Genetic polymorphisms of paraoxonase-1 are associated with chronic kidney disease in Japanese women.

Paraoxonase-1 (PON1) is an HDL cholesterol-associated antioxidant enzyme, and some of its polymorphisms are linked with systemic oxidative stress and cardiovascular events. In this study, we genotyped seven single nucleotide polymorphisms (SNPs) within the PON1 gene and determined their association with chronic kidney disease in 2,968 individuals from the general Japanese population. We found that a missense SNP (rs662) with a G-to-A substitution leading to an amino acid substitution (G[Arg]/A[Gln]), was significantly associated with albuminuria and estimated glomerular filtration rate (eGFR), especially in women. The A/A genotype in women had the highest prevalence of albuminuria and the lowest values of adjusted eGFR. In contrast, such relationships were not detected in men. Multivariate regression analysis found that the A/A genotype was an independent and significant factor for albuminuria and renal insufficiency (eGFR less than 60 ml/min/1.73 m(2)). The serum PON1 activity was lowest in subjects with the A/A genotype. In biopsy specimens, immunohistochemical analysis found increased PON1 expression on the endothelial surface of sclerotic renal arterioles and glomerular capillaries in patients with hypertension or diabetes. Our study shows that this PON1 G-to-A substitution may be a key player in a common pathway to chronic kidney and cardiovascular diseases in women.

A novel polymorphism in CDC6 is associated with the decline in lung function of ex-smokers in COPD.

The effect of smoking cessation on the rate of decline in lung function in patients with advanced stages of chronic obstructive pulmonary disease (COPD) has not been clarified. Saccharomyces cerevisiae cell division cycle 6 homolog (CDC6) protein possesses the pro-apoptotic properties. We tested our hypothesis that the individual susceptibility to rapid decline in lung function despite smoking cessation in patients with advanced stages of COPD is attributed to the genetic variants in the CDC6 gene. We prospectively followed 82 patients (ex-smokers) during 30months and evaluated the differences among the genotypes in the annual rate of decline in FEV(1.0) (%predicted) with ten single nucleotide polymorphisms (SNPs) in and around the CDC6 gene. We found significant differences in SNP5 (National Center for Biotechnology Information SNP reference: rs2077464), SNP6 (rs13706), SNP7 (rs7217852), and SNP8 (rs9904270) with a gene-dosage effect (ANOVA overall-P=0.029-0.030). The individual allele of SNP5G, SNP6A, SNP7G, and SNP8T were associated with rapid decline in FEV(1.0) (%predicted) [odds ratio (95% confidence interval)=2.35 (1.19-4.65), P=0.014]. The SNP5G/SNP6A/SNP7G/SNP8T haplotype was associated with an increased risk of deterioration of FEV(1.0) (%predicted) (P=0.017). Importantly, SNP6 caused a change in amino acids in CDC6 protein (Val441Ile), immediately upstream of the caspase-3-dependent cleavage site of CDC6 (Asp442) during apoptosis. These results suggest that CDC6 may be one of the susceptibility genes that contribute to rapid decline in lung function despite smoking cessation in these patients with COPD.

Gly80Ser polymorphism of phospholipase A2-IID is associated with cytokine inducibility in A549 cells.

BACKGROUND: The Gly80Ser polymorphism in phospholipase A2-IID (PLA2G2D, NCBI SNP reference: rs584367) is associated with a loss in body weight in patients with chronic obstructive pulmonary disease (COPD). The T allele missense mutation results in the 80th amino acid of the PLA2G2D protein changing from a glycine (Gly; C allele) to a serine (Ser; T allele). COPD patients carrying Ser lose a significant amount of weight compared with those carrying Gly. The mechanism for this weight loss following carriage of this Ser allele has not been clarified. OBJECTIVES: We aimed to evaluate whether this allelic change alters PLA2 enzymatic activity and/or pro-inflammatory cytokine inducibility. METHODS: A549 cells (a human pulmonary epithelial cell line) were transfected with PLA2G2D-Gly or PLA2G2D-Ser. We evaluated PLA2 activity and cytokine expressions in these cells. RESULTS: The enzymatic activity of sPLA2 in A549-PLA2G2D-Ser cells did not differ from the A549-PLA2G2D-Gly cells. A549-PLA2G2D-Ser cells spontaneously produced higher levels of interleukin (IL)-6 and IL-8 than A549-PLA2G2D-Gly cells. Upon tumor necrosis factor-alpha stimulation, IL-6 and IL-8 mRNA and protein levels in A549-PLA2G2D-Ser cells were elevated compared with those of A549-PLA2G2D-Gly cells. Upon hydrogen peroxide stimulation, IL-8 mRNA and protein levels in A549-PLA2G2D-Ser cells were higher than those of A549-PLA2G2D-Gly cells. CONCLUSIONS: PLA2G2D-Ser enhances the expression of IL-6 and IL-8 compared with PLA2G2D-Gly. This enhanced cytokine expression observed with the allelic change in PLA2G2D may be associated with the body weight loss seen in COPD patients.

