Youping Wang

IL-13 polymorphisms contribute to the risk of asthma: a meta-analysis.

OBJECTIVES The purpose of this study was to evaluate the effects of interleukin-13 (IL-13) polymorphisms on the risk of asthma using a meta-analysis. DESIGN AND METHODS Fifteen publications were identified by searching Pubmed, Embase, ISI, OVID, and EBSCO databases. Odds ratios with corresponding 95% confidence intervals were computed to estimate the association between IL-13 polymorphisms and risk of asthma. RESULTS The polymorphisms of R130Q (rs20541) and -1112C/T (rs1800925) in IL-13 gene were associated with significantly increased risks of asthma in overall analyses. Subgroup analyses showed that the elevated risks occurred in adult-onset asthma, Caucasians, and high quality studies. CONCLUSIONS This meta-analysis provides evidence that the R130Q and -1112C/T polymorphisms in IL-13 are risk factors for asthma.

TRPV1 Ablation Aggravates Inflammatory Responses and Organ Damage during Endotoxic Shock

ABSTRACT To test the hypothesis that ablation of transient receptor potential vanilloid type 1 (TRPV1) channels leads to exacerbated inflammatory responses and organ damage during endotoxic shock, lipopolysaccharide (LPS; 5 million endotoxin units/kg of body weight) was injected intraperitoneally (i.p.) into wild-type (WT) and TRPV1-null mutant (TRPV1−/−) mice. Mean arterial pressure and heart rate, determined by radiotelemetry, were severely depressed after LPS injection into WT and TRPV1−/− mice, with no distinction between the two strains. At 24 h after LPS injection, renal glomerular hypercellularity and hepatocellular injury were observed in both strains, accompanying further elevated serum levels of creatinine and alanine aminotransferase in TRPV1−/− mice compared to those in WT mice. At 6 or 24 h after LPS injection, neutrophil recruitment into kidneys and livers, serum cytokine (tumor necrosis factor alpha [TNF-α], interleukin 1β [IL-1β], IL-6) and renal chemokine (KC, macrophage inflammatory protein 2 [MIP-2]) levels, and renal VCAM-1 and ICAM-1 expression were greater in TRPV1−/− mice than WT mice. In addition, increased plasma calcitonin gene-related peptide (CGRP) levels observed in WT mice 6 h after LPS injection were absent in TRPV1−/− mice. Thus, TRPV1 ablation aggravates inflammatory responses, including neutrophil infiltration, proinflammatory cytokine production, and adhesion molecule expression, leading to intensified organ damage during endotoxic shock in the absence of worsened circulatory failure. The data indicate that TRPV1 activation may attenuate endotoxin-induced organ damage, possibly via its anti-inflammatory action rather than alteration of hemodynamics.

Role of the transient receptor potential vanilloid type 1 channel in renal inflammation induced by lipopolysaccharide in mice

To determine the role of the transient receptor potential vanilloid type 1 (TRPV1) channel in the regulation of renal inflammation, lipopolysaccharide (LPS, 3 mg/kg) was intraperitoneally injected into wild-type (WT) and TRPV1-null mutant (TRPV1(-/-)) mice. The kidney and serum were collected 6 or 24 h after LPS injection for morphological analysis and proinflammatory cytokine assay. LPS injection led to a similar degree of transient hypotension and bradycardia in WT and TRPV1(-/-) mice determined by a telemetry system. LPS administration caused parenchymal red blood cell congestion and fading of intact glomerular structure in TRPV1(-/-) compared with WT mice. Serum creatinine levels were higher 24 h after LPS injection in TRPV1(-/-) than in WT mice. Neutrophil and macrophage infiltration in the kidneys was greater 6 h for the former and 24 h for both after LPS injection in TRPV1(-/-) than in WT mice. Serum cytokine levels including tumor necrosis factor (TNF)-α, IL-1β, and IL-6 were higher 6 h after LPS injection in TRPV1(-/-) compared with WT mice. Likewise, renal chemokine levels including keratinocyte-derived chemokines and macrophage inflammatory protein were higher 6 h after LPS injection in TRPV1(-/-) than in WT mice. Renal VCAM-1 and ICAM-1 expression was further elevated 6 h for the former and 24 h for the latter after LPS injection in TRPV1(-/-) than in WT mice. Renal nuclear factor-κB (NF-κB) activity was further increased 6 h after LPS injection in TRPV1(-/-) compared with WT mice. Pharmacological blockade TRPV1 in WT mice showed aggravated renal and serum inflammatory responses resembling that of TRPV1(-/-) mice. Thus TRPV1 gene ablation exacerbates LPS-induced renal tissue and function injury, including aggravated renal neutrophil and macrophage infiltration, chemokine and adhesion molecule levels, and glomerular hypercellularity accompanying with further increased serum creatinine and cytokine levels. These results indicate that TRPV1 is activated during LPS challenge, which may constitute a protect mechanism against LPS-induced renal injury via reducing renal inflammatory responses.

