Mutsuo Yamaya

Interventions to Prevent Pneumonia Among Older Adults

Pneumonia is a common cause of death in older people. Antimicrobial drugs do not prevent pneumonia and, because of increasingly resistant organisms, their value in curing infection will become more limited. Establishing new strategies to prevent pneumonia through consideration of the mechanisms of this devastating illness is essential. The purpose of this review is to discuss how pneumonia develops in older people and to suggest preventive strategies that may reduce the incidence of pneumonia among older adults. Aspiration of oropharyngeal bacterial pathogens to the lower respiratory tract is one of the most important risk factors for pneumonia; impairments in swallowing and cough reflexes among older adults, e.g., related to cerebrovascular disease, increase the risk for the development of pneumonia. Thus, strategies to reduce the volumes and pathogenicity of aspirated material should be pursued. For example, since both swallowing and cough reflexes are mediated by endogenous substance P, pharmacologic therapy using angiotensin‐converting enzyme inhibitors, which decrease substance P catabolism, may improve both reflexes and result in the lowering of the risk of pneumonia. Similarly, since the production of substance P is regulated by dopaminergic neurons in the cerebral basal ganglia, treatment with dopamine analogs or potentiating drugs such as amantadine (and, of course, prevention of cerebral vascular disease, which can result in basal ganglia strokes) should affect the incidence of pneumonia. The purpose of this review is to consider promising pharmacologic treatments as methods of preventing pneumonia in older adults and to review other proven strategies, e.g., infection control and cerebrovascular disease prevention that will lessen the incidence of pneumonia.

Rhinovirus infection of primary cultures of human tracheal epithelium: role of ICAM-1 and IL-1β

Exacerbations of asthma are often associated with respiratory infection caused by rhinoviruses. To study the effects of rhinovirus infection on respiratory epithelium, a primary target for respiratory viruses, human rhinovirus (HRV)-2 and HRV-14 were infected to primary cultures of human tracheal epithelial cells. Viral infection was confirmed by showing that viral titers of supernatants and lysates from infected cells increased with time and by polymerase chain reaction. HRV-2 and HRV-14 infections upregulated the expression of intercellular adhesion molecule-1 (ICAM-1) mRNA, the major rhinovirus receptor, on epithelial cells, and they increased the production of interleukin (IL)-1β, IL-6, IL-8, and tumor necrosis factor (TNF)-α in supernatants. Antibodies to ICAM-1 inhibited HRV-14 infection of epithelial cells and decreased the production of cytokines after HRV-14 infection, but they did not alter HRV-2 infection-induced production of cytokines. IL-1β upregulated ICAM-1 mRNA expression and increased susceptibility to HRV-14 infection, whereas other cytokines failed to alter ICAM-1 mRNA expression. Furthermore, a neutralizing antibody to IL-1β significantly decreased viral titers of supernatants and ICAM-1 mRNA expression after HRV-14 infection, but a neutralizing antibody to TNF-α was without effect. Immunohistochemical studies revealed that both HRV-14 infection and IL-1β increased ICAM-1 expression on cultured epithelial cells. These findings imply that HRV-14 infection upregulated ICAM-1 expression on epithelial cells through increased production of IL-1β, thereby increasing susceptibility to infection. These events may be important for amplification of airway inflammation after viral infection in asthma.

Sleep Patterns and Mortality among Elderly Patients in a Geriatric Hospital

Background: Sleep disturbance is one of the major and unsolved problems in older people. Most of the previous sleep studies rely on self-reported documents, and memory disturbance in older people might bias sleep complaints and health status. Objective: Sleep disturbances were studied as a mortality risk. Methods: In 272 patients who were aged, infirmed and chronically institutionalized in a skilled-care geriatric hospital, the presence or absence of sleep disturbances were examined by hourly observations of patients over 2 weeks at baseline, and they were prospectively followed up for 2 years to assess mortality. Results: Mortality after 2 years was significantly higher in the nighttime insomnia, daytime sleepiness, and sleep-onset delay groups. Further, adjusted for age, gender and activities of daily living status, the presence of nighttime insomnia and sleep-onset delay remained associated with a higher risk of mortality. Conclusion: Sleep disturbance may be one of the symptoms indicating poor health or functional deficits, and be an independent risk factor for survival.

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.

Randomized Phase II Trial Comparing Nitroglycerin Plus Vinorelbine and Cisplatin With Vinorelbine and Cisplatin Alone in Previously Untreated Stage IIIB/IV Non–Small-Cell Lung Cancer

PURPOSE To investigate the efficacy and safety of nitroglycerin plus vinorelbine and cisplatin in patients with previously untreated stage IIIB/IV non-small-cell lung cancer (NSCLC) as the experimental arm for the next phase III trial. PATIENTS AND METHODS One hundred twenty patients with stage IIIB/IV NSCLC were randomly assigned to vinorelbine 25 mg/m2 on days 1 and 8 and cisplatin 80 mg/m2 on day 1, with transdermally applied nitroglycerin (25 mg/patient daily for 5 days; arm A) or with placebo patch (arm B) every 3 weeks for a maximum of four cycles in a double-blind and controlled trial. Primary efficacy end points were the best confirmed response rate and time to disease progression (TTP). RESULTS The response rate in arm A (72%; 43 of 60 patients) was significantly higher than that for patients in arm B (42%; 25 of 60 patients; P < .001). Median TTP in arm A was longer than that in arm B (327 v 185 days). No severe adverse effect was recognized for either arm. The rate of grade 1 to 2 headache in arm A (30%; 18 of 60 patients) was significantly higher than that in arm B (2%; one of 60 patients; P < .001, chi(2) test). CONCLUSION Use of nitroglycerin combined with vinorelbine and cisplatin may improve overall response and TTP in patients with stage IIIB/IV NSCLC. The arm A regimen is being evaluated in a large phase III trial.

