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Biomedical subjects

G Krishnaswamy

Publications and source records attributed to G Krishnaswamy.

At least 19 recordsLinked to original sources
PubMed2006

Inflammatory aspects of sleep apnea and their cardiovascular consequences.

Obstructive sleep apnea (OSA) is a common medical condition that occurs in a considerable percentage of the population. Substantial evidence shows that patients with OSA have an increased incidence of hypertension compared with individuals without OSA, and that OSA is a risk factor for the development of hypertension. It is established that OSA may be implicated in stroke and transient ischemic attacks. OSA is associated with coronary heart disease, heart failure, and cardiac arrhythmias. Pulmonary hypertension may be associated with OSA, especially in patients with pre-existing pulmonary disease. Although the exact cause that links OSA with cardiovascular disease is unknown, there is evidence that OSA is associated with a group of proinflammatory and prothrombotic factors that have been identified as important in the development of atherosclerosis. OSA is associated with increased daytime and nocturnal sympathetic activity. Autonomic abnormalities seen in patients with OSA include increased resting heart rate, decreased R-R interval variability, and increased blood pressure variability. Both atherosclerosis and OSA are associated with endothelial dysfunction, increased C-reactive protein, interleukin 6, fibrinogen, plasminogen activator inhibitor, and reduced fibrinolytic activity. OSA has been associated with enhanced platelet activity and aggregation. Leukocyte adhesion and accumulation on endothelial cells are common in both OSA and atherosclerosis. Clinicians should be aware that OSA may be a risk factor for the development of cardiovascular disease.

Biomarkers↗
PubMed2003

Moraxella catarrhalis induces mast cell activation and nuclear factor kappa B-dependent cytokine synthesis.

Human mast cells are often found perivascularly and at mucosal sites and may play crucial roles in the inflammatory response. Recent studies have suggested a prominent role for mast cells in host defense. In this study, we analyzed the effects of a common airway pathogen, Moraxella catarrhalis and a commensal bacterium, Neiserria cinerea, on activation of human mast cells. Human mast cell leukemia cells (HMC-1) were activated with either phorbol myristate acetate (PMA) and calcium ionophore or with varying concentrations of heat-killed suspensions of bacteria. Supernatants were assayed for the cytokines interleukin-4 (IL-4), granulocyte macrophage colony stimulating factor (GM-CSF), IL-6, IL-8, IL-13 and monocyte chemotactic protein-1 (MCP-1). Nuclear proteins were isolated and assayed by electrophoretic mobility shift assay (EMSA) for nuclear factor kappaB (NF-kappaB) nuclear binding activity. In some experiments, NF-kappaB inhibitor, Bay-11 was added to determine functional significance. Both M. catarrhalis and N. cinerea induced mast cell activation and selective secretion of two key inflammatory cytokines, IL-6 and MCP-1. This was accompanied by NF-kappaB activation. Neither spun bacterial supernatants nor bacterial lipopolysaccharide induced cytokine secretion, suggesting need for direct bacterial contact with mast cells. Scanning electron microscopy revealed active aggregation of bacteria over mast cell surfaces. The NF-kappaB inhibitor, Bay-11, inhibited expression of MCP-1. These findings suggest the possibility of direct interactions between human mast cells and common bacteria and provide evidence for a novel role for human mast cells in innate immunity.

Cell Line, Tumor↗
PubMed2002

Insulin: a novel factor in carcinogenesis.

Cancer is a leading cause of mortality in the United States. Despite much research on specific carcinogens, the cause of many cancers remains unclear. The identification of novel causative agents offers the potential for cancer prevention. Diseases such as obesity and diabetes mellitus, characterized by hyperinsulinemia, are associated with increased risk of endometrial, colorectal, and breast carcinomas. There is increasing evidence that insulin is a growth factor for tumor formation. The mechanisms underlying insulin-mediated neoplasia may include enhanced DNA synthesis with resultant tumor cell growth, inhibition of apoptosis, and altered sex hormone milieu. The reduced insulin levels seen with physical activity, weight loss, and a high fiber diet may account for decreased cancer risk. The role of newer drugs that restore sensitivity to insulin, thereby reducing hyperinsulinemia, is an exciting potential area of cancer prevention. In this review, we discuss the potential role of insulin as a tumor growth factor.