TRPV1 agonism inhibits endothelial cell inflammation via activation of eNOS/NO pathway

BACKGROUND AND AIMS Transient receptor potential vanilloid type 1 channel (TRPV1) is found to be expressed in endothelial cells (ECs) and activate endothelial nitric oxide synthase (eNOS). Recent studies implicate TRPV1 in attenuating inflammatory responses. However, the mechanisms underlying the beneficial effects remain unclear. In this study, we investigated whether TRPV1 suppresses inflammatory responses of ECs via eNOS/NO pathway. METHODS Human umbilical vein endothelial cells (HUVECs) and renal microvascular endothelial cells (MVECs) isolated from deoxycorticosterone (DOCA)-salt hypertensive mice were cultured in the presence of capsaicin (CAP, a specific TRPV1 agonist) with or without the specific inhibitor of TRPV1, NOS, or Ca2+-dependent phosphatidylinositol 3-kinase (PI3K)/Akt pathway, before lipopolysaccharide (LPS) stimulation. NO metabolites, protein expression, and inflammatory molecules were evaluated by Griess assay and immune assay-based multiplex analysis, respectively. Monocyte adhesion was determined by measuring the fluorescently labeled human monocytes attached to LPS-stimulated ECs. RESULTS In HUVECs, treatment with CAP increased NO production, and CAP-induced NO production was accompanied by increased eNOSser1177 phosphorylation. Additionally, CAP attenuated LPS-induced cytokine and chemokine production, adhesion molecule expression, activation of NF-κB, and monocyte adhesion in HUVECs, and these effects were abrogated by the inhibition of TRPV1, NOS, or Ca2+-dependent PI3K/Akt pathway. Moreover, these protective actions of TRPV1 were also observed in renal MVECs isolated from DOCA-salt hypertensive mice. CONCLUSIONS Our results indicate that TRPV1 activation suppresses the inflammatory response of ECs via the activation of Ca2+/PI3K/Akt/eNOS/NO pathway, the protective effects are also documented in ECs derived from salt-sensitive hypertensive mice.

Role of Substance P in Renal Injury During DOCA-Salt Hypertension

Substance P (SP), a neurokinin-1 receptor (NK-1R) agonist, is mainly produced and stored in primary sensory nerves and, upon its release, participates in cardiovascular and renal functional regulation. This study tests the hypothesis that activation of the NK-1Rs by SP occurs during hypertension induced by deoxycorticosterone (DOCA)-salt treatment, which contributes to renal injury in this model. C57BL/6 mice were subjected to uninephrectomy and DOCA-salt treatment in the presence or absence of administration of selective NK-1 antagonists, L-733,060 (20 mg/kg·d, ip) or RP-67580 (8 mg/kg·d, ip). Five weeks after the treatment, mean arterial pressure determined by the telemetry system increased in DOCA-salt mice but without difference between NK-1R antagonist-treated or NK-1R antagonist-untreated DOCA-salt groups. Plasma SP levels were increased in DOCA-salt compared with control mice (P < 0.05). Renal hypertrophy and increased urinary 8-isoprostane and albumin excretion were observed in DOCA-salt compared with control mice (P < 0.05). Periodic acid-Schiff and Massons trichrome staining showed more severe glomerulosclerosis and tubulointerstitial injury in the renal cortex in DOCA-salt compared with control mice, respectively (P < 0.05). Hydroxyproline assay and F4/80-staining showed that renal collagen levels and interstitial monocyte/macrophage infiltration were greater in DOCA-salt compared with control mice, respectively (P < 0.05). Blockade of the NK-1R with L-733,060 or RP-67580 in DOCA-salt mice suppressed increments in urinary 8-isoprostane and albumin excretion, interstitial monocyte/macrophage infiltration, and glomerulosclerosis and tubulointerstitial injury and fibrosis (P < 0.05). Thus, our data show that blockade of the NK-1Rs alleviates renal functional and tissue injury in the absence of alteration in blood pressure in DOCA-salt-hypertensive mice. The results suggest that elevated SP levels during DOCA-salt hypertension play a significant role contributing to renal damage possibly via enhancing oxidative stress and macrophage infiltration of the kidney.