Receptor for advanced glycation end products binds to phosphatidylserine and assists in the clearance of apoptotic cells

Clearance of apoptotic cells is necessary for tissue development, homeostasis and resolution of inflammation. The uptake of apoptotic cells is initiated by an ‘eat‐me’ signal, such as phosphatidylserine, on the cell surface and phagocytes recognize the signal by using specific receptors. In this study, we show that the soluble form of the receptor for advanced glycation end products (RAGE) binds to phosphatidylserine as well as to the apoptotic thymocytes. RAGE‐deficient (Rage−/−) alveolar macrophages showed impaired phagocytosis of apoptotic thymocytes and defective clearance of apoptotic neutrophils in Rage−/− mice. Our results indicate that RAGE functions as a phosphatidylserine receptor and assists in the clearance of apoptotic cells.

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.

Identification of Pendrin as a Common Mediator for Mucus Production in Bronchial Asthma and Chronic Obstructive Pulmonary Disease

Excessive production of airway mucus is a cardinal feature of bronchial asthma and chronic obstructive pulmonary disease (COPD) and contributes to morbidity and mortality in these diseases. IL-13, a Th2-type cytokine, is a central mediator in the pathogenesis of bronchial asthma, including mucus overproduction. Using a genome-wide search for genes induced in airway epithelial cells in response to IL-13, we identified pendrin encoded by the SLC26A4 (PDS) gene as a molecule responsible for airway mucus production. In both asthma and COPD mouse models, pendrin was up-regulated at the apical side of airway epithelial cells in association with mucus overproduction. Pendrin induced expression of MUC5AC, a major product of mucus in asthma and COPD, in airway epithelial cells. Finally, the enforced expression of pendrin in airway epithelial cells in vivo, using a Sendai virus vector, rapidly induced mucus overproduction in the lumens of the lungs together with neutrophilic infiltration in mice. These findings collectively suggest that pendrin can induce mucus production in airway epithelial cells and may be a therapeutic target candidate for bronchial asthma and COPD.

IL-28 Elicits Antitumor Responses against Murine Fibrosarcoma

IL-28 is a recently described antiviral cytokine. In this study, we investigated the biological effects of IL-28 on tumor growth to evaluate its antitumor activity. IL-28 or retroviral transduction of the IL-28 gene into MCA205 cells did not affect in vitro growth, whereas in vivo growth of MCA205IL-28 was markedly suppressed along with survival advantages when compared with that of controls. When the metastatic ability of IL-28-secreting MCA205 cells was compared with that of controls, the expression of IL-28 resulted in a potent inhibition of metastases formation in the lungs. IL-28-mediated suppression of tumor growth was mostly abolished in irradiated mice, indicating that irradiation-sensitive cells, presumably immune cells, are primarily involved in the IL-28-induced suppression of tumor growth. In vivo cell depletion experiments displayed that polymorphonuclear neutrophils, NK cells, and CD8 T cells, but not CD4 T cells, play an equal role in the IL-28-mediated inhibition of in vivo tumor growth. Consistent with these findings, inoculation of MCA205IL-28 into mice evoked enhanced IFN-γ production and cytotoxic T cell activity in spleen cells. Antitumor action of IL-28 is partially dependent on IFN-γ and is independent of IL-12, IL-17, and IL-23. IL-28 increased the total number of splenic NK cells in SCID mice and enhanced IL-12-induced IFN-γ production in vivo and expanded spleen cells in C57BL/6 mice. Moreover, IL-12 augmented IL-28-mediated antitumor activity in the presence or absence of IFN-γ. These findings indicate that IL-28 has bioactivities that induce innate and adaptive immune responses against tumors.

Nitroglycerin Treatment May Enhance Chemosensitivity to Docetaxel and Carboplatin in Patients with Lung Adenocarcinoma

Purpose: Nitroglycerin may improve the response to chemotherapy in advanced non–small cell lung cancer. The effects and mechanisms of nitroglycerin on the enhancement of chemosensitivity to docetaxel and carboplatin regimen (DCb) in patients with lung adenocarcinoma have not been reported. Experimental Design: Seventeen patients with operable lung adenocarcinoma and stable angina pectoris were selected to investigate the effects of nitroglycerin on immunoreactivity for hypoxia-inducible factor 1α (HIF-1α), vascular endothelial growth factor (VEGF), P-glycoprotein (P-gp), the production of which is regulated by HIF-1, and p53 proteins in their resected tumor by semiquantitative immunohistochemical analyses. Eight of 17 patients were treated with nitroglycerin patches before operation, but 9 of 17 patients were not. Furthermore, to study the relationship between changes in plasma VEGF levels by nitroglycerin treatment and response to DCb, 29 patients with advanced lung adenocarcinoma were treated with nitroglycerin for 3 days before chemotherapy using DCb. Results: The rates of immunoreactive cells for HIF-1α, VEGF, and P-gp in tumor tissues treated with nitroglycerin were lower than those without nitroglycerin, but those for p53 were not different between those treated with and without nitroglycerin. Furthermore, the rates of immunoreactive cells for VEGF and P-gp proteins were significantly associated with those for HIF-1α in tumor tissue. The magnitude of decrease in plasma VEGF levels after treatment with nitroglycerin was significantly associated with response to DCb in patients with advanced lung adenocarcinoma. Conclusions: Nitroglycerin treatment may improve response to DCb in patients with lung adenocarcinoma, partly through decreasing VEGF and P-gp production via reduction of HIF-1α.