Avadhesh Sharma - Academia.edu (original) (raw)

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Papers by Avadhesh Sharma

Lung, 1997

ABSTRACT To investigate the influence of interleukin-1 beta (IL-1 beta) on airway epithelial cell... more ABSTRACT To investigate the influence of interleukin-1 beta (IL-1 beta) on airway epithelial cell growth, we measured [3H]thymidine incorporation and cell numbers of cultured porcine tracheal epithelial cells in the presence or absence of human recombinant IL-1 beta with or without the following: goat antiporcine polyclonal antibody to platelet-derived growth factor (PDGF); IL-1 receptor antagonist; indomethacin; PD-145065, a combined endothelin-A and -B receptor antagonist; BQ-123, an antagonist selective for endothelin-A receptors; or phosphoramidon, an inhibitor, in part, of endothelin-converting enzymes, including neutral endopeptidase. We found that IL-1 beta stimulated the proliferation of airway epithelial cells, and this response was inhibited by the IL-1 receptor antagonist and by PD-145065 or BQ-123. However, neither indomethacin nor PDGF antibody was influential. The endothelin receptor antagonists also decreased basal thymidine incorporation by these cells as did phosphormidon, although to a lesser degree. Data from radioimmunoassays indicated that phosphormidon reduced the endogenous production of endothelin-1 from the cells, and IL-1 beta clearly increased it over time. We conclude that IL-1 beta is a stimulant of airway epithelial cell growth, and its mitogenic effects are mediated, in part, by endogenous endothelin-1 production.

Molecular and Cellular Biochemistry, 2004

In the present study, we hypothesized that endotoxemia produces metalloendopeptidase (MEPD)-depen... more In the present study, we hypothesized that endotoxemia produces metalloendopeptidase (MEPD)-dependent generation of endothelin-1 (ET-1) and alters NOS expression correlating with p38-mitogen-activated protein kinase (MAPK) phosphorylation in thoracic aorta. Male Sprague-Dawley rats (350-400 g) were subjected to two groups randomly; sham-treated (N = 10) and lipopolysaccharide (LPS)-treated (N = 10) (E. coli LPS 2 mg/kg bolus + 2 mg/kg infusion for 30 min). The animals in each group were further subdivided into vehicle and MEPD inhibitor phosphoramidon (1 mg/kg bolus, PHOS)-treated groups. LPS produces a significant decrease in mean arterial pressure (MAP) at 2 h post endotoxemia that was blocked by PHOS. PHOS attenuated LPS-induced increase in tumor necrosis factor-alpha (TNF-α) concentration at 2-and 24 h post-LPS administration. LPS significantly elevated plasma concentrations of ET-1 at 2-and 24 h post endotoxemia. An upregulated preproET-1 expression following both LPS and MEPD inhibition was observed in thoracic aorta at 2 h post treatment. PHOS effectively blocked conversion of preproET-1 to ET-1 in thoracic aorta locally at 24 h post treatment in endotoxic rats. PHOS inhibited LPS-induced upregulation of inducible NOS (iNOS), downregulation of endothelial NOS (eNOS) and elevation of NO byproducts (NO x) in thoracic aorta. PHOS also blocked LPS-induced upregulated p38-MAPK phosphorylation in thoracic aorta at 24 h post endotoxemia. The data revealed that LPS induces MEPD-sensitive inflammatory response syndrome (SIRS) at 2-and 24 h post endotoxemia. We concluded that inhibition of MEPD not only decreases the levels of ET-1 but also simultaneously downregulates protein expression of iNOS and phosphorylated p38-MAPK while increasing eNOS in thoracic aorta during SIRS in endotoxemia. We suggest that MEPD-dependent ET-1 and NO mechanisms may be involved in endotoxemia-induced altered p38-MAPK phosphorylation.

