Regulation of CCN1 (Cyr61) in a porcine model of intestinal ischemia/reperfusion.

Intestinal ischemia is a serious condition that may lead to both local and systemic inflammatory responses. Restoration of blood supply (reperfusion) to ischemic tissues often increases the extent of the tissue injury. Cysteine-rich angiogenic inducer 61 (Cyr61)/CCN1 is an extracellular matrix-associated signaling protein that has diverse functions.

Abandon the mouse research ship? Not just yet!

Many preclinical studies in critical care medicine and related disciplines rely on hypothesis-driven research in mice. The underlying premise posits that mice sufficiently emulate numerous pathophysiologic alterations produced by trauma/sepsis and can serve as an experimental platform for answering clinically relevant questions. Recently, the lay press severely criticized the translational relevance of mouse models in critical care medicine.

The matricellular "cysteine-rich protein 61" is released from activated platelets and increased in the circulation during experimentally induced sepsis.

Sepsis and sepsis-induced organ dysfunction remain lethal and common conditions among intensive care patients. Accumulating evidence suggests that the matricellular Cyr61/CCN1 (cysteine-rich, angiogenic-inducer, 61) protein is involved in the regulation of inflammatory responses and possesses organ-protective capabilities in diseases of an inflammatory etiology. However, its regulation in sepsis remains largely unexplored.

Effects of infliximab and hydrocortisone on in vitro cytokine responses after stimulation with lipopolysaccharide.

Background: Both glucocorticosteroids and biologic drugs such as the tumor necrosis factor (TNF)-α antagonist infliximab are used often in the treatment of rheumatoid arthritis or inflammatory bowel disease. In severe disease, or if allergic reactions occur during treatment with infliximab, combined therapy with these drugs often is instituted. Combining infliximab and glucocorticosteroids may increase substantially the risk of severe opportunistic infections or dissemination of malignant tumors because of their additive effects as immunosuppressants.

Local and systemic pro-inflammatory and anti-inflammatory cytokine patterns in patients with chronic subdural hematoma: a prospective study.

Objective And Design: Innate immune pro- and anti-inflammatory responses in patients with chronic subdural hematoma (CSDH) were investigated by measuring and comparing the systemic and subdural fluid levels of cytokines.

Materials And Method: Cytokine values were analyzed in samples obtained during surgery of 56 adult patients who were operated on for unilateral CSDHs using a Multiplex antibody bead kit.

Results: There were significantly higher levels of the pro-inflammatory IL-2R (p = 0.

The matri-cellular proteins 'cysteine-rich, angiogenic-inducer, 61' and 'connective tissue growth factor' are regulated in experimentally-induced sepsis with multiple organ dysfunction.

Organ failure is a severe complication in sepsis for which the pathophysiology remains incompletely understood. Recently, the matri-cellular cysteine-rich, angiogenic induced, 61 (Cyr61/CCN1); connective tissue growth factor (Ctgf/CCN2); and nephroblastoma overexpressed gene (Nov/CCN3) (CCN)-protein family have been attributed organ-protective properties. Their expression is sensitive to mediators of sepsis pathophysiology but a potential role in sepsis remains elusive.

Chemokines as markers of local inflammation and angiogenesis in patients with chronic subdural hematoma: a prospective study.

Objective: The goal of this study was to investigate the chemokines CCL2, CXCL8, CXCL9 and CXCL10 as markers of the inflammatory responses in chronic subdural hematoma (CSDH).

Methods: Samples of peripheral venous blood and CSDH fluid (obtained during surgery) in 76 adult patients were prospectively analyzed. Chemokine values were assessed by a Multiplex antibody bead kit.

Liver X receptor protects against liver injury in sepsis caused by rodent cecal ligation and puncture.

Background: Liver X receptor (LXR) is a transcription factor of the nuclear receptor family, regulating genes involved in metabolism, inflammation, and apoptosis. In the present investigation, we examined the role of LXR in organ injury and systemic inflammation in rodent models of polymicrobial peritonitis caused by cecal ligation and puncture (CLP).

Methods: Rats were subjected to CLP sepsis or a sham operation.

