Associations of the Serum KL-6 with Severity and Prognosis in Patients with Acute Exacerbation of Chronic Obstructive Pulmonary Disease.

BACKGROUND: As a biomarker of alveolar-capillary basement membrane injury, Krebs von den Lungen-6 (KL-6) is involved in the occurrence and development of pulmonary diseases. However, the role of the KL-6 in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) has yet to be elucidated. This prospective study was designed to clarify the associations of the serum KL-6 with the severity and prognosis in patients with AECOPD. METHODS: This study enrolled 199 eligible AECOPD patients. Demographic data and clinical characteristics were recorded. Follow-up was tracked to evaluate acute exacerbation and death. The serum KL-6 concentration was measured via an enzyme-linked immunosorbent assay. RESULTS: Serum KL-6 level at admission was higher in AECOPD patients than in control subjects. The serum KL-6 concentration gradually elevated with increasing severity of AECOPD. Pearson and Spearman analyses revealed that the serum KL-6 concentration was positively correlated with the severity score, monocyte count and concentrations of C-reactive protein, interleukin-6, uric acid, and lactate dehydrogenase in AECOPD patients during hospitalization. A statistical analysis of long-term follow-up data showed that elevated KL-6 level at admission was associated with longer hospital stays, an increased risk of future frequent acute exacerbations, and increased severity of exacerbation in COPD patients. CONCLUSION: Serum KL-6 level at admission is positively correlated with increased disease severity, prolonged hospital stay and increased risk of future acute exacerbations in COPD patients. There are positive dose-response associations of elevated serum KL-6 with severity and poor prognosis in COPD patients. The serum KL-6 concentration could be a novel diagnostic and prognostic biomarker in AECOPD patients.

Arsenic exposure and pulmonary function decline: Potential mediating role of TRAIL in chronic obstructive pulmonary disease patients.

BACKGROUND: Environmental arsenic (As) exposure is strongly related to the progression of chronic obstructive pulmonary disease (COPD). Pulmonary epithelial cells apoptosis is implicated in the pathophysiological mechanisms of COPD. However, the role of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), one biomarker of apoptosis, remains unclear in As-mediated pulmonary function alternations in COPD patients. METHODS: This study included 239 COPD patients. The serum level of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) was measured by enzyme-linked immunosorbent assay (ELISA). The blood As level was determined through inductively coupled plasma mass spectrometry (ICP-MS). RESULTS: Blood As levels exhibited a negative and dose-dependent correlation with pulmonary function. Per unit elevation of blood arsenic concentrations was related to reductions of 0.339 L in FEV1, 0.311 L in FVC, 1.171% in FEV1/FVC%, and 7.999% in FEV1% in COPD subjects. Additionally, a positive dose-response correlation of blood As with serum TRAIL was found in COPD subjects. Additionally, the level of serum TRAIL was negatively linked to lung function. Elevated TRAIL significantly mediated As-induced decreases of 11.05%, 13.35%, and 31.78% in FVC, FEV1, and FEV1%, respectively among the COPD patients. CONCLUSION: Blood As level is positively correlated with pulmonary function decline and serum TRAIL increase in individuals with COPD. Our findings suggest that elevated TRAIL levels may serve as a mediating mechanism through which As contributes to declining lung function in COPD patients.

A Prospective Cohort Study of Inter-Alpha-Trypsin Inhibitor Heavy Chain 4 as a Serologic Marker in Relation to Severity and Functional Outcome of Acute Intracerebral Hemorrhage.

