice after 9 days of CS exposure. Furthermore, single CS exposure induced the rapid up-regulation of KC and MIP-2 in bronchiolar epithelium in both 9-week-old and 69-week-old mice, and the much higher levels in 69-week-old mice were associated with greater nuclear translocation of NF-kappaB. In contrast, no age-related differences were observed in the bronchiolar expression of NF-E2-related factor 2-regulated antioxidant and detoxification genes, heme oxygenase-1, reduced nicotinamide adenine dinucleotide phosphate quinone reductase 1, and glutamate-cysteine ligase, modifier unit, or antioxidant activity in bronchoalveolar lavage fluid, regardless of CS exposure. In summary, aging increases susceptibility to CS-induced inflammation in a mouse model, and robust mRNA up-regulation and nuclear translocation of NF-kappaB in bronchiolar epithelium may be involved.

The role of catalase in pulmonary fibrosis.

BACKGROUND: Catalase is preferentially expressed in bronchiolar and alveolar epithelial cells, and acts as an endogenous antioxidant enzyme in normal lungs. We thus postulated epithelial damage would be associated with a functional deficiency of catalase during the development of lung fibrosis. METHODS: The present study evaluates the expression of catalase mRNA and protein in human interstitial pneumonias and in mouse bleomycin-induced lung injury. We examined the degree of bleomycin-induced inflammation and fibrosis in the mice with lowered catalase activity. RESULTS: In humans, catalase was decreased at the levels of activity, protein content and mRNA expression in fibrotic lungs (n = 12) compared to control lungs (n = 10). Immunohistochemistry revealed a decrease in catalase in bronchiolar epithelium and abnormal re-epithelialization in fibrotic areas. In C57BL/6J mice, catalase activity was suppressed along with downregulation of catalase mRNA in whole lung homogenates after bleomycin administration. In acatalasemic mice, neutrophilic inflammation was prolonged until 14 days, and there was a higher degree of lung fibrosis in association with a higher level of transforming growth factor-ß expression and total collagen content following bleomycin treatment compared to wild-type mice. CONCLUSIONS: Taken together, these findings demonstrate diminished catalase expression and activity in human pulmonary fibrosis and suggest the protective role of catalase against bleomycin-induced inflammation and subsequent fibrosis.

[Clinical analysis of home oxygen therapy in patients with pneumoconiosis at Iwamizawa Rosai Hospital].

Although home oxygen therapy (HOT) has become one of the standard therapies in the management of chronic respiratory failure, especially for patient with hypoxia, there are very few studies about HOT in patients with pneumoconiosis. Therefore, we clinically investigated the characteristics of 97 patients with pneumoconiosis and 30 patients with COPD on home oxygen therapy (HOT) followed at Iwamizawa Rosai Hospital during the period from 1990 to 2003. The mean survival time in patients with pneumoconiosis (42 months) by the Kaplan-Meier method was shorter than in patents with COPD (75 months). Among the patients with pneumoconiosis divided by chest radiography classification of pneumoconiosis, there was no significant difference in mean survival time. The survival time in pneumoconiosis patients with dyspnea grade IV was shorter than in patients with dyspnea grade III.

Aging affects lipopolysaccharide-induced upregulation of heme oxygenase-1 in the lungs and alveolar macrophages.

Lung injuries are generally more serious and cause high mortality in aged humans and animals. Heme oxygenase-1 (HO-1) is known to be readily inducible in alveolar macrophages (AMs) and airway epithelial cells to confer cytoprotection against oxidative stress. We thus investigated whether aging impairs the stress-induced upregulation of HO-1. In this study, we first quantified basal levels of HO-1 expression in lungs from male ICR mice of various ages. Second, young (9-11 weeks) and old (65-66 weeks) mice were subjected to intratracheal administration of lipopolysaccharide (LPS) and expression of HO-1 in the lungs was quantified at 2, 24 and 72 h. HO-1 expression in bronchiolar epithelial cells harvested by laser capture microdissection (LCM) was also specifically quantified in the two age groups. Third, we examined HO-1 expression in AMs lavaged from 22-week-old and 86-96-week-old male ICR mice in response to LPS for 24 h in vitro. We found that basal expression of HO-1 in the lungs did not differ with age. LPS-induced HO-1 upregulation was significantly impaired in the lungs of 65-66-week-old mice than in 9-11-week-old mice at 2 and 24 h, although there were no differences in the magnitude of HO-1 upregulation in bronchiolar epithelium at 2 h. LPS-induced upregulation of HO-1 was observed in AMs from 22-week-old mice (1.8-fold), but not in AMs from 86-96-week-old mice in vitro. In summary, we demonstrated age-related defects in HO-1 induction in the whole lungs and in AMs in response to LPS.

Curcumin attenuates elastase- and cigarette smoke-induced pulmonary emphysema in mice.

Curcumin, a yellow pigment obtained from turmeric (Curcumina longa), is a dietary polyphenol that has been reported to possess anti-inflammatory and antioxidant properties. The effect of curcumin against the development of pulmonary emphysema in animal models is unknown. The aim of this study was to determine whether curcumin is able to attenuate the development of pulmonary emphysema in mice. Nine-week-old male C57BL/6J mice were treated with intratracheal porcine pancreatic elastase (PPE) or exposed to mainstream cigarette smoke (CS) (60 min/day for 10 consecutive days or 5 days/wk for 12 wk) to induce pulmonary inflammation and emphysema. Curcumin (100 mg/kg) or vehicle was administrated daily by oral gavage 1 h and 24 h before intratracheal PPE treatment and daily thereafter throughout a 21-day period in PPE-exposed mice and 1 h before each CS exposure in CS-exposed mice. As a result, curcumin treatment significantly inhibited PPE-induced increase of neutrophils in bronchoalveolar lavage fluid at 6 h and on day 1 after PPE administration, with an increase in antioxidant gene expression at 6 h and significantly attenuated PPE-induced air space enlargement on day 21. It was also found that curcumin treatment significantly inhibited CS-induced increase of neutrophils and macrophages in bronchoalveolar lavage fluid after 10 consecutive days of CS exposure and significantly attenuated CS-induced air space enlargement after 12 wk of CS exposure. In conclusion, oral curcumin administration attenuated PPE- and CS-induced pulmonary inflammation and emphysema in mice.