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

Abstract

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.

Recombinant human Hsp70 protects against lipoteichoic acid-induced inflammation manifestations at the cellular and organismal levels

“…On the other hand, LPS administration resulted in approximately the same ROS concentration increase when much lower concentrations of the toxin were applied (1-20 ng/ml; Lotz et al 2004;Rozhkova et al 2010). It is noteworthy that although the delivery of both toxins (LTA and LPS) occurs via CD14 receptors (Lotz et al 2004;Leon et al 2008), only about 7,000 receptors can be activated in neutrophils, while in monocytes, more than 100,000 of these receptors can be expressed (Antal-Szalmas 2000). Furthermore, both LTA and LPS administration to myeloid cells results in the enhanced expression of CD11b/CD18 adhesion receptors (Carratelli et al 1996), as well as enhanced LPS activity (Detmers et al 1998).…”

“…The differences in the level and pattern of protection demonstrated by exogenous Hsp70 regarding LPS and LTA challenge may be explained by action via different pathways on neutrophils activation. Thus, LPS interacts with TLR4, while LTA interacts with TLR2 (Lotz et al 2004;Leon et al 2008). In both cases, the protective effect of Hsp70 is likely realized by the modification of TLR2 and TLR4 expression in target myeloid cells (Zhou et al 2005).…”

“…Lipoteichoic acid, which represents the major component of the Gram-positive bacterial cell wall, stimulates mammalian phagocytes by activating the TLR2, CD14, and CD36 receptors (Lotz et al 2004;Nilsen et al 2008). LPS activates phagocytes that explore components of the TLR4/CD14/MD2 complex as well as a few other proteins and receptors (Leon et al 2008). When bacterial pathogens are recognized by TLR2, these receptors often form heterodimers with TLR1 (Takeuchi et al 2001).…”

The interaction between a non-pathogenic and a pathogenic strain synergistically enhances extra-intestinal virulence in Escherichia coli

“…coli membrane lipopolysaccharide (LPS) is a well-known virulence factor (Leon et al, 2008;Parrillo et al, 1990). When injected into mice in sufficient quantity it is lethal and mimics septic shock.…”

IL-6 Trans-Signaling Modulates TLR4-Dependent Inflammatory Responses via STAT3

“…epsis is a chronic, systemic inflammatory disorder that places a large burden on the public health system worldwide, with ∼215,000 deaths and 750,000 cases of sepsis each year in the United States alone (1). In 45-60% of cases, sepsis is triggered by Gram-negative bacterial infections, and its most lethal form (endotoxic shock) is caused by LPS, the major component of the outer membrane of Gram-negative bacteria (2).…”