Animals↗
PubMed2001

Identification of a novel cytokine, ML-1, and its expression in subjects with asthma.

A novel gene, designated ML-1, was identified from a human genomic DNA clone and human T cell cDNA sequences. The second exon of ML-1 gene shares significant sequence identity with the gene encoding IL-17 (IL-17). ML-1 gene expression was up-regulated in activated PBMCs, CD4(+) T cells, allergen-specific Th0, Th1, and Th2 clones, activated basophils, and mast cells. Increased expression of the ML-1 gene, but not IL-17, was seen following allergen challenge in four asthmatic subjects, suggesting its role in allergic inflammatory responses. ML-1 from transiently transfected COS-7 cells was able to induce gene expression and protein production for IL-6 and IL-8 (at 10 ng/ml of ML-1: for IL-6, 599.6 +/- 19.1 pg/ml; for IL-8, 1724.2 +/- 132.9 pg/ml; and at 100 ng/ml of ML-1: for IL-6, 1005.3 +/- 55.6 pg/ml; for IL-8, 4371.4 +/- 280.5 pg/ml; p < 0.05 for both doses vs baseline) in primary bronchial epithelial (PBE) cells. Furthermore, increased expression of ICAM-1 was found in ML-1-stimulated PBE cells (mean fluorescence intensity (MFI) = 31.42 +/- 4.39 vs baseline, MFI = 12.26 +/- 1.77, p < 0.05), a functional feature distinct from IL-17 (MFI = 11.07 +/- 1.22). This effect was not inhibited by a saturating amount of IL-17. These findings demonstrate that ML-1 is a novel cytokine with a distinct function, and suggest a different receptor for ML-1 on PBE cells.

Amino Acid Sequence↗
PubMed2001

The human mast cell: functions in physiology and disease.

Mast cells are multifunctional, tissue-dwelling cells capable of secreting a wide variety of mediators. They develop from bone marrow-derived progenitor cells, primed with stem cell factor (SCF), which mediates its actions by interacting with the SCF receptor or c-kit on the cell surface. Mast cells continue their maturation and differentiation in peripheral tissue, developing into two well described subsets of cells, MCT and MCTC cells, varying in content of tryptase and chymase as well as in immunobiology. Mast cells are activated by numerous stimuli, including antigen (acting via the high affinity IgE receptor, Fc?RI), superoxides, complement proteins, neuropeptides and lipoproteins resulting in activation and degranulation. Following activation, these cells express mediators such as histamine, leukotrienes and prostanoids, as well as proteases, and many cytokines and chemokines, pivotal to the genesis of an inflammatory response. Recent data suggests that mast cells may play an active role in such diverse diseases as atherosclerosis, malignancy, asthma, pulmonary fibrosis and arthritis. Mast cells directly interact with bacteria and appear to play a vital role in host defense against pathogens. Drugs, such as glucocorticoids, cyclosporine and cromolyn have been demonstrated to have inhibitory effects on mast cell degranulation or mediator release.

Arteriosclerosis↗
PubMed2001

Treatment strategies for bronchial asthma: an update.

Advances in understanding the biomolecular basis of the disease's inflammatory and remodeling responses are offering new therapeutic choices--and sometimes new drug-delivery systems--in categories such as beta-agonists, glucocorticoids, and leukotriene blockers. Meanwhile, researchers are exploring novel targets, including intercellular signals and cell-adhesion and gene-activating molecules.

Administration, Inhalation↗
PubMed2001

Acute and chronic urticaria. Challenges and considerations for primary care physicians.

Urticaria and angioedema are common dermatologic problems seen by primary care physicians. A carefully taken history, physical examination, specific tests, and skin biopsy often provide useful diagnostic information. In patients with chronic urticaria, urticarial vasculitis and diseases that mimic urticaria need to be ruled out. A variety of treatment options are available for patients with urticaria and urticarial vasculitis. Pharmacologic therapy is useful when the specific cause is undetermined. When a trigger has been identified, the patient must avoid exposure to it. Patient education is an important component of management and should include instructions on crisis management, particularly for patients who have angioedema or a tendency for anaphylaxis.

