MicroRNA-421 promotes proliferation and invasion of non-small cell lung cancer cells through targeting PDCD4.

Recent evidence highlights that microRNAs serve as crucial regulators of tumorigenesis, including non-small cell lung cancer (NSCLC). The present study was designed to investigate the expression profile, clinical significance and biological role of miR-421 in NSCLC. The results showed that miR-421 expression was markedly increased in NSCLC tissues and cell lines. Further experimental data indicated that knockdown of miR-421 significantly inhibited NSCLC cell proliferation and induced cell cycle arrest in vitro. The migratory and invasive abilities of NSCLC cells were also attenuated following miR-421 knockdown. Furthermore, PDCD4 was identified as a direct target of miR-421, and its expression was inversely correlated with miR-421 expression in NSCLC tissues. PDCD4 also abrogated the oncogenic role of miR-421 in NSCLC cells. Collectively, our study revealed that miR-421 is significantly upregulated in NSCLC and might represent a potential therapeutic target for NSCLC patients.

T cell responses in senior patients with community-acquired pneumonia related to disease severity.

Senior individuals older than 65 years of age are at a disproportionally higher risk of developing pneumonia. Impaired capacity to defend against airway infections may be one of the reasons. It is generally believed that weaker regulatory T cell responses may be beneficial to host defense against pathogens. In senior patients with community-acquired bacterial pneumonia, we investigated the frequencies and functions of regulatory T cells. Interestingly, we found that compared to age- and sex-matched healthy controls, senior pneumonia patients presented lower frequencies of Foxp3-expressing and Helios-expressing CD4+ T cells. The quantity of Foxp3 and Helios being expressed, measured by their mRNA transcription levels, was also lower in CD4+ T cells from pneumonia patients. Furthermore, following TCR and TGF-ß stimulation, pneumonia patients presented impaired capacity to upregulate Foxp3 and Helios. Functional analyses revealed that CD4+ T cells from pneumonia patients secreted lower amounts of IL-10 and TGF-ß, two cytokines critical to regulatory T cell-mediated suppression. Also, the expression of granzyme B and perforin, which were cytolytic molecules potentially utilized by regulatory T cells to mediate the elimination of antigen-presenting cells and effector T cells, were reduced in CD4+CD25+ T cells from senior pneumonia patients. In addition, the CD4+CD25+ T cells from senior pneumonia patients presented reduced capacity to suppress effector CD4+ and CD8+ T cell proliferation. Moreover, the value of pneumonia severity index was inversely correlated with several parameters of regulatory T cell function. Together, our results demonstrated that senior pneumonia patients presented a counterintuitive impairment in regulatory T cell responses that was associated with worse prognosis.

Loss of regulatory characteristics in CD4+ CD25+/hi T cells induced by impaired transforming growth factor beta secretion in pneumoconiosis.

Pneumoconiosis is caused by the accumulation of airborne dust in the lung, which stimulates a progressive inflammatory response that ultimately results in lung fibrosis and respiratory failure. It is possible that regulatory cells in the immune system could function to suppress inflammation and possibly slow or reverse disease progression. However, results in this study suggest that in pneumoconiosis patients, the regulatory T cells (Tregs) and B cells are functionally impaired. First, we found that pneumoconiosis patients presented an upregulation of CD4+ CD25+ T cells compared to controls, whereas the CD4+ CD25+ and CD4+ CD25hi T cells were enriched with Th1- and Th17-like cells but not Foxp3-expressing Treg cells and evidenced by significantly higher T-bet, interferon (IFN)-γ, and interleukin (IL)-17 expression but lower Foxp3 and transforming growth factor (TGF)-ß expression. Regarding the CD4+ CD25hi T-cell subset, the frequency of this cell type in pneumoconiosis patients was significantly reduced compared to controls, together with a reduction in Foxp3 and TGF-ß and an enrichment in T-bet, RORγt, IFN-γ, and IL-17. This skewing toward Th1 and Th17 types of inflammation could be driven by monocytes and B cells, since after depleting CD14+ monocytes and CD19+ B cells, the levels of IFN-γ and IL-17 were significantly decreased. Whole peripheral blood mononuclear cells and isolated monocytes and B cells in pneumoconiosis patients also presented reduced capacity of TGF-ß secretion. Furthermore, monocytes and B cells from pneumoconiosis patients presented reduced capacity in inducing Foxp3 upregulation, a function that could be rescued by exogenous TGF-ß. Together, these data indicated a potential pathway for the progression of pneumoconiosis through a loss of Foxp3+ Treg cells associated with impaired TGF-ß secretion.

