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Biomedical subjects

Guha Krishnaswamy

Publications and source records attributed to Guha Krishnaswamy.

At least 19 recordsLinked to original sources
PubMed2007

Potential mechanisms connecting asthma, esophageal reflux, and obesity/sleep apnea complex--a hypothetical review.

Obstructive sleep apnea (OSA) and asthma are potentially linked at several levels. The pathophysiology of these two conditions seems to overlap significantly, as airway obstruction, inflammation, obesity, and several other factors are implicated in the development of both diseases. Gastroesophageal reflux disease (GERD), cardiovascular complications, obesity itself, and the underlying inflammatory processes are all complex contributory factors that provide hypothetical links. Furthermore, a collateral rise in prevalence of both OSA and asthma has been noticed during the past few years, occurring in association with the emerging epidemic of obesity, a common risk factor for both conditions. OSA and asthma share many other risk factors as well. We propose a hypothetical OSA-asthma relationship that has implications on the diagnosis and management of patients presenting with either condition singly. Clinicians should be aware that OSA might complicate asthma management. Based on this hypothesis, we suggest that the treatment of the individual patient who experiences both asthma and OSA needs to be multidisciplinary and comprehensive. This hypothetical association of asthma and OSA, though described anecdotally, has not been systematically studied. In particular, the influence of continuous positive airway pressure therapy (for sleep apnea) on asthma outcomes (such as quality of life, steroid utilization, emergency room visits) and fatality needs to be studied further.

Airway Obstruction↗
PubMed2007

Osteopontin: a novel inflammatory mediator of cardiovascular disease.

Osteopontin, also called cytokine Eta-1, is a multifunctional protein containing Arg-Gly-Asp-Ser (RGDS) cell-binding sequence. It interacts with alpha(v)beta1, alpha(v)beta3 and alpha(v)beta5 integrins and CD44 receptors. OPN is suggested to play a role during inflammation via the recruitment and retention of macrophages and T-cells to inflamed sites. OPN regulates the production of inflammatory cytokines and nitric oxide in macrophages. In this review, we will discuss diverse roles of OPN related to cardiovascular diseases, including atherosclerosis, valvular stenosis, hypertrophy, myocardial infarction and heart failure.

Animals↗
PubMed2006

The Dapsone hypersensitivity syndrome revisited: a potentially fatal multisystem disorder with prominent hepatopulmonary manifestations.

4,4'-Diaminodiphenylsulphone (Dapsone) is widely used for a variety of infectious, immune and hypersensitivity disorders, with indications ranging from Hansen's disease, inflammatory disease and insect bites, all of which may be seen as manifestations in certain occupational diseases. However, the use of dapsone may be associated with a plethora of adverse effects, some of which may involve the pulmonary parenchyma. Methemoglobinemia with resultant cyanosis, bone marrow aplasia and/or hemolytic anemia, peripheral neuropathy and the potentially fatal dapsone hypersensitivity syndrome (DHS), the focus of this review, may all occur individually or in combination. DHS typically presents with a triad of fever, skin eruption, and internal organ (lung, liver, neurological and other systems) involvement, occurring several weeks to as late as 6 months after the initial administration of the drug. In this sense, it may resemble a DRESS syndrome (Drug Rash with Eosinophilia and Systemic Symptoms). DHS must be promptly identified, as untreated, the disorder could be fatal. Moreover, the pulmonary/systemic manifestations may be mistaken for other disorders. Eosinophilic infiltrates, pneumonitis, pleural effusions and interstitial lung disease may be seen. This syndrome is best approached with the immediate discontinuation of the offending drug and prompt administration of oral or intravenous glucocorticoids. An immunological-inflammatory basis of the syndrome can be envisaged, based on the pathological picture and excellent response to antiinflammatory therapy. Since dapsone is used for various indications, physicians from all specialties may encounter DHS and need to familiarize themselves with the salient features about the syndrome and its management.

Journal Article↗
PubMed2006

Intestinal strongyloidiasis and hyperinfection syndrome.