Acute Disease↗
PubMed2001

Reactive and clonal thrombocytosis: proinflammatory and hematopoietic cytokines and acute phase proteins.

BACKGROUND: We quantitated proinflammatory and thrombopoietic cytokines in reactive thrombocytosis (RT) and clonal thrombocytosis (CT) to identify a cytokine profile that might aid in the distinction of these two disorders. METHODS: Serum levels of cytokines relevant to platelet biology--interleukins 3, 6, 11, and 1beta; thrombopoietin; tumor necrosis factor alpha; and C-reactive protein (CRP)--were measured by enzyme-linked immunosorbent assay in healthy subjects and in patients with CT and RT. RESULTS: Interleukin-6 and CRP levels were higher in RT patients than in controls or CT patients. Interleukin 1beta levels were higher in the RT group than in the CT and control groups. CONCLUSIONS: In RT, IL-6, IL-1beta, and CRP levels are elevated. In both RT and CT, IL-11 is elevated, but thrombopoietin levels are not.

Adult↗
PubMed2000

The molecular role of mast cells in atherosclerotic cardiovascular disease.

Human atherosclerosis has many characteristics of an inflammatory disorder. Recent data suggest that mast cells might be important in the pathogenesis of atherosclerotic disease. By secretion of pro-inflammatory cytokines, mast cells can assist in the recruitment of monocytes and lymphocytes into vascular tissue, thereby propagating the inflammatory response. Mast cell enzymes might activate pro-metalloproteinases, thereby destabilizing atheromatous plaques. Mast cells can facilitate foam cell formation by promoting cholesterol accumulation. However, mast cell tryptase could slow thrombus formation at sites of plaque rupture by interfering with coagulation. Therefore, mast cells can modulate coronary artery disease by both facilitatory and inhibitory pathways.

Arteriosclerosis↗
PubMed2000

The effects of HIV infection on endothelial function.

Endothelial dysfunction and/or injury is pivotal to the development of cardiovascular and inflammatory pathology. Endothelial dysfunction and/or injury has been described in Human Immunodeficiency Virus (HIV) infection. Elaboration of circulating markers of endothelial activation, such as soluble adhesion molecules and procoagulant proteins, occurs in HIV infection. Certain endothelial cells, such as those lining liver sinusoids, human umbilical vein endothelial cells, bone marrow stromal endothelial cells or brain microvascular endothelial cells, have been shown to be variably permissive for HIV infection. Entry of virus into endothelial cells may occur via CD4 antigen or galactosyl-ceramide receptors. Other mechanisms of entry including chemokine receptors have been proposed. Nevertheless, endothelial activation may also occur in HIV infection either by cytokines secreted in response to mononuclear or adventitial cell activation by virus or else by the effects of the secreted HIV-associated proteins, gp 120 (envelope glycoprotein) and Tat (transactivator of viral replication) on endothelium. Enhanced adhesiveness of endothelial cells, endothelial cell proliferation and apoptosis as well as activation of cytokine secretion have all been demonstrated. Synergy between select inflammatory cytokines and viral proteins in inducing endothelial injury has been shown. In HIV infection, dysfunctional or injured endothelial cells potentiate tissue injury, inflammation and remodeling, and accelerate the development of cardiovascular disease.

Animals↗
PubMed2000

Difficult-to-manage asthma. How to pinpoint the exacerbating factors.

In difficult-to-manage asthma, effective control depends on identification and alleviation of exacerbating factors, such as ongoing allergen exposure, chronic sinusitis, GERD, and emotional stress. Level of compliance with the prescribed medication regimen should be evaluated in all patients. Hormonal factors (i.e., menses, use of exogenous hormones by female patients, and hyperthyroidism) also can exacerbate asthma. When aggressive management fails, the possibility of a misdiagnosis should be considered. Other conditions that can mimic asthma include COPD, congestive heart failure, airway obstruction due to various causes, vocal cord dysfunction, and esophageal spasm. Referral to an asthma specialist is advised in severe or resistant cases.