Impairment of pulmonary function and changes in the right cardiac structure of pneumoconiotic coal workers in China.

INTRODUCTION: Information on the changes of pulmonary function and the right cardiac structure in patients with coal worker's pneumoconiosis in China is very scarce. This study was performed to clarify the changes of pulmonary function and right cardiac structure in patients with coal worker's pneumoconiosis in China. MATERIAL AND METHODS: Pulmonary function, pulmonary artery systolic pressure, and the right cardiac structure were evaluated by spirometry and color Doppler echocardiography. RESULTS: The pulmonary artery systolic pressure of patients with coal worker's pneumoconiosis was increased with disease severity. Patients with coal worker's pneumoconiosis also exhibited an impaired pulmonary function and altered right cardiac structure compared with control subjects. A significant linear correlation of the variables of pulmonary ventilation and diffusion function with the indicators of the right cardiac structure was found in patients with coal worker's pneumoconiosis in China. CONCLUSIONS: This study elucidated a deterioration of pulmonary function and right cardiac structure in patients with coal worker's pneumoconiosis in China.

Polymorphisms in cyclooxygenase-2 gene and risk of developing coal workers' pneumoconiosis: a case-control study.

BACKGROUND: Coal workers' pneumoconiosis (CWP) is characterized by progressive pulmonary fibrosis. Inflammation is crucial in the host response to silica and it contributes to pulmonary fibrosis. Cyclooxygenase-2 is involved in this process. The association between single-nucleotide polymorphisms in cyclooxygenase-2 gene with pneumoconiosis risk was investigated. METHODS: An association study was conducted by analyzing two single-nucleotide polymorphisms of cyclooxygenase-2 (rs689466 and rs20417) in a case-control study involving 90 patients and 90 healthy individuals (controls). Genotyping was performed by the TaqMan method. RESULTS: The rs689466 AG and GG and rs689466 GC polymorphisms were significantly less frequent in patients than in controls. Cyclooxygenase-2 rs689466 and rs20417 variant genotypes exhibited 21% and 12% decreased CWP risk, respectively. CONCLUSION: Cyclooxygenase-2 rs689466 and rs20417 polymorphisms were associated with CWP risk.

[Effects of whole lung lavage on pulmonary function and exercise capacity in patients with pneumoconiosis].

OBJECTIVE: To investigate the effects of whole lung lavage (WLL) on the pulmonary function and exercise capacity in patients with pneumoconiosis. METHODS: Forty-one patients with pneumoconiosis who quit dust-exposed work not more than 6 months before underwent WLL. Clinical symptom assessment, pulmonary function test, and cardiopulmonary exercise test were performed before and one week after WLL, and the results were compared. RESULTS: The patients with pneumoconiosis showed no significant changes in clinical symptoms after WLL. At one week after WLL, the patients with pneumoconiosis showed nonsignificant increases in forced vital capacity, forced expiratory volume in one second (FEV1.0), and percent predicted FEV1 (P > 0.05); peak oxygen uptake (peak VO2) increased from 2140.6 ± 353.2 ml/min before WLL to 2374.6 ± 362.4 ml/min after WLL, percent predicted peak VO2 increased from 82.2 ± 13.7% before WLL to 91.0 ± 14.0% after WLL, peak VO2/kg increased from 30.6 ± 3.5 ml/min×kg before WLL to 34.2 ± 3.7 ml/min×kg after WLL, and ventilatory equivalent for carbon dioxide decreased from 30.6 ± 3.1 before WLL to 26.1 ± 2.7 after WLL (P < 0.05). CONCLUSION: WLL can remarkably improve the oxygen uptake and ventilatory efficiency in patients with pneumoconiosis during exercise, so it can improve the exercise capacity of these patients.

Effects of total bilirubin on the prevalence of osteoporosis in postmenopausal women without potential liver disease.