Enhanced immediate inflammatory response to Streptococcus pneumoniae in the lungs of mice with pulmonary emphysema.

BACKGROUND AND OBJECTIVE: Pulmonary emphysema is associated with frequent respiratory infections but little is known about the reasons for this susceptibility to bacterial infection. We previously demonstrated an impaired inflammatory response to Streptococcus pneumoniae in an experimental emphysema mouse model at 24 h, or longer following bacterial inoculation. Toll-like receptors (TLR) have been recognized as regulators in the inflammatory response. We examined the expression of TLR on alveolar macrophages in experimental emphysema mice and evaluated the immediate inflammatory response of the emphysematous lung to streptococcal infection. METHODS: Elastase was administered once into mice trachea to induce pulmonary emphysema. Three weeks later, expression of TLR-2 and TLR-4 in the BAL cells was examined by immunostaining. Following the intratracheal inoculation of Streptococcus pneumoniae, pro-inflammatory cytokine concentrations were measured in the BAL fluids of the control and emphysema mice. RESULTS: The expression of TLR-2 and TLR-4 was significantly elevated in the alveolar macrophages of emphysema mice. Six hours after infection, neutrophils in the BAL fluid of emphysema mice were significantly increased, and the levels of tumour necrosis factor-alpha, IL-1beta and IL-6 were significantly elevated, compared with the control mice. At 3 h post inoculation, macrophage inflammatory protein-2 levels were significantly elevated. CONCLUSIONS: The immediate inflammatory response in the emphysematous lung is significantly enhanced in response to streptococcal infection. This may be partly attributed to the increased expression of TLR in the alveolar macrophages of emphysema mice.

Altered expression of antimicrobial molecules in cigarette smoke-exposed emphysematous mice lungs.

BACKGROUND AND OBJECTIVE: The natural history of COPD, a disease usually caused by cigarette smoking, is associated with frequent respiratory infections. Consistent with human COPD, bacterial clearance in the lungs has been reported to be impaired in mice exposed to cigarette smoke. In the airways, several antimicrobial molecules such as surfactant proteins (SP), beta-defensins (BD), secretory leucocyte protease inhibitor (SLPI) and lysozyme play important roles in the defence against invading pathogens. This study evaluated the expression of antimicrobial molecules in mice lungs with cigarette smoke-induced emphysematous changes. METHODS: Six B6C3F1 mice were exposed to cigarette smoke (2 cigarettes/day/mouse for 6 months) or room air. Gene expression within the lungs of mice in both groups was assessed by RT-PCR. RESULTS: The expression of SP-A, BD2, BD3 and SLPI was significantly elevated in the lungs of cigarette smoke-exposed mice compared with air-exposed mice. BD1 expression decreased in the smoke-exposed mice and lysozyme expression was unchanged. CONCLUSIONS: Chronic cigarette smoke exposure did not suppress the expression of antimicrobial molecules in the lung. Altered expression of antimicrobial molecules in this mouse model does not explain the impaired host defence against respiratory microbes seen in patients with COPD.

A nonfunctioning single nucleotide polymorphism in olfactory receptor gene family is associated with the forced expiratory volume in the first second/the forced vital capacity values of pulmonary function test in a Japanese population.