<b>Copyright information:</b>Taken from "Duration of streptozotocin-induced diab... more <b>Copyright information:</b>Taken from "Duration of streptozotocin-induced diabetes differentially affects p38-mitogen-activated protein kinase (MAPK) phosphorylation in renal and vascular dysfunction"Cardiovascular Diabetology 2005;4():3-3.Published online 5 Mar 2005PMCID:PMC555576.Copyright © 2005 Chen et al; licensee BioMed Central Ltd.mL) in control, 14-days and 28-days STZ-induced diabetes groups (A) (N = 6 in each group). Effect of duration (14-days and 28-days) of STZ-induced diabetes on the expression of preproET-1 protein in thoracic aorta (B), in kidney cortex (C) and in kidney medulla (D) and % change in densitometric units of preproET-1 (N = 3 in each group); * p ≤ 0.05 Vs control group, # p ≤ 0.05 Vs 14-days diab group.

Current Opinion in Nephrology and Hypertension, 2014

Purpose of review Research over the past decade has significantly deepened our understanding of m... more Purpose of review Research over the past decade has significantly deepened our understanding of mechanisms that drive the development of hypertension. In particular, a novel paradigm of inflammation as a common mediator of cardiovascular and kidney disease has emerged. This review will summarize the role of the immune system in cardiovascular disease, explore some of the most promising new therapeutic directions and consider their potential as new treatments for hypertension. Recent findings Recent data continue to demonstrate that targeting the immune system can prevent hypertension in a variety of experimental models. Tempering the enthusiasm for a long-awaited new approach to treating hypertension is decades of clinical data, showing that classic immunosuppression regimens are associated with significant side-effects-including cardiovascular disease-that effectively preclude their use in the setting of chronic hypertension. New, more specific therapies are being developed that target cytokines including IL-17, IL-6 and TNFa.

Cardiovascular diabetology, Jan 5, 2005

In the present study we tested the hypothesis that progression of streptozotocin (STZ)-induced di... more In the present study we tested the hypothesis that progression of streptozotocin (STZ)-induced diabetes (14-days to 28-days) would produce renal and vascular dysfunction that correlate with altered p38- mitogen-activated protein kinase (p38-MAPK) phosphorylation in kidneys and thoracic aorta. Male Sprague Dawley rats (350-400 g) were randomized into three groups: sham (N = 6), 14-days diabetic (N = 6) and 28-days diabetic rats (N = 6). Diabetes was induced using a single tail vein injection of STZ (60 mg/kg, I.V.) on the first day. Rats were monitored for 28 days and food, water intake and plasma glucose levels were noted. At both 14-days and 28-days post diabetes blood samples were collected and kidney cortex, medulla and aorta were harvested from each rat. The diabetic rats lost body weight at both 14-days (-10%) and 28-days (-13%) more significantly as compared to sham (+10%) group. Glucose levels were significantly elevated in the diabetic rats at both 14-days and 28-days post-S...

Life Sciences, 2010

We examined the effect of norepinephrine (NE) infusion on left ventricular function and apoptotic... more We examined the effect of norepinephrine (NE) infusion on left ventricular function and apoptotic genes during progression of polymicrobial sepsis. Methods: Male Sprague-Dawley rats (350-400 g) were made septic by intraperitoneal (i.p.) administration of 200 mg/kg cecal inoculum. Sham animals received 5% dextrose water, i.p. Echocardiography was performed at baseline, 3 days and 7 days post-sepsis/sham. NE (0.6 μg kg − 1 h − 1) was infused for 2 h, before the end of day 3 of echocardiography. At the end of day 7, rats were euthanized and heart tissues harvested for isolation of total RNA. PCR was performed using RT 2 profiler™ PCR array PARN-012 (Rat apoptosis array; SuperArray, MD) using RT 2 Real-Time™ SYBR Green PCR master mix PA-012. Key findings: NE-infusion resulted in a significant decrease in the left ventricular ejection fraction (EF) (62.56 ± 2.07 from the baseline 71.11 ± 3.23, p b 0.05) and fractional shortening (FS) (39.90± 2.64 from the sham group 54.41 ± 2.19, p b 0.05) at 7 days post-sepsis, respectively. Super Array data revealed that during sepsis, tumor necrosis factor (TNF-α) (2.85±0.07 fold, p b 0.0001), anti-apoptotic molecules, Prok2 (16.07± 0.48 fold, p b 0.0001) and interleukin-10 (IL-10) (23.5± 0.57 fold, p b 0.0001) were up regulated at day 1. At 7-days postsepsis, CD40lg (2.49 ± 0.54 fold, p b 0.08) and Birc1b (17.8± 0.58 fold, p b 0.0001) were up regulated compared to the sham, 1 and 3-days post-sepsis groups. Significance: The data suggest that upregulation of a series of pro-apoptotic molecules could be responsible for systolic and diastolic dysfunction during 3 and 7 days post sepsis.

