Kiyohisa Sekizawa

Nrf2‐deficient mice are highly susceptible to cigarette smoke‐induced emphysema

Inflammation, protease/anti‐protease imbalance and oxidative stress play important roles in the pathogenesis of emphysema. Nrf2 counteracts oxidative tissue damage and inflammation through transcriptional activation via the anti‐oxidant responsive element (ARE). To clarify the protective role of Nrf2 in the development of emphysema, the susceptibility of Nrf2‐knockout mice to cigarette smoke (CS)‐induced emphysema was examined. In Nrf2‐knockout mice, emphysema was first observed at 8 weeks and exacerbated by 16 weeks following CS‐exposure, whereas no pathological abnormalities were observed in wild‐type mice. Neutrophilic lung inflammation and permeability lung damage were significantly enhanced in Nrf2‐knockout mice 8 weeks after CS‐exposure. Importantly, neutrophil elastase activity in bronchoalveolar lavage fluids was markedly higher in Nrf2‐knockout mice preceding the pronounced neutrophil accumulation. The expression of secretory leukoprotease inhibitor, a potent inhibitor of neutrophil elastase, was inducible in wild‐type, but not in Nrf2‐knockout mice. This protease/anti‐protease imbalance, together with the lack of inducible expression of ARE‐regulated anti‐oxidant/anti‐inflammatory genes, may explain the predisposition of Nrf2‐knockout mice to neutrophilic inflammation. Indeed, specific activators of Nrf2 induced the expression of the SLPI gene in macrophages. These results indicate that Nrf2 protects against the development of emphysema by regulating not only the oxidant/anti‐oxidant balance, but also inflammation and the protease/anti‐protease balance.

HIGH INCIDENCE OF ASPIRATION PNEUMONIA IN COMMUNITY‐ AND HOSPITAL‐ACQUIRED PNEUMONIA IN HOSPITALIZED PATIENTS: A MULTICENTER, PROSPECTIVE STUDY IN JAPAN

point that there is no high-level evidence of which vitamin D metabolites are safer and faster in normalizing sHPTH, and more importantly, the optimal dose of vitamin D3 capable of normalizing rapidly sHPTH is still being discussed and has not been established. In addition, a number of studies have demonstrated that the commonly used doses of vitamin D ( 800 UI daily), also suggested by the drug industry, may fail to normalize PTH levels in older adults with sHPTH. The choice of calcitriol in the experimental design of our study was based mainly on the need to use a treatment that could rapidly resolve sHPTH and on the lack of available preparation of vitamin D3 at high concentrations in Italy at the time of the study. In conclusion, although we agree with the statement that plain vitamin D is the treatment of choice for vitamin D deficiency, we disagree with the interpretation of the manuscript given by Dr. Vieth, because the goal of identifying a treatment of choice for sHPTH was outside the scope of our study, whose most relevant outcome consists instead of the observation that persistence of sHPTH reduces BMD response to alendronate. To respond to the issue raised by Dr. Vieth, RCTs are needed to assess the vitamin D metabolite of choice in normalizing PTH.

Effects of Rhinovirus Infection on the Adherence of Streptococcus pneumoniae to Cultured Human Airway Epithelial Cells

To examine the effects of rhinovirus (RV) infection on the adherence of Streptococcus pneumoniae to human tracheal epithelial cells, cells were infected with RV-14, and S. pneumoniae were added to the culture medium. The number of S. pneumoniae adhering to epithelial cells increased after RV infection. Y-24180, a specific inhibitor of the platelet-activating factor receptor (PAF-R); PAF; and the pyrrolidine derivative of dithiocarbamate, an inhibitor of transcription factor nuclear factor-kappaB (NF-kappaB), decreased the number of S. pneumoniae adhering to cells after RV-14 infection. RV-14 infection increased PAF-R expression and the activation of NF-kappaB and promoter-specific transcription factor 1. These findings suggest that RV-14 infection stimulates S. pneumoniae adhesion to airway epithelial cells via increases in PAF-Rs that are partly mediated through activation of transcription factors. Increased adherence of S. pneumoniae may be one of the reasons that pneumonia develops after RV infection.