The forced expiratory volume in the first second (FEV1.0)/the forced vital capacity (FVC) is an important index of a single forced expiration. Ectopic expression of the human olfactory receptor (OR) gene family in the lungs has suggested its potential involvement of respiratory physiology. We hypothesized that the individual variability of FEV1.0/FVC value may be attributed to the genetic variance of the OR gene family caused by the nonfunctioning SNPs (nSNPs). We conducted quantitative trait locus (QTL) analyses of population having the 7 OR gene nSNPs and FEV1.0/FVC values by ANOVA, in 2970 samples in the Yamagata Takahata cohort. We found significant association of one nSNP [rs10838851, OR, family 4, subfamily X, member 1 (OR4X1) gene, Tyr273Ter*] with FEV1.0/FVC (%) (P = 0.008). The FEV1.0/FVC value (%) of population having OR4X1 gene nSNP Ter*/Ter*, Ter*/Tyr, and Tyr/Tyr were 78.9 +/- 0.2, 78.2 +/- 0.2, and 77.7 +/- 0.4, respectively. Haplotype-based analysis of the OR4X1 gene with FEV1.0/FVC values demonstrated that two exclusive haplotypes [Hap-1/Hap-2 (frequency 0.669/0.330): SNP1 (rs7106648)T/A-SNP2 (rs871249)G/A-SNP3 (rs713325)G/A-SNP4 (rs10838851)A (Ter*)/T (Tyr)-SNP5 (rs4752923)G/A-SNP6 (rs960640)G/A] were significantly associated with FEV1.0/FVC values (global P = 0.005). These results suggest that OR4X1 may be one of the genes that contribute to the individual variability of FEV1.0/FVC value in pulmonary function test.

Heart-type fatty acid-binding protein is more sensitive than troponin T to detect the ongoing myocardial damage in chronic heart failure patients.

BACKGROUND: Heart-type fatty acid-binding protein (H-FABP) is a small cytosolic protein and released into the circulation when the myocardium is injured. Previous studies have demonstrated that both H-FABP and troponin T (TnT) are detectable in venous blood samples in chronic heart failure (CHF) patients, suggesting the presence of ongoing myocardial damage (OMD). We hypothesized that a cytosolic marker (H-FABP) is more sensitive than a myofibrillar component (TnT) in the detection of OMD in CHF. METHODS AND RESULTS: We measured serum H-FABP and TnT levels in 126 consecutive CHF patients at admission, and patients were followed-up with a mean period of 474 +/- 328 days. Cutoff values for H-FABP (4.3 ng/mL) and TnT (0.01 ng/mL) were determined from previous studies. Positive rate of H-FABP was higher than that of TnT in all CHF patients (46% [58/126] versus 26% [33/126], P < .0001), and in severe CHF (New York Heart Association III/IV) patients (69% [34/49] versus 47% [23/49], P = .0121). There were 27 cardiac events during a follow-up period. In patients with cardiac events, H-FABP was more frequently detected than TnT (88% [24/27] versus 44% [12/27], P = .0103). There were 33 patients with positive H-FABP among 93 patients with negative TnT. Those patients had more severe New York Heart Association class, higher levels of brain natriuretic peptide, and higher rates of cardiac events (36% versus 5%, P < .0001) compared with those both H-FABP and TnT were negative. Kaplan-Meier analysis demonstrated that in patients with negative TnT, positive H-FABP group had higher risk for cardiac events than negative H-FABP group (P < .0001). A multivariate analysis with Cox proportional hazard model showed that H-FABP was the only independent predictor of cardiac events (hazard ratio 15.677, P = .0001). The area under the receiver operating characteristic curve was larger for H-FABP than for TnT (0.779 versus 0.581; P = .009), suggesting that H-FABP had greater predictive capacity for cardiac events than TnT. CONCLUSIONS: H-FABP was more sensitive to detect OMD and could identify patients at high risk more effectively than TnT.

Clarithromycin suppresses invasiveness of human lung adenocarcinoma cells.

