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Biomedical subjects

G Krishnaswamy

Publications and source records attributed to G Krishnaswamy.

At least 19 recordsLinked to original sources
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↗
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↗
PubMed1997

Prostaglandin H synthase expression is variable in human colorectal adenocarcinoma cell lines.

The expression of prostaglandin H synthases can be induced by many stimuli and is likely to be important in control of the cell cycle. The analysis of prostaglandin H synthase-1 and -2 expression in colon adenocarcinoma cell lines is a useful model system for studying the function of the prostaglandin H synthases, especially with regard to proliferation and adhesion. Prostaglandin H synthase-1 protein is not found in any of eight human colon adenocarcinoma cell lines. Expression of prostaglandin H synthase-2 is variable for the eight cell lines: three constitutively expressed active protein, four did not express this gene at all, and one had mRNA but no active protein. Thus, five colorectal adenocarcinoma cell lines exhibit "null" expression of prostaglandin synthase-2. The three cell lines with constitutive expression of prostaglandin H synthase-2 produce PGE2. Prostaglandin E2 production could be inhibited by aspirin and NS398 without inhibiting proliferation, while direct addition of prostaglandin E2 inhibits proliferation. Adhesion to collagen IV and fibronectin was stronger in those cell lines that expressed prostaglandin H synthase-2. The constitutive expression of prostaglandin H synthase-2 is associated with increased adhesion to extracellular matrix components and a potential inhibition of proliferation through the production of prostaglandin E2. The absence of PGH synthase-2 expression in some cell lines may result from the original tumor's need to inactivate these associated functions. Our evidence suggests that PGH synthase-2 is a possible candidate for a tumor suppressor gene at 1q23-qter.

Adult↗
PubMed1997

Immunologic investigations of T-cell regulation of human IgE antibody secretion and allergic responses.

The pathophysiology of allergic disease is multifactorial, involving an intricate network of interactions among cells, mediators, and cytokines. Substantial progress has been made in defining the role of antigen-specific T cells and cytokines in the regulation of immunoglobulin E (IgE) synthesis and the atopic diseases. The development of antigen-specific T-cell lines and clones has facilitated efforts to characterize human T-cell subsets and their cytokine repertoires. Molecular methods currently available include techniques for the quantitative analysis of cytokine gene expression and secretion from activated T cells ex vivo as well as in tissues. The availability of these newly developed techniques has become essential to the investigation of the pharmacologic regulation of T cells and cytokines both in vitro and in vivo. Future investigations will contribute to our understanding of the differential regulation of T-cell subsets and their relationships to allergic diseases, ultimately leading to a better understanding of the molecular pathogenesis of allergic diseases and the design of more effective therapeutic interventions.

Cytokines↗
PubMed1997

Multifunctional cytokine expression by human mast cells: regulation by T cell membrane contact and glucocorticoids.

Human mast cells readily release a variety of mediators, including cytokines, in response to IgE receptor crosslinking, but the mechanisms governing the expression of cytokines are still unclear. Using a human mast cell line, HMC-1, we show expression of cytokine transcripts as early as 2 h after activation with ionomycin and phorbol myristate acetate (PMA). Resting HMC-1 cells expressed transcripts for interleukin-1 receptor antagonist (IL-1RA), IL-2, IL-4, IL-5, GM-CSF, and weakly for IL-8, and stimulation with ionomycin and PMA induced additional transcripts for IL-6 and IL-13 and upregulated expression of IL-8 transcripts. HMC-1 cells secreted IL-4, IL-8, and GM-CSF protein after activation and dexamethasone significantly inhibited the production of these cytokines. Of significance is the finding that the addition of membranes purified from activated T cells to mast cell cultures induced transcripts selectively for IL-8 and none for other proinflammatory cytokines. Flow cytometry revealed that resting HMC-1 cells express CD40, a molecule involved in contact-dependent signaling of monocytes and B cells by T cells. However, activation of HMC-1 by anti-CD40 antibody did not induce IL-8 gene expression or protein production. This study demonstrates that human mast cells are capable of expressing multiple cytokines that can be inhibited by glucocorticoids. It also raises the possibility that T cells may activate mast cell cytokine synthesis by novel contact-dependent mechanisms. This phenomenon of T cell regulation of mast cell function requires further study.