Role of the monocyte chemoattractant protein-1/C-C chemokine receptor 2 signaling pathway in transient receptor potential vanilloid type 1 ablation-induced renal injury in salt-sensitive hypertension

Our recent studies indicate that the transient receptor potential vanilloid type 1 (TRPV1) channel may act as a potential regulator of monocyte/macrophage recruitment to reduce renal injury in salt-sensitive hypertension. This study tests the hypothesis that deletion of TRPV1 exaggerates salt-sensitive hypertension-induced renal injury due to enhanced inflammatory responses via monocyte chemoattractant protein-1 (MCP-1)/C-C chemokine receptor 2 (CCR2)-dependent pathways. Wild type (WT) and TRPV1-null mutant (TRPV1−/−) mice were subjected to uninephrectomy and deoxycorticosterone acetate (DOCA)-salt treatment for four weeks with or without the selective CCR2 antagonist, RS504393. DOCA-salt treatment increased systolic blood pressure (SBP) to the same degree in both strains, but increased urinary excretion of albumin and 8-isoprostane and decreased creatinine clearance with greater magnitude in TRPV1−/− mice compared to WT mice. DOCA-salt treatment also caused renal glomerulosclerosis, tubulointerstitial injury, collagen deposition, monocyte/macrophage infiltration, proinflammatory cytokine and chemokine production, and NF-κB activation in greater degree in TRPV1−/− mice compared to WT mice. Blockade of the CCR2 with RS504393 (4 mg/kg/day) had no effect on SBP in DOCA-salt-treated WT or TRPV1−/− mice compared to their respective controls. However, treatment with RS504393 ameliorated renal dysfunction and morphological damage, and prevented the increase in monocyte/macrophage infiltration, cytokine/chemokine production, and NF-κB activity in both DOCA-salt hypertensive strains with a greater effect in DOCA-salt-treated TRPV1−/− mice compared to DOCA-salt-treated WT mice. No differences in CCR2 protein expression in kidney were found between DOCA-salt-treated WT and TRPV1−/− mice with or without RS504393 treatment. Our studies for the first time indicate that deletion of TRPV1 aggravated renal injury in salt-sensitive hypertension via enhancing MCP-1/CCR2 signaling-dependent inflammatory responses.

Jia-Shen decoction-medicated serum inhibits angiotensin-II induced cardiac fibroblast proliferation via the TGF-β1/Smad signaling pathway

Jia-Shen decoction (JSD) is a traditional Chinese medicine, which is used widely to treat chronic heart failure. However, the underlying mechanism remains to be elucidated. The present study aimed to investigate the mechanism underlying the effects of JSD on cardiac fibroblast (CF) proliferation and differentiation. The CFs were obtained from the hearts of neonatal (1-3-day old) Sprague-Dawley rats and treated with JSD-medicated serum (JSDS) with or without angiotensin II (Ang II). Cell proliferation was assessed using Cell Counting Kit-8 reagent. In addition, the mRNA expression levels of transforming growth factor-β1 (TGF-β1) and phosphorylated small mothers against decapentaplegic (p-Smad)2/3 and their protein expression levels were analyzed. CF proliferation was significantly increased in the Ang II-treated group, compared with the control group (P<0.05). The expression levels of collagen, α-smooth muscle actin, TGF-β1 and p-Smad2/3 were also increased in the Ang II-treated group (P<0.05). Following JSDS treatment, the increased levels of collagen and cell proliferation were inhibited, and the increased expression levels of p-Smad2 and p-Smad3 were also inhibited (P<0.05). These data suggested that JSDS may inhibit CF proliferation via attenuating the TGF-β1/Smad signaling pathway.

Protective effects of Jiashen Prescription (加参方) on myocardial infarction in rats

ObjectiveTo evaluate the effects of Jiashen Prescription (加参方, JSP) on myocardial infarction (MI) size and cardiac function at the early stage of MI in rats.MethodsOne hundred male Sprague-Dawley rats were subjected to sham-operation or MI induced by ligating the left anterior descending coronary artery. The rats with MI were treated with vehicle, JSP 3 and 6 g/(kg·d), or losartan 10 mg/(kg·d) for 1 week.ResultsCompared with the vehicle-treated MI rats, 6 g/(kg·d) JSP reduced MI size 3 days after MI (P<0.05), and attenuated the MI-induced increases in left ventricular end-diastolic and end-systolic dimension and decreases in fractional shortening and ejection fraction 1 week after MI (P<0.05). In addition, 6 g/(kg·d) JSP and losartan were equally effective in reducing MI size and enhancing cardiac functional recovery.ConclusionJSP reduces MI size and improves cardiac function after MI, suggesting that JSP has potential as a therapy for MI.