BACKGROUND: It has been speculated that clarithromycin (CAM), a 14-membered ring macrolide, possesses antitumor effects besides antimicrobial and anti-inflammatory effects. METHOD: We evaluated the effects of CAM on the growth and invasiveness of A549 lung adenocarcinoma cells. RESULTS: Although CAM did not affect the growth of A549 cells, the Matrigel invasion assay showed that the potential of invasion was diminished by CAM treatment. When analyzed by flow cytometry, CAM suppressed alpha(2)- and beta(1)-integrin expression. Furthermore, thymidine phosphorylase (TP) expression was diminished by CAM treatment in a dose-dependent manner. A specific TP inhibitor also suppressed beta(1)-integrin expression in flow cytometric analysis. CONCLUSIONS: These results suggest that CAM may suppress invasive activity of A549 cells in part by diminishing the expression of TP, alpha(2)- and beta(1)-integrin, which may be a downstream signal of the TP pathway, and that CAM could be useful in the treatment of lung adenocarcinoma.

Impaired systemic cell-mediated immunity and increased susceptibility to acute respiratory tract infections in patients with COPD.

Although it has been reported that chronic obstructive pulmonary disease (COPD) is frequently associated with systemic immune disturbances, negative impact of these disturbances on the increased prevalence of acute respiratory tract infections (aRTIs) has remained unclear. We evaluated circulating levels of interferon-gamma (IFN-gamma), soluble interleukin-2 receptor (sIL-2R), neopterin, and soluble intercellular adhesion molecule-1 (sICAM-1) in 35 clinically stable patients with COPD and in 22 age-matched healthy controls, since these molecules are considered to reflect the in vivo status of systemic cell-mediated immunity (CMI). We found that circulating levels of sIL-2R (1.52+/-1.25 vs. 0.97+/-0.48 ng/ml; P<0.05), neopterin (7.23+/-4.24 vs. 4.95+/-1.52 nmol/l; P<0.05), and sICAM-1 (665+/-302 vs. 328+/-164 ng/ml; P<0.0001), but not IFN-gamma (7.55+/-4.72 vs. 6.65+/-1.13 pg/ml; P=NS) were significantly higher in patients with COPD than in the controls. Importantly, follow-up study for 12 months demonstrated that patients in subgroup with relatively higher circulating levels of sIL-2R (2.20+/-1.44 ng/ml, n=18) had significantly higher risk of developing aRTIs (P=0.0204) than those in subgroup with relatively lower circulating levels of sIL-2R (0.80+/-0.23 ng/ml, n=17). These results may suggest that impaired systemic CMI observed in COPD patients is associated with the increased susceptibility to aRTIs in these patients.

Circulating levels of soluble Fas ligand in cachexic patients with COPD are higher than those in non-cachexic patients with COPD.

OBJECTIVE: Apoptosis may be involved in the pathophysiology of cachexia in patients with chronic obstructive pulmonary disease (COPD). The purpose of this study is to assess the potential role of the Fas-Fas ligand (FasL) system in cachexic patients with COPD. PATIENTS AND METHODS: We measured the circulating levels of soluble FasL (sFasL), with a newly developed, highly sensitive enzyme-linked immunosorbent assay system in seventy patients with COPD and forty-seven control subjects. RESULTS: The levels of sFasL in the COPD patients were significantly lower than those in the control subjects (46+/-29 vs. 55+/-28 pg/ml; p<0.05), whereas the levels of soluble Fas (sFas) remained unchanged between the two groups. The significant correlation between the levels of sFasL and sFas, observed in the control subjects (r=0.304; p<0.05), was absent in the COPD patients. Cachexic COPD patients with a relatively lower BMI (BMI <20 kg/m(2), n=45) and %fat (%fat <20%, n=34), showed significantly increased levels of sFasL compared to non-cachexic COPD patients with a relatively higher BMI (BMI > or =20 kg/m(2), n=25) and %fat (%fat > or =20%, n=36) (BMI; 51+/-33 vs. 36+/-15 pg/ml; p<0.05. %fat; 55+/-33 vs. 37+/-21 pg/ml; p<0.01), due to the inverse relationships between the body composition measurements and the levels of sFasL observed exclusively in the patients (BMI; r=-0.307; p<0.05. %fat; r=-0.283; p<0.05). CONCLUSION: These results may suggest that the Fas-FasL system does not play a significant role in the potential triggers of enhanced apoptosis leading to skeletal muscle wasting and adipose tissue depletion in cachexic patients with COPD.