Anti-Inflammatory Agents↗
PubMed1996

A newly developed PCR assay of H. pylori in gastric biopsy, saliva, and feces. Evidence of high prevalence of H. pylori in saliva supports oral transmission.

We have recently developed a new PCR assay for the detection of H. pylori. In this study, the polymerase chain reaction (PCR) assay was used to detect H. pylori in 88 gastric biopsy, 85 saliva, and 71 fecal specimens from 88 patients. H. pylori infection was confirmed in 71 of 88 patients by culture and/or histological stain of gastric biopsies. Serum IgG antibody to H. pylori was also measured and resulted in 97% sensitivity and 94% specificity. H. pylori DNA was detected by the PCR assay in gastric biopsy specimens from all 71 patients (100% sensitivity) with proven gastric H. pylori infection but not from 17 noninfected patients (100% specificity). In saliva specimens, H. pylori DNA was identified in 57 of the 68 patients (84%) with proven gastric H. pylori infection and in three of the 17 patients without gastric H. pylori infection. However, the PCR assay was only able to detect H. pylori DNA in the feces from 15 of 61 patients (25%) with proven gastric H. pylori infection and one of the 10 patients without gastric H. pylori infection. The results show that the PCR assay is reliable for detecting the presence of H. pylori in gastric biopsy and saliva specimens. The data indicate that H. pylori exists in a higher prevalence in saliva than feces and that the fecal-oral route may be an important means of transmission of this infection in developing countries but not as significant as previously suspected in the developed countries. It is likely that the oral-oral route is more prominent.

Antibodies, Bacterial↗
PubMed1996

Persistent urticarial eruption in an asthmatic patient.

This case demonstrates the importance of recognizing urticarial vasculitis in patients with chronic urticarial eruptions. The salient points in history that point towards the diagnosis of urticarial vasculitis include the presence of painful urticarial lesions that last longer than 24 hours and that heal leaving residual pigmentation. In some cases the urticaria may evolve into palpable purpura. An associated systemic illness that may resemble systemic lupus erythematosus should also suggest the diagnosis, which is established by skin biopsy. Histopathology reveals a leukocytoclastic vasculitis involving postcapillary venules. When associated with systemic vasculitis, the urticaria is likely to be of the hypocomplementemic variety, with immunoglobulin and complement deposition on biopsies, and with serum complement studies demonstrating classical pathway activation, low C1q levels, and anti-C1q precipitins. A variety of agents have been used in the management of urticarial vasculitis, including aspirin, nonsteroidal anti-inflammatory agents, corticosteroids, colchicine, dapsone, hydroxychloroquine, and cytotoxic agents such as cyclophosphamide and azathioprine.

Adult↗
PubMed1996

Lymphoblastoid interferon-alpha inhibits T cell proliferation and expression of eosinophil-activating cytokines.

T cell-derived cytokines, such as interleukin-5 (IL-5) and granulocyte-macrophage colony-stimulating factor (GM-CSF) activate eosinophils, whereas other cytokines, such as tumor necrosis factor (TNF)-alpha and IL-13, determine eosinophil recruitment. Interferon-alpha (IFN-alpha), a leukocyte-derived cytokine, has been shown to have beneficial effects in eosinophil-mediated disorders, such as the hypereosinophilic syndrome and a murine model of allergic asthma, where it inhibited eosinophil recruitment. We tested the hypothesis that IFN-alpha acted in eosinophil-mediated disorders by modulating T cell cytokine expression. Peripheral blood mononuclear cells (PBMC) or human ragweed-specific TH1 (2B8) and TH2 (2D2) T cell clones were cultured in the presence of 5 micrograms/ml of phytohemagglutinin (PHA) or 25 micrograms/ml of antigen Amb a 1 (short ragweed allergen), respectively, and lymphoblastoid IFN-alpha (varying from 0 to 10,000 U/ml). We assessed T cell proliferation by [3H]thymidine incorporation and production of IL-5 and GM-CSF by ELISA. Expression of cytokine transcripts was analyzed by the reverse transcription-polymerase chain reaction technique (RT-PCR). IFN-alpha induced a dose-dependent suppression of T cell proliferation of both PBMC (p < 0.001) and the T cell clones (p < 0.001). IFN-alpha inhibited gene expression of IL-5, GM-CSF, TNF-alpha, and IL-13 in PBMC. Furthermore, IFN-alpha significantly inhibited mitogen-induced and antigen-induced production of IL-5 and GM-CSF. IFN-alpha may benefit eosinophil-mediated disorders by inhibiting T cell function and production of cytokines active on human eosinophils.