It is still uncertain whether total bilirubin per se is a risk factor for osteoporosis in postmenopausal women and no study has so far examined this important issue. This study was designed to assess the sheer effects of total bilirubin on the prevalence of osteoporosis in postmenopausal women without potential liver disease. In the present study, postmenopausal female subjects without potential liver disease (n = 918) who underwent measurement of bone mineral density were enrolled. Correlation and logistic regression analysis were used to assess the relationship between total bilirubin and other variables. As a result, subjects with osteoporosis had a significantly lower total bilirubin level (P = 0.005). A 0.1 mg/dl increase in total bilirubin was associated with reduced odds ratio of the risk by 38 % for osteoporosis [OR 0.62 (95 % CI 0.52-0.88), P = 0.012] after adjustment for several variables. Total bilirubin was independently associated with BMD [coefficient = 0.41, 95 % CI (0.35-0.47), P < 0.001 for lumbar spine and coefficient = 0.44, 95 % CI (0.36-0.48), P < 0.001 for femur neck]. A positive correlation could be observed with significant difference between total bilirubin and z-score (r = 0.33, P < 0.001 for lumbar spine and r = 0.37, P < 0.001 for femur neck) and total bilirubin was positively correlated with serum calcium (r = 0.13, P < 0.001) as well. Therefore, this study demonstrates an independent inverse association between total bilirubin and the prevalence of osteoporosis in postmenopausal women without potential liver disease. Total bilirubin would be useful as a provisional new risk factor of osteoporosis in such a population.

Serum total bilirubin is inversely associated with brachial-ankle pulse wave velocity in men with hypertension.

Serum total bilirubin has been suggested to have the potential anti-inflammatory and antioxidant effects on the vasculature. This study was designed to investigate the association of bilirubin with brachial-ankle pulse wave velocity (baPWV), a marker of arterial stiffness and cardiovascular disease. Hypertensive male subjects (n = 2,361) were classified into groups according to the 50th, 75th, and 95th percentiles of baPWV value. Correlation and regression analysis were used to assess the relationship between baPWV and other variables. Hypertensive subjects with baPWV above the 50th, 75th, and 95th percentiles had a significantly lower bilirubin level than those with baPWV under them (0.97 ± 0.40 vs. 1.00 ± 0.41 mg/dl, P < 0.001; 0.95 ± 0.39 vs. 0.99 ± 0.41 mg/dl, P = 0.001; 0.92 ± 0.36 vs. 0.99 ± 0.42 mg/dl, P = 0.048, respectively). Bilirubin is inversely related to baPWV (R (2) = 0.0032, P = 0.003) and C-reactive protein (CRP) (correlation coefficient = -0.13, P < 0.001). A 0.1 mg/dl increase in bilirubin was associated with a 19, 20, and 34 % reduced odds ratio for baPWV above the 50th, 75th, and 95th percentiles, respectively [odds ratio (OR) 0.77 (95 % confidence interval (CI) 0.62-0.95), P = 0.015; OR 0.80 (95 % CI 0.64-0.99), P = 0.044; OR 0.68 (95 % CI 0.45-1.00), P = 0.048, respectively] after adjustment for several variables. This study demonstrates an independent inverse association between bilirubin and baPWV in hypertensive men. Additionally, reduced CRP may be one of mediators on the mechanisms how bilirubin reduces baPWV.

[Study of optimization of whole lung lavage applied to pneumoconiosis].

OBJECTIVE: To observe and evaluate the performances of intermittent positive pressure ventilation, beta-2 adrenergic receptor agonist, and pressure lavage in promoting residual fluid absorption and improving blood oxygen saturation during massive whole lung lavage (WLL). METHODS: A total of 155 patients were randomly divided into pressure ventilation (PV) group (n = 28), adrenaline (Ad) group (n = 31), PV plus Ad group (n = 29), pressure infusion bag (PIB) group (n = 30), and control group (n = 32). The patients underwent staged MWLL of bilateral lungs. The blood oxygen saturation (SpO2) of arterial blood of finger, chest X-ray findings, clinical symptoms, and lung functions were observed before and after MWLL. RESULTS: There were no significant differences in change in clinical symptoms among the five groups after MWLL (P > 0.05). The Ad group showed 6.3% increase in forced vital capacity (FVC) and 10.9% increase in forced expiratory flow at 25% of vital capacity (FEF(25%)) after MWLL (P < 0.05). The control group showed 5.7% decrease in FVC, 10.9% increase in forced expiratory volume in one second (FEV(1.0)), and 12.0% increase in FEF(25%) after MWLL (P < 0.05). No significant difference was found in other groups (P > 0.05). During and after MWLL, the incidence rates of hypoxemia in PV group, PV plus Ad group, and control group were 0, 0, and 12.5% (8/64), respectively (P < 0.01). There were no significant differences in total amount of lavage fluid and amount of residual fluid in the lung among all groups (P > 0.05). The smallest difference between the optical densities of the two lung fields on chest x-ray at 3 h after WLL was 0.152 ± 0.053 in the PV plus Ad group, compared to 0.194 ± 0.074 in the PV group, 0.197 ± 0.054 in the PIB group, 0.214 ± 0.054 in the Ad group, and 0.241 ± 0.109 in the control group, with significant differences between the saline group and other groups except Ad group (P < 0.05). CONCLUSION: Pressure ventilation, adrenaline, and pressure lavage can promote the transportation and absorption of residual fluid in the lung and decrease the incidence of hypoxemia during WLL.