In spite of recent advances with experiments on animal models, strongyloidiasis, an infection caused by the nematode parasite Strongyloides stercoralis, has still been an elusive disease. Though endemic in some developing countries, strongyloidiasis still poses a threat to the developed world. Due to the peculiar but characteristic features of autoinfection, hyperinfection syndrome involving only pulmonary and gastrointestinal systems, and disseminated infection with involvement of other organs, strongyloidiasis needs special attention by the physician, especially one serving patients in areas endemic for strongyloidiasis. Strongyloidiasis can occur without any symptoms, or as a potentially fatal hyperinfection or disseminated infection. Th2 cell-mediated immunity, humoral immunity and mucosal immunity have been shown to have protective effects against this parasitic infection especially in animal models. Any factors that suppress these mechanisms (such as intercurrent immune suppression or glucocorticoid therapy) could potentially trigger hyperinfection or disseminated infection which could be fatal. Even with the recent advances in laboratory tests, strongyloidiasis is still difficult to diagnose. But once diagnosed, the disease can be treated effectively with antihelminthic drugs like Ivermectin. This review article summarizes a case of strongyloidiasis and various aspects of strongyloidiasis, with emphasis on epidemiology, life cycle of Strongyloides stercoralis, clinical manifestations of the disease, corticosteroids and strongyloidiasis, diagnostic aspects of the disease, various host defense pathways against strongyloidiasis, and available treatment options.

Journal Article↗
PubMed2006

The human mast cell: an overview.

Mast cells are fascinating, multifunctional, tissue-dwelling cells that have been traditionally associated with the allergic response. However, recent studies suggest these cells may be capable of regulating inflammation, host defense, and innate immunity. The purpose of this review is to present salient aspects of mast cell biology in the context of mast cell function in physiology and disease. After their development from bone marrow-derived progenitor cells that are primed with stem cell factor, mast cells continue their maturation and differentiation in peripheral tissue, developing into two well-described subsets of cells, MC(T) and MC(TC) cells. These cells can be distinguished on the basis of their tissue location, dependence on T lymphocytes, and their granule contents. Mast cells can undergo activation by antigens/allergens, superoxides, complement proteins, neuropeptides, and lipoproteins. After activation, mast cells express histamine, leukotrienes, and prostanoids, as well as proteases, and many cytokines and chemokines. These mediators may be pivotal to the genesis of an inflammatory response. By virtue of their location and mediator expression, mast cells may play an active role in many diseases, such as allergy, parasitic diseases, atherosclerosis, malignancy, asthma, pulmonary fibrosis, and arthritis. Recent data also suggest that mast cells play a vital role in host defense against pathogens by elaboration of tumor necrosis factor alpha. Mast cells also express the Toll-like receptor, which may further accentuate their role in the immune-inflammatory response. This chapter summarizes the many well-known and novel functional aspects of human mast cell biology and emphasizes their unique role in the inflammatory response.

Cell Differentiation↗
PubMed2006

Mast cell histamine and cytokine assays.

Mast cells are crucial to the development of chronic allergic inflammation and are likely to play a critical role in host defense. In this chapter methodology for histamine and cytokine assays is provided. Crosslinkage of IgE receptor I (Fc epsilonRI) on cord blood-derived mast cells by myeloma IgE and anti-human IgE is used to induce histamine release. Histamine levels were measured in the culture supernatants using an enzyme-linked immunosorbent assay. A human mast cell line (HMC-1), derived from a patient with mast cell leukemia, was activated with interleukin (IL)-1beta to study cytokine production and gene expression. Cytokine gene expression was evaluated by reverse transcriptase polymerase chain reaction and cytokine production was assayed in culture supernatants using an enzyme-linked immunosorbent assay kit.

Cell Line↗
PubMed2006

Mast cell activation by lipoproteins.

Mast cells are activated by a number of agents that act independently from immunoglobulin E (IgE)-mediated hypersensitivity. One of these agents is oxidized low-density lipoprotein (oxLDL). OxLDL has been implicated in the pathogenesis of atherosclerosis and has been shown to induce microvascular dysfunction by the activation of mast cells. In this chapter, we describe the method for isolation of human LDL, oxidation of LDL, and demonstrate that oxLDL activates mast cells by measuring messenger ribonucleic acid (mRNA) levels and protein levels of interleukin (IL)-8 an inflammatory cytokine. IL-8 is a potent chemoattractant for neutrophils and monocytes, which would result in a chronic inflammatory response. IL-8 mRNA levels were measured by reverse-transcription polymerase chain reaction and protein levels by enzyme-linked immunoassay.

Cell Line↗
PubMed2006

Bacterial activation of mast cells.

Mast cells often are found in a perivascular location but especially in mucosae, where they may response to various stimuli. They typically associate with immediate hypersensitive responses and are likely to play a critical role in host defense. In this chapter, a common airway pathogen, Moraxella catarrhalis, and a commensal bacterium, Neiserria cinerea, are used to illustrate activation of human mast cells. A human mast cell line (HMC-1) derived from a patient with mast cell leukemia was activated with varying concentrations of heat-killed bacteria. Active aggregation of bacteria over mast cell surfaces was detected by scanning electron microscopy. The activation of mast cells was analyzed by nuclear factor-kappaB (NF-kappaB) activation and cytokine production in culture supernatants. Both M. catarrhalis and N. cinerea induce mast cell activation and the secretion of two key inflammatory cytokines, interleukin-6 and MCP-1. This is accompanied by NF-kappaB activation. Direct bacterial contact with mast cells appears to be essential for this activation because neither cell-free bacterial supernatants nor bacterial lipopolysaccharide induce cytokine secretion.