Algorithms↗
PubMed1999

Vulnerable plaque.

Explore the source record for details and available documents.

Arteriosclerosis↗
PubMed1999

Long-term exercise and atherogenic activity of blood mononuclear cells in persons at risk of developing ischemic heart disease.

CONTEXT: Increasing evidence demonstrates that atherosclerosis is an immunologically mediated disease in which the secretion of atherogenic and atheroprotective cytokines, by infiltrating blood mononuclear cells, plays an important role. It is not known whether long-term exercise alters this atherogenic and atheroprotective activity directly. OBJECTIVE: To determine the effect of long-term exercise on the atherogenic activity of blood mononuclear cells in persons at risk of developing ischemic heart disease. DESIGN: Before-after trial using a 6-month individualized, supervised exercise program, with an enrollment period from December 1996 to October 1997. SETTING: Hospital-based community wellness center. PARTICIPANTS: Of 110 persons who responded to a public request for volunteers, 52 met the inclusion criteria (risk ratio for myocardial infarction > or =1.7 based on serum complement and/or C-reactive protein levels, and normal exercise treadmill test results). Forty-three of the 52 enrollees (25 women [mean age, 49.7 years] and 18 men [mean age, 48.1 years]) completed the study; 9 withdrew for personal reasons. Additional risk factors for ischemic heart disease included hypercholesterolemia (65.1 %), a family history of coronary heart disease (62.8%), inactivity (60.5%), hypertension (32.6%), obesity (25.6%), smoking (11.6%), and diabetes mellitus (4.7%). MAIN OUTCOME MEASURES: Blood levels were compared at baseline and after the exercise program had been completed for the following: spontaneous and phytohemagglutinin-induced production of interleukin 1 alpha, tumor necrosis factor alpha, and interferon gamma (atherogenic cytokines), and interleukin 4, interleukin 10, and transforming growth factor beta 1 (atheroprotective cytokines) by blood mononuclear cells; lymphocyte phenotypes and mitogenic responses to phytohemagglutinin; and serum C-reactive protein levels. RESULTS: Subjects exercised for a mean of 2.5 (range, 0.3-7.4) hours per week. Mononuclear cell production of atherogenic cytokines fell by 58.3 % (P<.001) following the exercise program, where as the production of atheroprotective cytokines rose by 35.9% (P<.001). Changes in transforming growth factor beta 1 and in phytohemagglutinin-induced atherogenic cytokine production after the exercise program were proportionate to the time subjects spent performing repetitive lower-body motion exercises (P<.02), indicating a dose-response relationship. After the exercise program, changes in cellular function were reflected systemically by a 35% decrease in serum levels of C-reactive protein (P=.12). CONCLUSIONS: Our data suggest that long-term exercise decreases the atherogenic activity of blood mononuclear cells in persons at risk of developing ischemic heart disease. This may be a mechanism whereby physical activity protects against ischemic heart disease.

Arteriosclerosis↗
PubMed1999

Differential regulation of antigen-induced IL-4 and IL-13 generation from T lymphocytes by IFN-alpha.

BACKGROUND: IL-4 and IL-13 are related cytokines with similar functional properties. Differential regulation of IL-4 and IL-13 has not been described. OBJECTIVE: We have examined the effects of IFN-alpha on antigen-driven proliferation, IL-4 generation, and IL-13 generation from human PBMCs and T-cell clones. METHODS: Proliferation was assessed by 3H-thymidine incorporation. Cytokine generation was assessed by reverse transcription PCR and ELISA. Messenger RNA stability was assessed in the presence of actinomycin D. RESULTS: IFN-alpha induced a concentration-dependent inhibition of antigen-driven proliferation of TH1 and TH2 clones (median effective concentration, 150 to 200 U/mL); the sensitivity of TH1 and TH2 clones to IFN-alpha was not significantly different (P =.6). IFN-alpha induced an analogous concentration-dependent inhibition of antigen-driven IL-13 generation from TH1 and TH2 clones (median effective concentration, 100 U/mL); this effect was evident by 12 hours of culture and persisted beyond 48 hours. However, IL-4 generation from TH2 clones was insensitive to IFN-alpha at all concentrations and times tested (1 to 10,000 U/mL). A similar inhibitory effect of IFN-alpha on mitogen-driven proliferation and IL-13 generation from PBMCs was demonstrated; once again, IL-4 generation from PBMCs was insensitive to IFN-alpha. IL-13 mRNA stability was unaffected by IFN-alpha, suggesting transcriptional regulation. CONCLUSION: IFN-alpha differentially regulates antigen-stimulated IL-4 and IL-13 generation.