Frontiers in Bioscience, 2009

Frontiers in Bioscience, 2005

$Research paper thumbnail of Norepinephrine decreases ejection fraction and downregulates sepsis-induced elevated antiapoptotic genes in a hyperdynamic polymicrobial septic rat model$

The FASEB Journal

The purpose of this research is to establish an in vitro cardiac system using primary human cardi... more The purpose of this research is to establish an in vitro cardiac system using primary human cardiomyocyte cultures (PHCC). We hypothesized that norepinephrine (NE) and endothelin-1 (ET-1) will contribute to human cardiomyocyte growth. PHCC were obtained from Celprogen, San Pedro, CA and grown with varied concentrations of NE or ET-1 for 72h. Protein expressions of contractile proteins were analyzed via Immunoblot and immunocytochemistry. Analysis of confocal images showed a significant decrease in nuclear area in all NE treatment groups. NE (10 μmol) stimulated significant increases in fluorescent intensities of the contractile proteins, f-actin, troponin and tropomyosin. The protein expression of myosin light chain was significantly lower with increasing concentrations of NE. In addition, the average cell area increased in all groups of ET-1. ET-1 (1, 10, 100 nmol) exhibited a significant decrease of fluorescent intensities of f-actin, troponin and tropomyosin. PHCC were also grown in the presence of LPS (1, 10, 100μg/ml) in a 6-well plate for 72h. Viability data showed the cells recovered from the endotoxin treatment and maintain steady growth in each concentration of LPS. In contrast to NE, ET-1 exhibited a decrease on the expression of contractile proteins in PHCC. Grant Funding Source: Office of Chief Science Officer, PCOM

PLOS ONE, 2016

Autoimmune vasculitis is an endothelial inflammatory disease that results from the deposition of ... more Autoimmune vasculitis is an endothelial inflammatory disease that results from the deposition of immune-complexes (ICs) in blood vessels. The interaction between Fcgamma receptors (FcγRs) expressed on inflammatory cells with ICs is known to cause blood vessel damage. Hence, blocking the interaction of ICs and inflammatory cells is essential to prevent the IC-mediated blood vessel damage. Thus we tested if uncoupling the interaction of FcγRs and ICs prevents endothelium damage. Herein, we demonstrate that dimeric FcγR-Igs prevented nitric oxide (NO) mediated apoptosis of human umbilical vein endothelial cells (HUVECs) in an in vitro vasculitis model. Dimeric FcγR-Igs significantly inhibited the IC-induced upregulation of inducible nitric oxide synthase (iNOS) and nitric oxide (NO) release by murine monocytic cell line. However, FcγR-Igs did not affect the exogenously added NO-induced upregulation of pro-apoptotic genes such as Bax (15 fold), Bak (35 fold), cytochrome-C (11 fold) and caspase-3 (30 fold) in HUVECs. In conclusion, these data suggest that IC-induced NO could be one of the major inflammatory mediator promoting blood vessel inflammation and endothelial cell death during IC-mediated vasculitis which can be effectively blocked by dimeric decoy FcγRs.

The Faseb Journal, Mar 1, 2008

The Faseb Journal, Apr 1, 2007