Role of Kupffer cells and toll-like receptor 4 in acetaminophen-induced acute liver failure.

Background: Significant morbidity associated with acute liver failure (ALF) is from the systemic inflammatory response syndrome (SIRS). Toll-like receptor 4 (TLR4) has been shown to play an integral role in the modulation of SIRS. However, little is known about the mechanistic role of TLR4 in ALF.

Disparate roles of marrow- and parenchymal cell-derived TLR4 signaling in murine LPS-induced systemic inflammation.

Systemic inflammatory response syndrome (SIRS) occurs in a range of infectious and non-infectious disease processes. Toll-like receptors (TLRs) initiate such responses. We have shown that parenchymal cell TLR4 activation drives LPS-induced systemic inflammation; SIRS does not develop in mice lacking TLR4 expression on parenchymal cells.

LPS-induced murine systemic inflammation is driven by parenchymal cell activation and exclusively predicted by early MCP-1 plasma levels.

Systemic inflammation remains a major cause of morbidity and mortality in the United States, across many disease processes. One classic murine model to study this syndrome is lipopolysaccharide (LPS)-induced Toll-like receptor 4 (TLR4)-dependent systemic inflammation. Although most studies have focused on inflammatory cell TLR4 responses, parenchymal cells also express TLR4.

Nifedipine in compounded oral and topical preparations.

The purpose of this study was to evaluate nifedipine oral and topical compounding formulas and procedures. Topical preparations were compounded in Plastibase 50 W, using combinations of two drug sources and four types of light exposure. Oral preparations were compounded using combinations of two drug sources, two types of light exposure, and four suspending vehicles.

Sirolimus affects cardiomyocytes to reduce left ventricular mass in heart transplant recipients.

Aims: The cellular mechanisms underlying cardiac hypertrophy may result from changes in cardiac myocyte growth and differentiation. We tested whether sirolimus, an immunosuppressive agent that inhibits mTOR, a protein that regulates cell division and differentiation, might modify cardiac hypertrophy after cardiac transplantation.

Methods And Results: Fifty-eight cardiac transplant recipients were withdrawn from treatment with calcineurin inhibitors (CNIs) and treated with sirolimus.

Constitutive repression of interleukin-1alpha in endothelial cells.

Activation of complement stimulates inflammation and provides an initial vigorous defense against infection. Insertion of the membrane attack complex in cell membranes of vascular endothelial cells induces changes in cell differentiation that promote coagulation, thrombosis, inflammation, and immunity. These changes are mediated by production of interleukin (IL)-1alpha by endothelial cells, which acts locally on endothelial cells to contain infection and promote healing of the affected site.

Monocyte-mediated T cell suppression by HIV-2 envelope proteins.

HIV-2 is associated with an attenuated form of HIV disease. We investigate here the immunosuppressive effects of the HIV-2 envelope protein, gp105. We found that gp105 suppresses activation of T cells through a monocyte-mediated mechanism.

Pivotal advance: endogenous pathway to SIRS, sepsis, and related conditions.

TLRs are usually thought to recognize substances produced by microorganisms and thus, to initiate host defenses. This concept, however, fails to explain some functions of this family of receptors. Recognition of endogenous substances may explain the broader functions of TLRs in physiology and disease.

Toward a modern concept of sepsis: new answers to ancient questions.

It is commonly thought that bacterial endotoxin such as lipopolysaccharide (LPS) causes sepsis. Authors argue that LPS is merely a disease marker. The real mechanism of sepsis lies in the Toll-like receptors that suppress sepsis caused by tissue injury or endotoxin.

In vivo and in vitro degradation of heparan sulfate (HS) proteoglycans by HPR1 in pancreatic adenocarcinomas. Loss of cell surface HS suppresses fibroblast growth factor 2-mediated cell signaling and proliferation.

Heparan sulfate proteoglycans (HSPGs) function as a co-receptor for heparin-binding growth factors, such as fibroblast growth factors (FGFs) and heparin-bound epidermal growth factor (HB-EGF). The HS side chain of HSPGs can be cleaved by HPR1 (heparanase-1), an endoglycosidase that is overexpressed in many types of malignancies. In the present study, we demonstrated that HPR1 expression in pancreatic adenocarcinomas inversely correlated with the presence of heparan sulfate (HS) in the basement membrane.

In vivo effects of lipopolysaccharide and TLR4 on platelet production and activity: implications for thrombotic risk.

Gram-negative bacteria release LPS, which activates Toll-like-receptor-4 (TLR4) in the host, initiating an inflammatory response to infection. Infection increases risk for thrombosis. Platelets contribute to defense from infection and to thrombosis.

Differential regulation of endothelial cell activation by complement and interleukin 1alpha.

Activation of complement on endothelium triggers physiological changes that promote coagulation, thrombosis, and inflammation. Unlike agonists such as cytokines and endotoxin that induce these changes through transcription of many genes, complement, particularly the membrane attack complex, primarily induces release of IL-1alpha by the endothelial cells; the cytokine may then be removed by normal blood flow or may promote activation of the full range of endothelial cell responses in an autocrine or paracrine manner. We studied the intracellular signaling pathways used by complement to activate interleukin (IL)-1alpha transcription in cultured endothelial cells.