In vivo evidence of endothelial injury in chronic obstructive pulmonary disease by lung scintigraphic assessment of (123)I-metaiodobenzylguanidine.

UNLABELLED: Scintigraphic evaluation of (123)I-metaiodobenzylguanidine ((123)I-MIBG) in the lungs is considered to recognize endothelial cell lesions. The aim of this study was to clarify the involvement of the pulmonary microvascular injury in the pathogenesis of chronic obstructive pulmonary disease (COPD). METHODS: We investigated lung (123)I-MIBG kinetics and clinical indices in 25 COPD patients and 12 control subjects. Mean uptake ratios of lung to mediastinum (L/M) were calculated in anterior planer images at 30 min (early image) and 270 min (delayed image) after intravenous injection of (123)I-MIBG. Pulmonary mean washout rate (WR) of the (123)I-MIBG was also calculated. RESULTS: The L/M ratios in both early and delayed images of COPD patients, as well as its WR, were significantly lower than those of the control subjects (L/M early: 1.26 +/- 0.18 vs. 1.54 +/- 0.11, P < 0.0001; L/M delayed: 1.20 +/- 0.12 vs. 1.33 +/- 0.09, P < 0.001; WR: 27.4% +/- 5.3% vs. 34.2% +/- 5.7%, P < 0.01). There were significant relationships between lung WR of the (123)I-MIBG and other diagnostic tests for the severity of COPD, such as forced expiratory volume in 1 s (% FEV(1.0): r = 0.386, P < 0.05), carbon monoxide diffusing capacity/alveolar volume (DL(CO)/V(A): r = 0.449, P < 0.01), arterial blood oxygen pressure (PaO(2): r = 0.474, P < 0.01), alveolar-arterial oxygen tension gradient [A-a]DO(2) (r = -0.446, P < 0.01), and percentage of low-attenuation area (r = -0.458, P < 0.01) in the study population. CONCLUSION: Because lung WR of the (123)I-MIBG is considered to be independent of an alteration of the pulmonary vascular surface area, these results suggest that the microvascular endothelial cell injury plays a significant role in the pathogenesis of COPD.

Intersubunit disulfide bridge is not required for the protective role of SP-B against lung inflammation.

Surfactant protein B (SP-B) is known to promote surfactant phospholipid film formation and reduce surface tension. Native SP-B is a homodimer in which subunit association is stabilized via covalent linkage through cysteine 48. We hypothesized that loss of the intersubunit bridge would alter SP-B function and lead to increased inflammation in response to challenge by hyperoxia or endotoxin. Transgenic mice in which SP-B cysteine 48 was mutated to serine were generated and crossed into the SP-B(-/-) background. Wild-type mice and transgenic mice carrying a single copy (SP-Bmon(+)) or two copies (SP-Bmon(++)) of the transgene were exposed to 95% O2 for 3 days or intratracheally injected with 10 microg of endotoxin. Interleukin-1beta, major intrinsic protein 2, and interleukin-6 in lung homogenates after 3 days of hyperoxia were significantly higher (P < 0.001) in SP-Bmon(+) mice than SP-Bmon(++) or wild-type mice. At 16 h after endotoxin injection, cytokines in lung tissues were higher in SP-Bmon(+) mice compared with wild-type mice (P < 0.05). Consistent with prolonged recovery in SP-Bmon(+) mice, the percentage of apoptotic cells in alveolar lavage was significantly lower in SP-Bmon(+) mice than in SP-Bmon(++) and wild-type mice. Overall, increased inflammation in SP-Bmon(+) mice was corrected to a large extent by increased gene dosage, indicating that formation of the intersubunit disulfide bridge is not critical for SP-B function.

Influence of corticosteroid therapy on the serum antibody response to influenza vaccine in elderly patients with chronic pulmonary diseases.