Adult↗
PubMed1996

Resolution of the neutropenia of Felty's syndrome by longterm administration of recombinant granulocyte colony stimulating factor.

Felty's syndrome is characterized by neutropenia, splenomegaly, and recurrent infection in patients with rheumatoid arthritis. We used recombinant granulocyte colony stimulating factor (rGCSF) in a patient with Felty's syndrome and recurrent sepsis. rGCSF induced a statistically significant increase in the patient's absolute neutrophil and total white blood cell counts. During 14 months of followup taking rGCSF, disseminated varicella zoster was the only infectious complication. Except mild thrombocytopenia and a transient flare of arthritis, no serious adverse effects occurred. rGCSF may be a safe and effective therapy for Felty's syndrome in selected patients.

Aged↗
PubMed1996

Effect of interferon alpha on HLA-DR expression by human buccal epithelial cells.

/We have studied the effect of interferon alpha (IFN-alpha) on MHC class II expression by human buccal epithelial cells (BEC), and mRNA expression by BEC and mucosal-associated mononuclear cells (MAMC). In 6 experiments, freshly collected BEC were suspended at a concentration of 1.0 x 10(5)/ml in RPMI 1640 and incubated in the presence of 0-10,000 IU/ml of human lymphoblastoid IFN-alpha (HuIFN-alpha). Zero and six hour samples were analyzed by single color flow cytometry using FITC-labeled murine IgG1 monoclonal antibody to HLA-DR. Preparations were also analyzed for expression of cytokine transcripts (IL-2, IL-4, IL-5, IL-6, IL-8, IFN-gamma, GM-CSF) by reverse transcriptase polymerase chain reaction (RT-PCR). Increasing concentrations of IFN-alpha resulted in proportionate increases in the percentage of HLA-DR + BEC (r = 0.7897, p = 0.0627) and in the percentage of HLA-DR+ staining at higher intensities (10(1) to 10(2) log fluorescence intensity) (LFI) (r = 0.4010, p = 0.0424). The percentage of HLA-DR + BEC rose from a mean of 1.5% with no IFN-alpha to 7% with 10,000 IU/ml IFN-alpha (p < 0.05). The percentage of HLA-DR + BEC staining at 10(1) to 10(2) LFI rose from a mean of 8.3% with no added IFN-alpha to 19.2% with 10,000 IU/ml IFN-alpha (p < 0.05). Unstimulated BEC constitutively expressed IL-8 and GM-CSF. IFN-alpha stimulated preparations also expressed IFN-gamma, possibly due to the presence of MAMC, which comprised 2-9% of the total cell population. These data indicated that HuIFN-alpha upregulates MHC class II expression by human BEC, possibly by enhancing IFN-gamma production by MAMC present in the culture preparations.

Cells, Cultured↗
PubMed1995

Appearance of drug-resistant tuberculosis in rural Tennessee.

Drug-resistant tuberculosis (DRTB) is a growing national health concern in both urban populations and rural areas and is exacerbated by the growing epidemic of human immunodeficiency virus (HIV) infection. Between 1989 and 1992, 7 cases of DRTB (5 with multidrug-resistance) were diagnosed in an eight-county region of East Tennessee. During 1990 and 1991 alone, 5 of 100 patients with tuberculosis had drug-resistant strains (5%). All 7 patients with DRTB had 100% resistance to isoniazid; 5 also had resistance to streptomycin, 2 to rifampin, and 1 to pyrazinamide and ethambutol. All patients were white, U.S.-born, and without evidence of HIV infection. Contact investigation revealed that more contacts of patients with DRTB (13 of 74, 18%) were infected than were contacts of patients with drug-sensitive tuberculosis (46 of 290, 16%). Our study demonstrates that DRTB is not confined to geographically distinct areas, but may be a subtle and easily missed diagnosis in presumably low-risk rural populations.

Adult↗