GW24-e2125 PROTECTIVE EFFECTS OF A PRESCRIPTION OF JIASHEN ON MYOCARDIAL INFARCTION VIA INHIBITION OF INFLAMMATION IN RATS

Objectives To determine the role of inflammation in myocardial protection induced by a prescription of Jiashen (PJS) in the early period of myocardial infarction (MI) in rats. Methods MI was induced by the ligation of left anterior descending coronary artery in Sprague-Dawley rats. The rats were divided into five groups: sham-operated group; MI + vehicle group; PJS-3g (3 g/kg/day) group; PJS-6g (6g/kg/day) group and losartan (10 mg/kg/day) group. Infarct size (IS) was determined by Evans blue and 2,3,5-Triphenyltetrazolium chloride (TTC) 3 days after MI; the left ventricular structure and function were measured by echocardiography performed 1 week after MI; and myocardial inflammatory mediators including tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β), monocyte chemoattractant protein-1 (MCP-1) were measured by ELISA. Results Compared with the MI + vehicle group, treatment with PJS at the dose of 6 g/kg/day reduced myocardial IS (P < 0.05), left ventricular end diastolic diameter (LVEDD) and left ventricular end systolic diameter (LVESD) (P < 0.01), and enhanced left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) (P < 0.01). Compared with the MI + vehicle group, administration of PJS dose-dependently attenuated the increased levels of TNF-α, IL-1β and MCP-1 in ischaemic myocardium (P < 0.01). PJS at the dose of 6 g/kg/day had equally effectiveness with losartan. Conclusions Our studies showed that consistent with losartan-induced cardioprotection, PJS administered after MI reduced myocaidial IS and improved cardiac function that was associated with the decreased inflammatory mediators. The data indicate that PJS exert its cardioprotection possibly via inhibiting inflammatory response.

GW24-e3612 Effects of prescription of Jiashen on ventricular remodelling and infiltration of monocyte/macrophages in the early period after myocardial infarction in rats

Objectives This study was designed to test the hypothesis that PJS modulates inflammatory processes to prevent cardiac functional deterioration and reduce ventricular remodelling after MI. Methods Male Sprague-Dawley rats (9-10 weeks) were subjected to sham-MI or MI by ligating the left anterior descending coronary artery for 1 and 4 weeks. The rats were divided into five groups: sham, MI, PJS (3 g/kg/day), PJS (6 g/kg/day), and losartan (an AT1 antagonist, 10 mg/kg/day). The vehicle, PJS, or losartan was given by oral gavage once a day after MI. Cardiac functions were determined by echocardiographic measurements at 1 and 4 weeks after MI. Fibrinogen at the site of infarction and in ischaemic myocardium were determined by Masson staining. Results of quantitative analysis were used to detect the level of hydroxyproline. Monocyte/macrophages expression was detected by immunohistochemistry staining and quantitative analysis. Results 1) The echocardiographic measurement showed that Both LVEDd and LVESd in the PJS-6 and Losartan groups were significantly shorter than in the MI group at both week 1 and week 4 post-MI. Both FS and EF were well-maintained in the PJS-6 and Losartan groups than in the MI group at both week 1 and week 4 post-MI. 2) Masson trichrome staining of cardiac sections: At 1 and 4 weeks after myocardial infarction, fibrinogen proliferation was much more obvious in MI group than in sham operation group.a detectable reduction of fibrinogen with PJS-6 and Losartan groups at the site of infarction was not found but was reduced at ischaemic sites. Results of quantitative analysis shows: compared to the MI group, the PJS-6 and losartan groups significantly decrease at both the infarction and ischaemia areas the level of fibrinogen. 3) Immunohistochemical results of monocyte/macrophages shows: At 1 and 4 weeks after myocardial infarction, monocyte/macrophages was much more obvious in MI group than in sham operation group compared to the MI group, the PJS-6 and losartan groups significantly decrease at both the infarction and ischaemia areas of monocyte/macrophages. Conclusions Our studies demonstrate that the PJS improves cardiac function, inhibits cardiac remodelling and suppresses infiltration of monocyte/macrophages after myocardial infarction. The data indicate that PJS inhibits its ventricular remodelling possibly via inhibiting infiltration of monocyte/macrophages. The results suggest that PJS may have a promising potential for the prevention and treatment of MI.