Cells, Cultured↗
PubMed2006

Paul Ehrlich's "Mastzellen"--from aniline dyes to DNA chip arrays: a historical review of developments in mast cell research.

It has been more than a century since the discovery of the mast cell by the genius and tenacity of Paul Ehrlich, who described this cell when he was a medical student. One cannot deny that this discovery also coincides with the golden age of immunology. The discovery of this important cell type in immunological history was no serendipity: it was a result of Ehrlich's prodigious laboratory talent and his ability to combine intuition and deduction despite the limited resources of his times. Since then, we have learned much more about the immune response, immunoglobulin E, and the development and function of mast cells in various pathological states. What follows is a review of Paul Ehrlich's discovery of the mast cell (mästzellen) and a chronological review of subsequent developments in mast cell research, including the recent use of proteomics and genomics to understand mast cell biology.

Aniline Compounds↗
PubMed2005

Induction of p38- and gC1qR-dependent IL-8 expression in pulmonary fibroblasts by soluble hepatitis C core protein.

BACKGROUND: Recent studies suggest that HCV infection is associated with progressive declines in pulmonary function in patients with underlying pulmonary diseases such as asthma and chronic obstructive pulmonary disease. Few molecular studies have addressed the inflammatory aspects of HCV-associated pulmonary disease. Because IL-8 plays a fundamental role in reactive airway diseases, we examined IL-8 signaling in normal human lung fibroblasts (NHLF) in response to the HCV nucleocapsid core protein, a viral antigen shown to modulate intracellular signaling pathways involved in cell proliferation, apoptosis and inflammation. METHODS: NHLF were treated with HCV core protein and assayed for IL-8 expression, phosphorylation of the p38 MAPK pathway, and for the effect of p38 inhibition. RESULTS: Our studies demonstrate that soluble HCV core protein induces significant increases in both IL-8 mRNA and protein expression in a dose- and time-dependent manner. Treatment with HCV core led to phosphorylation of p38 MAPK, and expression of IL-8 was dependent upon p38 activation. Using TNFalpha as a co-stimulant, we observed additive increases in IL-8 expression. HCV core-mediated expression of IL-8 was inhibited by blocking gC1qR, a known receptor for soluble HCV core linked to MAPK signaling. CONCLUSION: These studies suggest that HCV core protein can lead to enhanced p38- and gC1qR-dependent IL-8 expression. Such a pro-inflammatory role may contribute to the progressive deterioration in pulmonary function recently recognized in individuals chronically infected with HCV.

Carrier Proteins↗
PubMed2005

HIV-1 Tat protein-induced VCAM-1 expression in human pulmonary artery endothelial cells and its signaling.

Expression of cell adhesion molecule in endothelial cells upon activation by human immunodeficiency virus (HIV) infection is associated with the development of atherosclerotic vasculopathy. We postulated that induction of vascular cell adhesion molecule-1 (VCAM-1) by HIV-1 Tat protein in endothelial cells might represent an early event that could culminate in inflammatory cell recruitment and vascular injury. We determined the role of HIV-1 Tat protein in VCAM-1 expression in human pulmonary artery endothelial cells (HPAEC). HIV-1 Tat protein treatment significantly increased cell-surface expression of VCAM-1 in HPAEC. Consistently, mRNA expression of VCAM-1 was also increased by HIV-1 Tat protein as measured by RT-PCR. HIV-1 Tat protein-induced VCAM-1 expression was abolished by the NF-kappaB inhibitor pyrrolidine dithiocarbamate (PDTC) and the p38 MAPK inhibitor SB-203580. Furthermore, HIV-1 Tat protein enhanced DNA binding activity of NF-kappaB, facilitated nuclear translocation of NF-kappaB subunit p65, and increased production of reactive oxygen species (ROS). Similarly to VCAM-1 expression, HIV-1 Tat protein-induced NF-kappaB activation and ROS generation were abrogated by PDTC and SB-203580. These data indicate that HIV-1 Tat protein is able to induce VCAM-1 expression in HPAEC, which may represent a pivotal early molecular event in HIV-induced vascular/pulmonary injury. These data also suggest that the molecular mechanism underlying the HIV-1 Tat protein-induced VCAM-1 expression may involve ROS generation, p38 MAPK activation, and NF-kappaB translocation, which are the characteristics of pulmonary endothelial cell activation.