Background: The inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4) may regulate immunity and inflammation. The current study was conducted to determine its role as a biomarker for reflecting the severity and predicting outcomes of intracerebral hemorrhage (ICH). Methods: In this prospective cohort study, 185 patients with supratentorial ICH were enrolled, among whom 62 had blood obtained not only at admission but also on days 1, 3, 5, 7, 10, and 14. In addition, 62 healthy controls underwent blood collection at the start of the study. The serum ITIH4 levels were then quantified. We recorded early neurological deterioration (END) and poor prognosis (modified Rankin Scale [mRS] scores of 3-6]) six months after ICH. Results: Serum ITIH4 levels decreased prominently in the early phase after ICH, continued to decline until day 5, then gradually increased until day 14, and were significantly lower during 14 days in patients than in controls. Serum ITIH4 levels on admission were independently associated with serum C-reactive protein levels, National Institutes of Health Stroke Scale (NIHSS) scores and hematoma volume. Admission serum ITIH4 levels were independently associated with mRS scores, END, and poor prognosis. No substantial differences existed in the areas under the receiver operating characteristic curve of END and poor prognosis prediction between the serum ITIH4 levels, NIHSS scores, and hematoma volume. Prediction models, in which serum ITIH4 levels, NIHSS scores, and hematoma volume were integrated, were relatively reliable and stable using a series of statistical methods. In addition, the prediction model of poor prognosis had a higher discriminatory ability than the NIHSS scores and hematoma volume alone. Conclusion: A dramatic decline in serum ITIH4 levels during the early period following ICH is independently related to the inflammatory response, stroke severity, and poor neurologic outcomes, suggesting that serum ITIH4 may be a useful prognostic biomarker of ICH.

Macrophage migration inhibitory factor as a serum prognostic marker in patients with aneurysmal subarachnoid hemorrhage.

BACKGROUND: Macrophage migration inhibitory factor (MIF) has been implicated in inflammation. We clarified whether serum MIF could be used as a marker of inflammation, brain damage and outcome after aneurysmal subarachnoid hemorrhage (aSAH). METHODS: Serum samples from 102 aSAH adults and 102 healthy controls were determined. The World Federation of Neurological Surgeons (WFNS) scale was used for neurological evaluation and radiological severity was estimated in accordance with the Fisher scale. RESULTS: Serum MIF, C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α) and S100B concentrations were significantly higher in patients than in controls. Serum MIF concentrations correlated with WFNS scores and Fisher scores and serum concentrations of CRP, IL-6, TNF-α and S100B. Serum MIF was identified as an independent predictor for 6-month unfavorable outcome (defined as Extended Glasgow Outcome Scale score of 1-4). Area under receiver operating characteristic curve of serum MIF concentrations was similar to those of WFNS scores, Fisher scores and serum S100B concentrations and significantly exceeded those of serum CRP, IL-6 and TNF-α concentrations. CONCLUSIONS: Serum MIF provides information about inflammation, brain injury severity and outcome after aSAH, which can be useful as a complement to clinical data.

Changes in plasma thrombospondin-1 concentrations following acute intracerebral hemorrhage.

BACKGROUND: Angiogenesis is a fundamental process for brain development and repair. Thrombospondin-1 is the first identified endogenous angiogenesis inhibitor. Its expression in rat brain is upregulated after intracerebral hemorrhage (ICH). We determined whether plasma thrombospondin-1 concentrations are associated with injury severity and prognosis in ICH patients. METHODS: This observational, prospective study recruited 110 patients and 110 age- and gender-matched healthy controls. Blood samples were collected from the patients at admission and from the healthy controls at study entry to measure plasma thrombospondin-1 concentrations. The endpoints included 1-week mortality, 6-month mortality, 6-month overall survival and 6-month unfavorable outcome (modified Rankin Scale score >2). RESULTS: Plasma thrombospondin-1 concentrations were markedly higher in patients than in healthy controls. Thrombospondin-1 was an independent predictive factor for all endpoints and plasma thrombospondin-1 concentrations were highly associated with injury severity reflected by hematoma volume and National Institutes of Health Stroke Scale score. Under receiver operating characteristic curves, plasma thrombospondin-1 concentrations had similar predictive values compared with hematoma volume and National Institutes of Health Stroke Scale score. CONCLUSIONS: Increased plasma thrombospondin-1 concentrations following ICH are independently associated with injury severity and short-term and long-term clinical outcomes.

Contribution of baicalin on the plasma protein binding displacement and CYP3A activity inhibition to the pharmacokinetic changes of nifedipine in rats in vivo and in vitro.