Interstitial Pneumonia Developed in a Worker Dealing with Particles Containing Indium-tin Oxide

The use of indium compounds in the electronics and semiconductor industry has risen sharply from the 1990s, and indium demand increased to a record 335 tons in 2000 in Japan, which was about 5 times that in 1990 . Indium-tin oxide (ITO) is a sintered alloy containing a large portion of indium oxide and a small portion of tin oxide, and is used in the making of thin-film transistor liquid crystal displays (LCDs) for television screens, portable computer screens, cell phone displays and video monitors. Japan was the world’s largest consumer of indium, with three-fourths of it going for ITO coatings in 2000. More than one-half of the world’s indium consumption is for ITO coatings . Due to the increasingly frequent industrial use of ITO, the potential occupational exposure to this material has attracted much attention. Although there are no available data about the potential of ITO to induce lung damage in humans, pulmonary and testicular toxicity was reported recently when ITO was given to hamsters in intermittent intratracheal instillations . This is the first case history to our knowledge describing a man with interstitial pneumonia consistent with the inhalation of ITO particles.

Association of susceptibility to the development of lung adenocarcinoma with the heme oxygenase-1 gene promoter polymorphism.

Heme oxygenase-1 (HO-1) acts in cytoprotection against oxidants and aromatic hydrocarbons in cigarette smoke. A (GT)n dinucleotide repeat in the 5′-flanking region of the human HO-1 gene (alias HMOX1) reduces HO-1 inducibility and shows length polymorphism, which is grouped into three classes: class S (<27 GT), class M (27–32 GT), and class L (≥33 GT) alleles. To investigate the correlation between the HO-1 gene polymorphism and the development of lung adenocarcinoma, we screened 151 Japanese patients with lung adenocarcinoma and 153 control subjects. Patients and control subjects were frequency-matched by age, gender, smoking history and proportion of chronic pulmonary emphysema. The proportion of class L allele frequencies, as well as that of genotypic frequencies in L allele carriers (LL, LM, and LS), were significantly higher in patients with lung adenocarcinoma than those of control subjects. The adjusted odds ratio (OR) for lung adenocarcinoma with class L allele vs non-L allele (M+S) was 1.6 [95% confidence interval (CI) 1.0–2.5, P=0.03] and that with L allele carriers vs. non-L allele carriers was 1.8 (95% CI 1.1–3.0, P=0.02). Furthermore, the risk of lung adenocaricinoma for L allele carriers versus non-L allele carriers was much increased in the group of male smokers (OR=3.3, 95% CI 1.5–7.4, P=0.004). However, in the female non-smokers, the proportion of L allele carriers did not differ between patients and control subjects (OR=0.93, 95% CI 0.4–2.0, P=0.85). These findings suggest that the large size of a (GT)n repeat in the HO-1 gene promoter may be associated with the development of lung adenocarcinoma in Japanese male smokers.

Mechanisms of mucin production by rhinovirus infection in cultured human airway epithelial cells.

Mucus hypersecretion relates to exacerbations of bronchial asthma and chronic obstructive pulmonary disease (COPD) caused by rhinovirus (RV) infection. We examined the mechanisms of RV infection-induced mucin production in human tracheal surface epithelial cells and submucosal gland cells. RV14 up-regulated the mRNA expression of MUC2, MUC3, MUC5AC, MUC5B and MUC6, and increased MUC5AC and total mucin concentration in supernatants and lysates of the surface cells. An inhibitor of the nuclear factor kappaB caffeic acid phenylethyl ester, inhibitors of selective p44/42 mitogen-activated protein kinase-kinase PD98059 and U0126, and a selective Src inhibitor PP1 attenuated MUC5AC mRNA expression, and secretion and production of MUC5AC and total mucin glycoprotein in the surface cells. In the gland cells, RV14 also increased mRNA expression of MUC2, MUC5AC, MUC5B and MUC7, and the inhibitors attenuated the secretion of total mucin glycoprotein. Src-related p44/42 mitogen-activated protein kinase pathway may be associated with RV-induced mucin hypersecretion in human airways.