Antioxidants↗
PubMed2005

Hepatitis C virus and the lung: implications for therapy.

Hepatitis C virus (HCV) infection is a chronic blood-borne disease that affects > 4,000,000 individuals in the United States. The majority of individuals with HVC infection acquire a chronic hepatitis that predisposes them to the complications of cirrhosis and hepatoma. Chronic HCV infection is, however, associated with multiple extrahepatic manifestations as well, including recently recognized effects on the lung. These include primary effects on lung function, as well as secondary effects in the settings of progressive liver disease and drug treatment for HCV. In this article, we discuss the emerging clinical data that support a role for HCV infection in lung disease, describe the multiple pulmonary manifestations of this viral infection, and outline the therapies available for specific pulmonary complications of chronic HCV infection.

Asthma↗
PubMed2004

MAPK-dependent regulation of IL-1- and beta-adrenoreceptor-induced inflammatory cytokine production from mast cells: implications for the stress response.

BACKGROUND: Catecholamines, such as epinephrine, are elaborated in stress responses, and mediate vasoconstriction to cause elevation in systemic vascular resistance and blood pressure. Our previous study has shown that IL-1 can induce mast cells to produce proinflammatory cytokines which are involved in atherogenesis. The aim of this study was to determine the effects of epinephrine on IL-1-induced proatherogenic cytokine production from mast cells. RESULTS: Two ml of HMC-1 (0.75 x 106 cells/ml) were cultured with epinephrine (1 x 10-5 M) in the presence or absence of IL-1 beta (10 ng/ml) for 24 hrs. HMC-1 cultured alone produced none to trace amounts of IL-6, IL-8, and IL-13. IL-1 beta significantly induced production of these cytokines in HMC-1, while epinephrine alone did not. However, IL-6, IL-8, and IL-13 production induced by IL-1 beta were significantly enhanced by addition of epinephrine. The enhancing effect appears to involve NF-kappa B and p38 MAPK pathways. Flow cytometry showed the presence of beta1 and beta2 adrenoreceptors on resting mast cells. The enhancing effect of proatherogenic cytokine production by epinephrine was down regulated by the beta1 and beta2 adrenoceptor antagonist, propranolol, but not by the beta1 adrenoceptor antagonist, atenolol, suggesting the effect involved beta2 adrenoceptors. The enhancing effect of epinephrine on proatherogenic cytokine production was also down regulated by the immunosuppressive drug, dexamethasone. CONCLUSIONS: These results not only confirm that an acute phase cytokine, IL-1 beta, regulates mast cell function, but also show that epinephrine up regulates the IL-1 beta induction of proatherogenic cytokines in mast cells. These data provide a novel role for epinephrine, a stress hormone, in inflammation and atherogenesis.

Adrenergic beta-Antagonists↗
PubMed2004

Atherosclerosis as an inflammatory disease: implications for therapy.

Cardiovascular disease remains a leading cause of mortality in the United States despite the use of new pharmacologic therapy, lifestyle modifications, and different coronary interventions. Atherosclerosis represents a wide variety of pathologic lesions with different clinical impacts. In this review, we address the current understanding of the pathophysiological mechanisms underlying the development of atherosclerosis. We define atherosclerosis as a multifactorial process representing a series of molecular and cellular mechanisms and involving multiple interactions between lipid metabolism, monocyte activation, endothelial cells, cytokines and/or other intracellular metabolic pathways. We also imply that control of atherosclerosis could be achieved through therapeutic interventions at different sites of the inflammatory process. Therapeutic targets could include cytokine pathways, growth factors, transcription factors, defective genes and other intracellular metabolic pathways.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2004

Obstructive sleep apnea, inflammation, and cardiopulmonary disease.

