Discovery and Development of Toll-Like Receptor 4 (TLR4) Antagonists: A New Paradigm for Treating Sepsis and Other Diseases

Abstract. Sepsis remains the most common cause of death in intensive care units in the USA, with a current estimate of at least 750,000 cases per year, and 215,000 deaths annually. Despite extensive research still we do not quite understand the cellular and molecular mechanisms that are involved in triggering and propagation of septic injury. Endotoxin (lipopolysaccharide from Gram-negative bacteria, or LPS) has been implicated as a major cause of this syndrome. Inflammatory shock as a consequence of LPS release remains a serious clinical concern. In humans, inflammatory responses to LPS result in the release of cytokines and other cell mediators from monocytes and macrophages, which can cause fever, shock, organ failure and death. A number of different approaches have been investigated to try to treat and/or prevent the septic shock associated with infections caused by Gram-negative bacteria, including blockage of one or more of the cytokines induced by LPS. Recently several novel amphipathic compounds have been developed as direct LPS antagonists at the LPS receptor, TLR4. This review article will outline the current knowledge on the TLR4-LPS synthesis and discuss the signaling, in vitro pre-clinical and in vivo clinical evaluation of TLR4 antagonists and their potential use in sepsis and a variety of diseases such as atherosclerosis as well as hepatic and renal malfunction. KEY WORDS: drug discovery; LPS; sepsis; toll-like receptor antagonists

Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700

Perioperatives Management von Patienten mit schwerer pulmonaler Hypertonie in der orthopädischen Chirurgie: erfahrungsbasierte Empfehlungen

Introduction: It is known that pulmonary hypertension is associated with worse outcome in both cardiac and non-cardiac surgery. The aims of our retrospective analysis were to evaluate the outcomes of our patients with pulmonary hypertension undergoing major orthopedic surgery and to give experience-based recommendations for the perioperative management.Material and methods : From 92 patients with pulmonary hypertension undergoing different kinds of surgical procedures from 2011-2014 in a tertiary academic hospital we evaluated 16 patients with major orthopedic surgery for perioperative morbidity and mortality. Results: Regarding the in-hospital morbidity and mortality, one patient died postoperatively due to pulmonary infection and right heart failure (6.25%) and 6 patients suffered significant postoperative complications (37.5%; bleeding = 1, infection = 1, wound healing deficits = 3; dysrhythmia = 1). Conclusion: Our data show that major orthopedic surgery is feasible with satisfactory outcome even in cases of severe pulmonary hypertension by an individualized, disease-adapted interdisciplinary treatment concept.Einleitung: Patienten mit pulmonaler Hypertonie sind sowohl bei kardiochirurgischen, wie auch nicht-kardiochirurgischen Operationen einem erhöhten Risiko für schwere intra- und postoperative Komplikationen ausgesetzt. Mit unserer retrospektiven Analyse möchten wir einerseits die Ergebnisse von Patienten mit pulmonaler Hypertonie zeigen, die sich einem größeren orthopädischen Eingriff unterziehen mussten und andererseits auf unseren Erfahrungen basierende Empfehlungen zum perioperativen Management dieser Patienten geben.Material und Methoden: Im Zeitraum von 2011-2014 wurden insgesamt 92 Patienten mit schwerer pulmonaler Hypertonie in verschiedenen chirurgischen Disziplinen unserer Einrichtung operiert; von diesen untersuchten wir 16 Patienten mit größeren orthopädischen Eingriffen hinsichtlich der perioperativen Komplikationsraten und Sterblichkeit.Ergebnisse: Ein einziger Patient verstarb im perioperativen Verlauf an einer Pneumonie mit konsekutivem Rechtsherzversagen (6,25%); bei 6 Patienten kam es zu gravierenden Komplikationen (37,5%; Blutung = 1, Infektion = 1, Wundheilungsstörungen = 3; Herzrhythmusstörungen = 1).Schlussfolgerungen: Unsere Ergebnisse zeigen, dass auch größere orthopädische Operationen bei Patienten mit schwerer pulmonaler Hypertonie mit einem höheren, aber aus unserer Sicht vertretbaren perioperativen Risiko durchführbar sind und empfehlen dafür ein individualisiertes, interdisziplinäres Behandlungskonzept

Up-regulation interleukin-6 and interleukin-8 by activated protein C in lipopolysaccharide-treated human umbilical vein endothelial cells

Objective: To investigate the effect of activated protein C (APC) on inflammatory responses in human umbilical vein endothelial cells (HUVEC) stimulated with lipopolysaccharide (LPS). Methods: The second passage of collagenase digested HUVEC was divided into the following groups: serum free medium control group (SFM control), phosphate buffer solution control group (PBS control), LPS group with final concentration of 1 μg/ml (LPS group), APC group with final concentration of 7 μg/ml, Pre-APC group (APC pretreatment for 30 min prior to LPS challenge), and Post-APC group (APC administration 30 min after LPS challenge). Supernatant was harvested at 0, 4, 8, 12 and 24 h after LPS challenge. Interleukin-6 (IL-6) and Interleukin-8 (IL-8) levels were analyzed with ELISA. Cells were harvested at 24 h after LPS challenge, and total RNA was extracted. Messenger RNA levels for IL-6 and IL-8 were semi-quantitatively determined by RT-PCR. Results: Compared with control group, IL-6 and IL-8 levels steadily increased 4 to 24 h after LPS stimulation. APC treatment could increase LPS-induced IL-6 and IL-8 production. The mRNA levels of IL-6 and IL-8 exhibited a similar change. Conclusion: APC can further increase the level of IL-6 and IL-8 induced by LPS. The effect of these elevated cytokines is still under investigation