Impact of hypertonic saline on the release of selected cytokines after stimulation with LPS or peptidoglycan in ex vivo whole blood from healthy humans.

The question of specific immunomodulating qualities of hypertonic saline (HTS) has not been settled. It has proven difficult to distinguish between immunomodulation directly attributable to HTS and influence because of favorable circulatory effects. The nature of immune activator may also play a role.

Liver X receptor agonist GW3965 dose-dependently regulates lps-mediated liver injury and modulates posttranscriptional TNF-alpha production and p38 mitogen-activated protein kinase activation in liver macrophages.

Modulation of the host inflammatory response to infection may be a key approach to improve the outcome of patients with sepsis and organ injury. We previously reported that pretreatment of rats with the liver X receptor (LXR) agonist GW3965 reduced the liver injury associated with endotoxemia and attenuated the production of TNF-alpha by rat Kupffer cells. Here, we examine the dose-dependent effect of GW3965 on liver injury and cytokine production in a rat model of endotoxemia and explore the mechanisms underlying TNF-alpha attenuation in Kupffer cells.

Differences in LPS and PepG induced release of inflammatory cytokines in orthopedic trauma.

Trauma is associated with immune paresis which may predispose to postoperative sepsis. We characterized the ex vivo cytokine responses to bacterial cell wall components in whole blood from 8 patients undergoing a major musculoskeletal trauma in the form of total hip replacement. Preoperatively, at the end of operation, and at days 1 and 6 postoperatively, patient blood was obtained, anticoagulated, and incubated at 37 degrees C in the presence of peptidoglycan (PepG) or lipopolysaccharide (LPS).

Immunmodulation of serum in orthopaedic trauma.

Background: The aim of this study was to test the hypothesis that inhibitory substances circulating in the patient's serum after trauma might impair leukocyte function by evaluating the effect of such serum on cytokine release in a whole blood model.

Methods: Hip replacement surgery was considered a standardized musculoskeletal trauma, and seven women and three men undergoing elective total hip replacement were included in the study. Ex vivo lipopolysaccharide (LPS) and peptidoglycan (PepG) induced tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL-10) releases were measured in whole blood sampled preoperatively and added serum taken before, at the end of operation and at postoperative day 1 and 6.

Nitric oxide administration restores the hepatic artery buffer response during porcine endotoxemia.

The hepatic artery buffer response, which is lost during endotoxemia, plays a central role in the autoregulation of liver perfusion. A temporarily decreased synthesis of nitric oxide during early endotoxemia might be responsible for this dysfunction; hence exogenous administration of nitric oxide could reestablish the autoregulation of hepatic blood flow and help prevent hepatic damage later in septic shock. Fifteen pigs were treated with lipopolysaccharide +/- the nitric oxide donor nitroprusside-sodium via the portal vein.

Systemic administration of enamel matrix derivative to lipopolysaccharide-challenged pigs: effects on the inflammatory response.

Background: Periodontitis is the primary clinical indication for enamel matrix derivative (EMD). Recent investigations, showing that EMD inhibits the production of tumor necrosis factor-alpha (TNF-alpha) when added to human whole blood, indicate a novel role for EMD as a modulator of systemic inflammation. In the present study, we investigated the systemic effects of EMD in lipopolysaccharide (LPS)-challenged pigs.

Activation of cytokine synthesis by systemic infusions of lipopolysaccharide and peptidoglycan in a porcine model in vivo and in vitro.

Background: The incidence of gram-positive and mixed bacterial infections in surgical patients has increased, and there has been an alarming rise in the number of drug-resistant bacteria. Peptidoglycan (PepG) is a cell wall component of gram-positive bacteria that stimulates inflammatory responses both ex vivo and in vivo. The systemic effects of PepG on inflammation have not been studied in a large animal model.

Liver X receptor is a key regulator of cytokine release in human monocytes.

Aberrant regulation of innate immune responses and uncontrolled cytokine bursts are hallmarks of sepsis and endotoxemia. Activation of the nuclear liver X receptor (LXR) was recently demonstrated to suppress inflammatory genes. Our aim was to investigate the expression of LXR in human monocytes under normal and endotoxemic conditions and to study the influence of LXR activation on endotoxin-induced cytokine synthesis and release.