Baicalin purified from the root of Radix scutellariae is widely used in clinical practices. This study aimed to evaluate the effect of baicalin on the pharmacokinetics of nifedipine, a CYP3A probe substrate, in rats in vivo and in vitro. In a randomised, three-period crossover study, significant changes in the pharmacokinetics of nifedipine (2 mg/kg) were observed after treatment with a low (0.225 g/kg) or high (0.45 g/kg) dose of baicalin in rats. In the low- and high-dose groups of baicalin-treated rats, C max of total nifedipine decreased by 40%±14% (P<0.01) and 65%±14% (P<0.01), AUC0-∞ decreased by 41%±8% (P<0.01) and 63%±7% (P<0.01), Vd increased by 85%±43% (P<0.01) and 224%±231% (P<0.01), and CL increased by 97%±78% (P<0.01) and 242%±135% (P<0.01), respectively. Plasma protein binding experiments in vivo showed that C max of unbound nifedipine significantly increased by 25%±19% (P<0.01) and 44%±29% (P<0.01), respectively, and there was a good correlation between the unbound nifedipine (%) and baicalin concentrations (P<0.01). Furthermore, in vitro results revealed that baicalin was a competitive displacer of nifedipine from plasma proteins. In vitro incubation experiments demonstrated that baicalin could also competitively inhibit CYP3A activity in rat liver microsomes in a concentration-dependent manner. In conclusion, the pharmacokinetic changes of nifedipine may be modulated by the inhibitory effects of baicalin on plasma protein binding and CYP3A-mediated metabolism.

Inhibitory Effects of Baicalin on the Expression and Activity of CYP3A Induce the Pharmacokinetic Changes of Midazolam in Rats.

Baicalin, a flavonoid compound isolated from Scutellaria baicalensis, has been shown to possess antiinflammatory, antiviral, antitumour, and immune regulatory properties. The present study evaluated the potential herb-drug interaction between baicalin and midazolam in rats. Coadministration of a single dose of baicalin (0.225, 0.45, and 0.90 g/kg, i.v.) with midazolam (10 mg/kg, i.v.) in rats resulted in a dose-dependent decrease in clearance (CL) from 25% (P < 0.05) to 34% (P < 0.001) with an increase in AUC0-∞ from 47% (P < 0.05) to 53% (P < 0.01). Pretreatment of baicalin (0.90 g/kg, i.v., once daily for 7 days) also reduced midazolam CL by 43% (P < 0.001), with an increase in AUC0-∞ by 87% (P < 0.01). Multiple doses of baicalin decreased the expression of hepatic CYP3A2 by approximately 58% (P < 0.01) and reduced midazolam 1'-hydroxylation by 23% (P < 0.001) and 4'-hydroxylation by 21% (P < 0.01) in the liver. In addition, baicalin competitively inhibited midazolam metabolism in rat liver microsomes in a concentration-dependent manner. Our data demonstrated that baicalin induced changes in the pharmacokinetics of midazolam in rats, which might be due to its inhibition of the hydroxylation activity and expression of CYP3A in the liver.

Concentration-dependent inhibitory effects of baicalin on the metabolism of dextromethorphan, a dual probe of CYP2D and CYP3A, in rats.

Baicalin has been shown to possess many pharmacological effects, including antiviral, antioxidant, anti-cancer and anti-inflammatory properties. In the current study, we reveal the inhibitory effects of baicalin on the metabolism of dextromethorphan (DXM), a dual probe substrate of CYP2D and CYP3A, in rats. Lineweaver-Burk plots demonstrated that baicalin inhibited the activities of CYP2D and CYP3A in a non-competitive manner in rat liver microsomes (RLMs). Concomitant administration of baicalin (0.90 g/kg, i.v.) and DXM (10 mg/kg, i.v.) increased the maximum drug concentration (C(max)) (37%) and the area under concentration-time curve (AUC) (42%) and decreased the clearance (CL) (27%) of DXM in a randomised, crossover study in rats (P < 0.01). The change in the AUC of DXM was significantly correlated with the C(max) and AUC of baicalin (P < 0.05). The inhibitory effects of multiple doses of baicalin (0.90 g/kg, i.v., 12 days) on the metabolism of DXM were similar to those observed following a single dose in rats. The activity of CYP3A in excised liver samples from rats following multiple baicalin treatment was significantly decreased compared to that of the control group (P < 0.05), whereas multiple doses of baicalin had no obvious effect on the activity of CYP2D. Taken together, these data demonstrate that baicalin inhibits the metabolism of DXM in a concentration-dependent manner in rats, possibly through inhibiting hepatic CYP2D and CYP3A activities.