Gamma glutamyltransferase as a novel marker of coronary artery calcification in women.

AIMS: Gamma glutamyltransferase (GGT) has attracted great interest as a potential novel marker of cardiovascular risk. However, its association with coronary artery calcification (CAC) score-determined coronary artery atherosclerosis is unknown. This study was designed to assess the association of GGT with CAC score. METHODS: Participants, 311 asymptomatic men and 220 asymptomatic women who underwent evaluation of CAC by cardiac computed tomography, were retrospectively investigated. Correlation and logistic regression analysis were used to assess the association of GGT with CAC score and other variables. RESULTS: Women but not men with higher GGT had a higher incidence of CAC score above 100 and a higher prevalence of metabolic syndrome (P = 0.012 and 0.007, respectively). GGT was positively correlated with C-reactive protein (CRP) in women (r = 0.336, P < 0.001). GGT was independently associated with the incidence of CAC score above 100 in women [odds ratio (OR) 1.228, 95% confidence interval (CI) 1.206-1.252, P = 0.001] but not in men. CONCLUSION: In asymptomatic women, GGT is independently and positively associated with CAC score and it can be useful as a provisional new risk factor for CAC. Additionally, metabolic syndrome and CRP may be the mediators of the mechanisms by which GGT increases CAC in asymptomatic women.

[Correlation analysis between cytokines levels in serum and bronchoalveolar lavage fluid, blood T cell subsets and pneumoconiosis severity].

OBJECTIVE: To analyze the correlation between the pneumoconiosis severity and the cytokines levels in serum and bronchoalveolar lavage fluid (BALF) or blood T cell subsets. METHODS: The subjects were divided into five groups: control group (6 cases), group exposed to dusts (6 cases) and 3 pneumoconiosis groups (36 in stage I, 12 in stage II and 10 in stage III). ELISA was used to detect IL-6, sIL-2R and TNF-α levels in serum and BALF. The subsets of blood T cells were classified by flow cytometer. RESULTS: As compared with control group and group exposed to dusts, the levels of serum IL-6 and sIL-2R in patients with II or III stages significantly increased, which were positively correlated with pneumoconiosis stages (r(1) = 0.74, r(2) = 0.81, P < 0.05). The level of serum TNF-α significantly decreased in patients with III stages, as compared with control group and group exposed to dusts. There was a negative correlation between serum TNF-α level and pneumoconiosis severity (r = -0.58, P < 0.05). There was a positive correlation between the levels of IL-6, sIL-2R and TNF-α in BALF and the levels of IL-6, sIL-2R and TNF-α in serum (r(1) = 0.77, r(2) = 0.96 and r(3) = 0.88, P < 0.05). The proportion of CD(4)(+)T cells and the ratio of CD(4)(+)/CD(8)(+) decreased dramatically in patients with II and III stages. But there was no correlation between these values and disease severity. CONCLUSION: The immune function in Th cell was inhibited. The levels of IL-6, sIL-2R and TNF-α in serum and BALF were associated with the severity of pneumoconiosis.

[Application of transbronchial lung biopsy in pneumoconiosis diagnosis].