Elevated serum heparanase-1 levels in patients with pancreatic carcinoma are associated with poor survival.

Background: It has previously been shown that heparanase-1 (HPR1), an endoglycosidase, is up-regulated in pancreatic carcinoma. The purpose of this study was to test whether serum HPR1 levels in pancreatic carcinoma patients are elevated, and whether higher serum HPR1 levels are associated with a shortened survival.

Methods: Serum HPR1 levels in 40 healthy donors, 31 pancreatic carcinoma patients, and 11 patients treated with gemcitabine were measured by a novel enzyme-linked immunoadsorbent assay.

The etiology of sepsis: turned inside out.

The sepsis syndrome is thought to occur when microbial products activate Toll-like receptors stimulating widespread inflammation, in turn causing organ failure, shock and death. However, recent discoveries reveal that: (i) not only microbial substances but also endogenous molecules can trigger Toll-like receptors; (ii) Toll-like receptor-4, the endotoxin receptor, is constitutively suppressed; and (iii) the first step in sepsis could be the release of Toll-like receptor-4 from suppression. These discoveries suggest that endotoxin might not always initiate the sepsis syndrome and they explain why anti-endotoxin therapies fail.

Conditional signaling by Toll-like receptor 4.

Signaling through Toll-like receptor 4 (TLR4) is thought to initiate innate and adaptive immune responses. Signaling of TLR4 is usually studied using isolated cells, which are activated by sub-nanomolar concentrations of lipopolysaccharide (LPS). However, in normal tissues, cells bearing TLR4 reside in microenvironments containing large amounts of endogenous substances that can stimulate the receptor.

Selective suppression of Toll-like receptor 4 activation by chemokine receptor 4.

The response of Toll-like receptor 4 (TLR4) to lipopolysaccharide (LPS) is thought vital for resisting infection. Since aberrant TLR4 signaling may initiate inflammatory conditions such as the sepsis syndrome, we sought a component of normal cells that might provide local control of TLR4 activation. We found that antibodies that block chemokine receptor 4 (CXCR4) function enhanced TLR4 signaling, while increased expression of CXCR4 or addition of the CXCR4 ligand SDF-1 suppressed TLR4 signaling induced by LPS.

Acute vascular rejection and accommodation: divergent outcomes of the humoral response to organ transplantation.

Background: The most difficult barrier to organ transplantation is humoral rejection, a condition initiated by binding of antibodies to blood vessels in the graft. Fortunately, humoral rejection is not the only outcome of antibody binding to the graft. In some cases, accommodation, a condition in which the graft does not undergo humoral injury despite the existence of humoral immunity directed against it, occurs and the graft remains seemingly inured.

Cutting edge: an endogenous pathway to systemic inflammatory response syndrome (SIRS)-like reactions through Toll-like receptor 4.

Systemic inflammatory response syndrome (SIRS) is typically associated with trauma, surgery, or acute pancreatitis. SIRS resembles sepsis, triggered by exogenous macromolecules such as LPS acting on Toll-like receptors. What triggers SIRS in the absence of infection, however, is unknown.

Activation of mammalian Toll-like receptors by endogenous agonists.

Toll-like receptors activate innate and adaptive immune systems in mammals. This ancient family of receptors has been evolving since before the taxonomic split between the plant and animal kingdoms. The discovery of the mammalian Toll-like receptors was heralded as confirmation of a predicted biological system explicitly designed to detect exogenous molecules from micro-organisms.

Evolutionary clues to the functions of the Toll-like family as surveillance receptors.

The origin of the Toll-like family of receptors pre-dates the evolutionary split between the plant and animal kingdoms. These receptors are remarkably conserved across the taxonomic kingdoms and have fundamental roles in triggering immune responses. How they trigger such responses, and how these mechanisms arose in evolution, is a topic of extensive debate.

Apoptosis and cellular activation in the pathogenesis of acute vascular rejection.

Acute vascular or humoral rejection, a vexing outcome of organ transplantation, has been attributed by some to activation and by others to apoptosis of endothelial cells in the graft. We asked which of these processes causes acute vascular rejection by tracing the processes during the development of acute vascular rejection in porcine cardiac xenografts performed in baboons. Apoptosis, assayed by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL), expression of activated caspase-3, and proapoptotic genes Bax and Bcl-x(L), was not detected until acute vascular rejection was well advanced, and even then, apoptosis was largely confined to myocytes.

Receptor-mediated monitoring of tissue well-being via detection of soluble heparan sulfate by Toll-like receptor 4.

Perturbations to the well-being of tissues in plants and invertebrates generate fragments of endogenous molecules that are recognized by innate immune receptors. Vertebrates have homologous receptors on specialized cells such as dendritic cells, but whether these receptors respond to fragments of endogenous molecules is not known. We tested the idea that Toll-like receptors on dendritic cells might recognize polysaccharide fragments of heparan sulfate proteoglycan.