ACE inhibitors and protection against pneumonia in elderly patients with stroke

Pneumonia is the most common cause of death from nosocomial infection in the elderly. The increased incidence of pneumonia and the high mortality are consequences of a number of age-related factors, including coexisting illnesses, therapeutic interventions, and the aging process itself.1 Pneumonia has been estimated to occur in about one third of patients with stroke.2 The most important factor contributing to the risk of pneumonia in patients with stroke is suggested to be dysphagia with aspiration.1 Angiotensin-converting enzyme (ACE) inhibitors have been shown to improve silent aspiration3 and prevent pneumonia in elderly patients with stroke.4 However, little is known about whether ACE inhibitors have a beneficial role in reducing the risk of pneumonia as compared to other classes of antihypertensive drugs in elderly patients with stroke. Thus, we investigated whether ACE inhibitors can reduce the risk of pneumonia …

Effects of Rhinovirus Infection on Histamine and Cytokine Production by Cell Lines from Human Mast Cells and Basophils

To understand the biochemical events that occur in the airways after rhinovirus (RV) infection, we developed for the first time a model in which the cell lines from human mast cells (HMC-1) and basophils (KU812) can be infected with RV14, a major group RV. Viral infection was confirmed by demonstrating that viral titers in culture supernatants, and RV RNA increased with time. RV14 infection alone and a combination of PMA plus calcium ionophore A23187, did not increase histamine production by these cells, although IgE plus anti-IgE increased the histamine production. However, histamine content in the supernatants increased in response to PMA plus A23187, or IgE plus anti-IgE after RV14 infection. PMA plus A23187 or IgE plus anti-IgE induced the production of IL-8 and GM-CSF in supernatants of HMC-1 cells and IL-4 and IL-6 in supernatants of KU812 cells. RV14 infection further increased the production of the cytokines, whereas RV14 infection alone did not alter the production of the cytokines by these cells. An Ab to ICAM-1 inhibited RV14 infection of the cells and decreased the production of cytokines and histamine after RV14 infection. RV14 infection enhanced the increases in intracellular calcium concentration and activation of NF-κB by PMA plus A23187 in the cells. These findings suggest that RV14 infection may prime the cytokine and histamine production from mast cells and basophils and may cause airway inflammation in asthma.

Relation between exhaled carbon monoxide levels and clinical severity of asthma

Carbon monoxide (CO) can be detected in exhaled air and is increased in asthmatic patients not treated with corticosteroids. However, it is uncertain whether exhaled CO is related to severity of asthma.

Suppression of eosinophilic airway inflammation by treatment with α-galactosylceramide

To clarify the essential role of NKT cells in allergy, we investigated the contribution of NKT cells to the pathogenesis of eosinophilic airway inflammation using α‐galactosylceramide (α‐GalCer), a selective ligand for NKT cells. Although continuous administration of α‐GalCer during ovalbumin (OVA) sensitization increased OVA‐specific IgE levels and worsened eosinophil inflammation, a single administration of α‐GalCer at the time of OVA challenge completely prevented eosinophilic infiltration in wild‐type mice. This inhibitory effect of α‐GalCer was associated with a decrease in airway hyperresponsiveness, an increase in IFN‐γ, and decreases in IL‐4, IL‐5 and IL‐13 levels in the bronchoalveolar lavage fluids. Analysis of lung lymphocytes revealed that production of IFN‐γ increased in NK cells, but not in T or NKT cells, following α‐GalCer administration. Induction of vascular cell adhesion molecule‐1 in the lungs of wild‐type mice was also significantly attenuated by treatment with α‐GalCer. These effects of α‐GalCer were abrogated in Jα281–/– mice, which lack NKT cells, and in wild‐type mice treated with anti‐IFN‐γ Ab. Hence, our data indicate that α‐GalCer suppresses allergen‐induced eosinophilic airway inflammation, possibly by inducing a Th1 bias that results in inhibition of eosinophil adhesion to the lung vessels.