OBJECTIVE: To evaluate the role of transbronchial lung biopsy (TBLB) pathology in pneumoconiosis diagnosis. METHODS: During Jan 2003 to Jun 2010 in our hospital. 418 patients exposed to dusts were examined with TBLB. The chest radiographs of all subjects showed the pneumoconiosis-like opacities. Because the dust property or accumulated doses didn't match with abnormality on chest radiographs or there were no a series of chest radiographs, it was required for subjects to perform the TBLB for diagnosis. Three hundred seventy nine cases with satisfying samples served as the study subjects. The dust deposition, fibrosis and birefringent particles were found in TBLB pathological examinations. From May 2005, the Prussian blue iron reaction test was conducted on the TBLB samples. A panel made pneumoconiosis diagnosis according to GBZ 70-2002 and GBZ 70-2009 Pneumoconiosis Diagnostic Criteria, consulting subjects' accounts and pathologic results. RESULTS: Among 379 subjects, 376 cases (99.2%) showed the lung interstitial fibrosis, 228 cases (60.2%) demonstrated the dust deposition, 111 cases (29.3%) expressed the birefringent particles by polarized light microscopy. Birefringent particles positive rate was 37.8% (62/164) in 164 patients exposed to either silica or potter dusts or cement dusts or coal-silica dusts or foundry dusts, which was much higher than that (22.7%, 49/215) in patients exposed to other dusts (welding fume or asbestos or aluminum dusts) (P < 0.05). The positive rate of Prussian blue iron reaction in 177 patients exposed to welding fume or burnishing dusts was 53.1% (94/177), which was significantly higher than that (23.2%, 13/56) in patients exposed to other dusts (cement dusts, casting dusts or silica) (P < 0.001). There were no significantly differences in rates of lung fibrosis, dust deposition and birefringent particles between pneumoconiosis and none-pneumoconiosis subjects. The rate of lung fibrosis in pneumoconiosis cases was significantly higher than that in non- pneumoconiosis cases (P < 0.05). CONCLUSION: TBLB could provide the evidence of exposure to dusts and pathological changes, which may be useful to the pneumoconiosis diagnosis.

[Pathologic analysis of transbronchial lung biopsy in workers exposed to dusts].

OBJECTIVE: To explore the role of transbronchial lung biopsy (TBLB) in pathologic diagnosis of pneumoconiosis. METHODS: In our hospital during May 2011 and Sep 2011, the TBLB samples from 35 cases occupationally exposed to dusts were compared with the video-assisted thoracoscopic surgery or lobectomy samples from 27 cases not exposed to dusts for pathological indexes, including fibrotic proliferation, nodule or nodule-like, dust deposition and needle-shaped birefringent particles. RESULTS: In group exposed to dusts, there were 6 cases (17.1%) with the moderate dust deposition and 28 cases (80.0%) with fibrotic proliferation. But in group not exposed to dusts, there were 0 case with the moderate dust deposition and 11 cases (40.0%) with fibrotic proliferation. There were significant differences between two groups (P < 0.05). In group exposed to dusts, there were 6 cases (17.1%) with Nodules-like and needle-shaped birefringent particles, but in group not exposed to dusts, there was 0 case with Nodules-like and needle-shaped birefringent particles. CONCLUSION: TBLB could provide the evidence of pathological changes in lung tissue induced by dusts, and TBLB play an important role in pneumoconiosis diagnosis.

Inverse relation of total serum bilirubin to coronary artery calcification score detected by multidetector computed tomography in males.

BACKGROUND: Serum total bilirubin has been suggested to have potential anti-inflammatory and antioxidant effects on the vasculature, acting against plaque formation and subsequent atherosclerosis. This study was designed to assess the association of serum total bilirubin with coronary artery calcification (CAC). HYPOTHESIS: Individuals with higher bilirubin level would be less likely to develop CAC. METHODS: Male subjects (N = 3408) underwent evaluation of CAC by cardiac computed tomography. Correlation and logistic regression analysis were performed to assess the relationships between CAC score and other variables. RESULTS: Subjects with a higher CAC score had significantly lower total bilirubin level (P = 0.001). Total bilirubin level was negatively correlated with CAC score (r = -0.052, P = 0.002). A 0.1-mg/dL increase in bilirubin was associated with a reduced odds ratio (OR) of the risk by 29.2% for a CAC score above 100 (OR: 0.708, 95% confidence interval: 0.542-0.927, P = 0.012) after adjustment for several variables. Bilirubin was inversely correlated with high-sensitivity C-reactive protein (hsCRP) (r = -0.117, P < 0.001). CONCLUSIONS: This study demonstrated an independent inverse association between serum total bilirubin and CAC score in males. Low serum bilirubin concentration would be useful as a potential risk factor for CAC in males. Additionally, reduced hsCRP may be 1 of the mechanisms for how bilirubin reduces CAC.