Annual influenza vaccination is strongly recommended for patients with chronic pulmonary diseases, such as bronchial asthma, chronic obstructive pulmonary disease (COPD), and interstitial pulmonary diseases. However, many of these patients regularly receive systemic and/or inhaled corticosteroid therapy, and the impact of corticosteroid therapy on influenza vaccine efficacy and safety is unclear. Patients with chronic pulmonary diseases were enrolled in the study and divided into three groups based on their maintenance therapy: (A) without corticosteroid therapy (17 males, three females; mean age, 72.3 ± 7.9), (B) oral corticosteroid therapy (four males, seven females; mean age, 66.1 ± 10.6), and (C) inhaled corticosteroid therapy (eight males, nine females; mean age, 62.4 ± 16.0). All patients received influenza vaccine, and serum hemagglutination inhibition (HI) antibodies against influenza strains A/H1N1, A/H3N2, and B were measured at baseline (before vaccination) and 4-6 weeks after vaccination. Sufficient antibody titers or significant increases were observed after vaccination compared with titers before vaccination in all three groups. No systemic reactions were reported. Long-term oral/inhaled corticosteroid therapy was not associated with vaccination side effects and did not affect the immune response to the influenza vaccine.

Relationship between habit of cigarette smoking and airflow limitation in healthy Japanese individuals: the Takahata study.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by chronic airflow limitation. The prevalence of airflow limitation in Japan is 10.9% (16.4% of males and 5.0% of females). Cigarette smoking is well known as a major cause of COPD. However, few epidemiological studies have evaluated the effects of cigarette smoking on pulmonary function in healthy subjects. METHODS: Subjects aged 40 years or older (n=2,917), who had participated in a community-based annual health check in Takahata, Japan, from 2004 through 2005, were enrolled in the study. The smoking histories of these subjects were investigated using a self-reported questionnaire. Forced vital capacity (FVC), forced expiratory volume in 1 second (FEV(1)), and forced expiratory flow at 25-75% of FVC (FEF(25-75)) were measured by standard procedures using spirometric machines. RESULTS: There were 554 current smokers (18.6%) and 403 former smokers (13.8%). The prevalence of airflow limitation defined by FEV(1)/FVC <0.7 in this population was 10.6%, and prevalence of airflow limitation defined by 5th percentile lower limit of normal was 6.4%. In smokers, percent predicted values of measured spirometric parameters (%FVC, %FEV(1) and %FEF(25-75)) decreased significantly with age, except for male %FVC. Also, percent predicted values of measured spirometric parameters decreased significantly with increasing pack-years, except for female %FEF(25-75). CONCLUSION: Cigarette smoking increased the prevalence and severity of airflow limitation. It is concluded that cigarette smoking increases the risk of airflow limitation in a healthy Japanese population.

Vesnarinone represses the fibrotic changes in murine lung injury induced by bleomycin.

We investigated the potential usefulness of vesnarinone, a novel cytokine inhibitor, for the treatment of lung fibrosis using a murine model of bleomycin (BLM)-induced pulmonary fibrosis. Mice were fed a control diet (n=42), or a diet containing low (n=42) or high (n=42) dose of vesnarinone. Dietary intake of vesnarinone minimized the BLM toxicity as reflected by significant decreases in numbers of inflammatory cells, KC, and soluble TNF receptors in the bronchoalveolar lavage fluid. A quantitative evaluation of histology demonstrated significantly mild lung parenchymal lesions in BLM-treated mice fed with diet containing high dose of vesnarinone than in the control diet group. Consistent with the histopathology, hydroxyproline levels in lung tissue from BLM-treated mice fed with diet containing vesnarinone were significantly lower than that from mice fed with control diet. We concluded that vesnarinone inhibits BLM-induced pulmonary fibrosis, at least in part, by the inhibition of acute lung injuries in the early phase.

Association of CC chemokine ligand 5 genotype with urinary albumin excretion in the non-diabetic Japanese general population: the Takahata study.