Postoperative serum attenuates LPS-induced release of TNF-alpha in orthopaedic surgery.

Studies with ex vivo stimulation of whole blood samples from injured patients have revealed a diminished production capacity for a broad range of secretory products, including inflammatory cytokines. Recent interest has focused on the release of mediators in serum that depress the cell-mediated immune response following trauma. The involvement of the lipid mediator prostaglandin E2 (PGE2) has been assumed because it is a potent endogenous immunosuppressor.

Lipopolysaccharide attenuates mRNA levels of several adenylyl cyclase isoforms in vivo.

Signals that elevate intracellular levels of cyclic adenosine monophosphate (cAMP) are among the factors that control lipopolysaccharide (LPS)-mediated inflammatory mediator production by macrophages. cAMP signaling is also involved in maintaining body functions that are commonly impaired in sepsis, including the endothelial cell barrier function and heart function. Several agents successfully used for sepsis intervention target cAMP signaling, and it was recently shown that liver and lung may be protected from inflammation injury by cAMP-elevating phosphodiesterase inhibitors.

Mediator responses in surgical infections.

Background: Surgical infections, and sepsis in particular, are characterized by extensive release of mediators. Our laboratories have been interested in understanding how these substances contribute to morbidity and mortality during various stages of surgical infections in order to develop new and more effective therapeutics and treatment strategies.

Methods: In a series of in vitro studies, human plasma was exposed to lipopolysaccharide (LPS), and whole blood was treated with peptidoglycan from Staphylococcus aureus.

The role of the surgeon as intensivist: an international perspective.

Purpose Of Review: Critical care is a young specialty. It emerged less than 50 years ago in response to new technologies that could prolong the survival of patients who previously would have died. The diseases that posed this threat to life were varied and the original practitioners of critical care came from a variety of medical backgrounds, and created a multidisciplinary specialty.

Peptidoglycan--an endotoxin in its own right?

Studies aimed at dissecting the complex pathophysiology of sepsis with multiple organ failure have traditionally focused on lipopolysaccharide of gram-negative bacteria, which is widely regarded as the classical endotoxin. However, gram-positive sepsis now accounts for up to 50% of all cases, calling for a shift of focus. Peptidoglycan (PepG) is the major cell wall component of gram-positive bacteria and has been increasingly recognized as an important proinflammatory molecule.

Activation of the liver X receptor protects against hepatic injury in endotoxemia by suppressing Kupffer cell activation.

Recent reports have demonstrated that liver X receptors (LXRs) of the nuclear receptor family have anti-inflammatory effects on macrophages. Here we examine whether activation of LXR by the synthetic agonist GW3965 can ameliorate the liver injury/dysfunction caused by endotoxins in the rat. Male Wistar rats received GW3965 (0.

Effects of forskolin on Kupffer cell production of interleukin-10 and tumor necrosis factor alpha differ from those of endogenous adenylyl cyclase activators: possible role for adenylyl cyclase 9.

Proinflammatory cytokines like tumor necrosis factor alpha (TNF-alpha) that are released from Kupffer cells may trigger liver inflammation and damage. Hence, endogenous mechanisms for limiting TNF-alpha expression are crucial for avoiding the development of sepsis. Such mechanisms include the anti-inflammatory actions of interleukin-10 (IL-10) as well as signaling induced by the intracellular second messenger cyclic AMP (cAMP).

Peptidoglycan of Staphylococcus aureus induces enhanced levels of matrix metalloproteinase-9 in human blood originating from neutrophils.

Enhanced plasma levels of matrix metalloproteinase 9 (MMP-9) detected in patients with severe sepsis are thought to contribute to the development of organ dysfunction in endotoxemia. We have recently reported that peptidoglycan, the major wall component of gram-positive bacteria, increases MMP-9 levels in lung and liver and organ injury in the rat. Thus far, it is unclear whether MMP-9 is part of the septic response to peptidoglycan in human blood.