Adult↗
PubMed1999

Human endothelium as a source of multifunctional cytokines: molecular regulation and possible role in human disease.

Endothelial cells, by virtue of their capacity to express adhesion molecules and cytokines, are intricately involved in inflammatory processes. Endothelial cells have been shown to express interleukin-1 (IL-1), IL-5, IL-6, IL-8, IL-11, IL-15, several colony-stimulating factors (CSF), granulocyte-CSF (G-CSF), macrophage CSF (M-CSF) and granulocyte-macrophage CSF (GM-CSF), and the chemokines, monocyte chemotactic protein-1 (MCP-1), RANTES, and growth-related oncogene protein-alpha (GRO-alpha). IL-1 and tumor necrosis factor-alpha (TNF-alpha) produced by infiltrating inflammatory cells can induce endothelial cells to express several of these cytokines as well as adhesion molecules. Induction of these cytokines in endothelial cells has been demonstrated by such diverse processes as hypoxia and bacterial infection. Recent studies have demonstrated that adhesive interactions between endothelial cells and recruited inflammatory cells can also signal the secretion of inflammatory cytokines. This cross-talk between inflammatory cells and the endothelium may be critical to the development of chronic inflammatory states. Endothelial-derived cytokines may be involved in hematopoiesis, cellular chemotaxis and recruitment, bone resorption, coagulation, and the acute-phase protein synthesis. As many of these processes are critical to the maturation of an inflammatory and reparative state, it appears likely that endothelial-derived cytokines play a crucial role in several diseases, including atherosclerosis, graft rejection, asthma, vasculitis, and sepsis. Genetic and pharmacologic manipulation of endothelial-derived cytokines provides an additional approach to the management of chronic inflammatory diseases.

Arteriosclerosis↗
PubMed1998

Multifunctional cytokine expression by human coronary endothelium and regulation by monokines and glucocorticoids.

Human endothelium is capable of expressing a variety of molecules, including cytokines and growth factors, critical to inflammation. This aspect of coronary endothelium has not been studied in detail. In this study, we report, for the first time, expression of multifunctional cytokines by human coronary artery endothelial cells (HCAEC) and their regulation by inflammatory cytokines and glucocorticoids. We also compared expression of cytokine transcripts in two additional cell lines derived from pulmonary artery (HPAEC) and umbilical vein (HUVEC) endothelium. HCAEC expressed transcripts for interleukin 5 (IL-5), IL-6, IL-8, and monocyte chemotactic protein-1 (MCP-1) constitutively. Induction of IL-1alpha, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), and MCP-1 was seen following treatment with TNFalpha. We found no expression of IL-1RA, IL-2, IL-4, IL-13, TNF-alpha, or IFN-gamma in HCAEC. IL-1beta and TNF-alpha synergistically induced IL-6 and GM-CSF and additively induced IL-8 and MCP-1 production, while IL-2, IL-10, IFN-alpha, and IFN-gamma had little or no additional effects. Interestingly, no IL-1alpha or IL-5 protein product was found even after maximal stimulation of HCAEC. No significant differences were seen in the profile of cytokine genes expressed by HCAEC, HPAEC, or HUVEC. Glucocorticoids inhibited IL-8 production from all three cell lines. This study demonstrates that human coronary endothelial cells are capable of expressing a wide variety of multifunctional cytokines which may be of relevance to vascular inflammation.

Cell Line↗