Albuminuria is an early marker of vascular damage, and its development in diabetic nephropathy is associated with genotype of inflammatory CC chemokine ligand 5 (CCL5). This study investigated whether the association of CCL5 and albuminuria is a general phenomenon. We characterized a Japanese population consisting of 2,749 non-diabetic individuals over 40 years in Takahata, Japan. The urine albumin-creatinine ratio (UACR) was obtained from morning spot urine. We genotyped SNPs within the CCL5 gene that displayed frequent minor allele frequencies in Japanese (i.e., rs2107538, rs2280789, rs3817655 and rs9909416). Assessment of possible association and linkage disequilibrium (LD) revealed that all four SNP genotypes are correlated significantly with UACR (P = 0.004-0.005), and these four SNPs variations showed an obvious consistency of genotypes by detecting almost complete linkage disequilibrium (D' = 1 and r (2) > 0.95). We found two exclusive haplotypes in the CCL5 gene (haplotype1: rs2107538G/rs2280789T/rs3817655T/rs9909416G, frequency 0.64 and haplotype2: rs2107538A/rs2280789C/rs3817655A/rs9909416A, frequency 0.35) among the population. A significant association with elevated UACR was identified with haplotype1 (P = 0.002). Homozygotes for haplotype1 displayed strikingly-elevated UACR (48.5 +/- 6.6 mg/g, n = 1,116) compared to the rest (28.6 +/- 1.6 mg/g, n = 1,530) (P = 0.001). In conclusion, these results suggested that genetic variation of CCL5 might be an important risk factor for albuminuria in the non-diabetic Japanese general population.

Circulating levels of heart-type fatty acid-binding protein in a general Japanese population: effects of age, gender, and physiologic characteristics.

BACKGROUND: Serum heart-type fatty acid-binding protein (H-FABP) has been widely used as a marker of cardiac myocyte injury. This study was carried out to examine the relationships of H-FABP levels with age, gender, and other physiologic characteristics in a large population of community-dwelling residents. METHODS AND RESULTS: Serum H-FABP levels were measured in 2,099 subjects who received an annual health check-up (age 40-87 years). The relationships between H-FABP and blood pressure, laboratory data, electrocardiogram (ECG) findings, and lifestyle factors were cross-sectionally analyzed. Mean H-FABP values were significantly higher in men than in women. Serum H-FABP levels were increased with aging significantly. Both the multivariate regression and multiple logistic regression analyses indicated that serum H-FABP levels were independently affected by age, body mass index, creatinine clearance, and ECG abnormality score. CONCLUSION: Serum H-FABP levels were affected by age, gender, obesity, renal function, and ECG abnormality in a large group of volunteers. These effects should be taken into account in determining appropriate reference values for H-FABP. In addition, high serum H-FABP levels may represent latent cardiac injury and have important clinical implications.

Increased surfactant protein-D and foamy macrophages in smoking-induced mouse emphysema.

BACKGROUND AND OBJECTIVE: The molecular mechanisms underlying COPD remain undetermined. The lungs of surfactant protein-D (SP-D) deficient mice show emphysema and an excessive number of foamy macrophages. This study aims to elucidate roles of SP-D and foamy macrophages in smoking-induced mouse emphysema. METHODS: Twenty B6C3F1 mice were exposed to cigarette smoke (2 cigarettes/day/mouse for 6 months). The mice were killed, and formalin-fixed, paraffin-embedded lung sections were carried out on seven mice, BAL was carried out on six mice, and seven mice were used to make lung homogenates. In in vitro studies, A549 cells were transduced with the SP-D expression plasmid and treated with cigarette smoke extract to evaluate cell viability. RESULTS: Emphysema was induced in the mice by chronic cigarette smoke exposure. Increased expression of matrix metalloproteinase-9 and -12 was observed, and foamy alveolar macrophages accumulated in the smoke-exposed lungs. Immunostaining of BAL cells revealed the major source of matrix metalloproteinase-12 to be foamy alveolar macrophages. Furthermore, SP-D was elevated in emphysema lungs. Expression of transcription factors, Fra-1, junB and C/EBPbeta (which induce SP-D) were significantly elevated in emphysema lungs. The in vitro expression of SP-D gene in A549 cells prolonged cell survival following exposure to cigarette smoke condensate. CONCLUSIONS: The accumulation of foamy alveolar macrophages may play a key role in the development of smoking-induced emphysema. Increased SP-D may play a protective role in the development of smoking-induced emphysema, in part by preventing alveolar cell death.