Obstructive sleep apnea (OSA) occurs commonly in the U.S. population and is seen in both obese as well as non-obese individuals. OSA is a disease characterized by periodic upper airway collapse during sleep, which then results in either apnea, hypopnea, or both. The disorder leads to a variety of medical complications. Neuropsychiatric complications include daytime somnolence, cognitive dysfunction, and depression. Increased incidence of motor vehicle accidents has been documented in these patients and probably reflects disordered reflex mechanisms or excessive somnolence. More importantly, vascular disorders such as hypertension, stroke, congestive cardiac failure, arrhythmias, and atherosclerosis occur frequently in these patients. The lungs may be affected by pulmonary hypertension and worsening of asthma. Recent data from several laboratories demonstrate that obstructive sleep apnea is characterized by an inflammatory response. Cytokines are elaborated during the hypoxemic episodes leading to inflammatory responses as marked clinically by elevated C-reactive protein (CRP). As elevated CRP levels are considered markers of the acute phase response and characterize progression of vascular injury in coronary artery disease, it is likely that obstructive sleep apnea could lead to worsening of vasculopathy. Moreover, as inflammatory mechanisms regulate bronchial asthma, it is also likely that cytokines and superoxide radicals generated during hypoxemic episodes could exacerbate reactive airway disease. Patients with Cough, Obstructive sleep apnea, Rhinosinusitis, and Esophageal reflux clustered together can be categorized by the acronym, "CORE", syndrome. The purpose of this manuscript is to review the inflammatory responses that occur in patients with obstructive sleep apnea and relate them to the occurrence of cardiopulmonary disease.

Acute-Phase Reaction↗
PubMed2004

Molecular regulation of interleukin-13 and monocyte chemoattractant protein-1 expression in human mast cells by interleukin-1beta.

Mast cells play pivotal roles in immunoglobulin (Ig) E-mediated airway inflammation, expressing interleukin (IL)-13 and monocyte chemoattractant protein-1 (MCP-1), which in turn regulate IgE synthesis and/or inflammatory cell recruitment. The molecular effects of IL-1beta on cytokine expression by human mast cells (HMC) have not been studied well. In this report, we provide evidence that human umbilical cord blood-derived mast cells (CBDMC) and HMC-1 cells express the type 1 receptor for IL-1. We also demonstrate that IL-1beta and tumor necrosis factor-alpha are able to induce, individually or additively, dose-dependent expression of IL-13 and MCP-1 in these cells. The induction of IL-13 and MCP-1 gene expression by IL-1beta was accompanied by the activation of IL-1 receptor-associated kinase and translocation of the transcription factor, nuclear factor (NF) kappaB into the nucleus. Accordingly, Bay-11 7082, an inhibitor of NF-kappaB activation, inhibited IL-1beta-induced IL-13 and MCP-1 expression. IL-1beta also induced IL-13 promoter activity while enhancing the stability of IL-13 messenger RNA transcripts. Dexamethasone, a glucocorticoid, inhibited IL-1beta-induced nuclear translocation of NF-kappaB and also the secretion of IL-13 from mast cells. Our data suggest that IL-1beta can serve as a pivotal costimulus of inflammatory cytokine synthesis in human mast cells, and this may be partly mediated by IL-1 receptor-binding and subsequent signaling via nuclear translocation of NF-kappaB. Because IL-1beta is a ubiquitously expressed cytokine, these findings have important implications for non-IgE-mediated signaling in airway mast cells as well as for innate immunity and airway inflammatory responses, such as observed in extrinsic and intrinsic asthma.

Active Transport, Cell Nucleus↗
PubMed2004

Eosinophilia in a patient with cyclical vomiting: a case report.

BACKGROUND: Eosinophilic gastritis is related to eosinophilic gastroenteritis, varying only in regards to the extent of disease and small bowel involvement. Common symptoms reported are similar to our patient's including: abdominal pain, epigastric pain, anorexia, bloating, weight loss, diarrhea, ankle edema, dysphagia, melaena and postprandial nausea and vomiting. Microscopic features of eosinophilic infiltration usually occur in the lamina propria or submucosa with perivascular aggregates. The disease is likely mediated by eosinophils activated by various cytokines and chemokines. Therapy centers around the use of immunosuppressive agents and dietary therapy if food allergy is a factor. CASE PRESENTATION: The patient is a 31 year old Caucasian female with a past medical history significant for ulcerative colitis. She presented with recurrent bouts of vomiting, abdominal pain and chest discomfort of 11 months duration. The bouts of vomiting had been reoccurring every 7-10 days, with each episode lasting for 1-3 days. This was associated with extreme weakness and cachexia. Gastric biopsies revealed intense eosinophilic infiltration. The patient responded to glucocorticoids and azathioprine. The differential diagnosis and molecular pathogenesis of eosinophilic gastritis as well as the molecular effects of glucocorticoids in eosinophilic disorders are discussed. CONCLUSIONS: The patient responded to a combination of glucocorticosteroids and azathioprine with decreased eosinophilia and symptoms. It is likely that eosinophil-active cytokines such as interleukin-3 (IL-3), granulocyte macrophage colony stimulating factor (GM-CSF) and IL-5 play pivotal roles in this disease. Chemokines such as eotaxin may be involved in eosinophil recruitment. These mediators are downregulated or inhibited by the use of immunosuppressive medications.

Journal Article↗