Late Administration of a Lipophilic Tyrosine Kinase Inhibitor Prevents Lipopolysaccharide and Escherichia coli-Induced Lethal Toxicity

Abstract

Septic shock induced by gram-negative bacteria results primarily from excessive stimulation by lipopolysaccharide (LPS) of macrophages to produce tumor necrosis factor (TNF)-alpha and interleukin (IL)-1. The cellular effects of LPS, TNF-alpha, and IL-1 are mediated via tyrosine phosphorylation pathways. A recent report indicated that selective inhibitors of tyrosine kinases, tyrphostins of the AG126 family, protect mice against LPS-induced lethal toxicity in mice. Protection was most effective when the tyrphostin was injected before the LPS. In the present study, tyrphostin AG556, which is more lipophilic than those of the AG126 family, was effective in preventing LPS-induced lethal toxicity when administered 2 h after LPS. AG556 also prevented viable Escherichia coli-induced lethal toxicity when given 2 h before and, to a lesser extent, 2 h after the bacterial inoculation. AG556 may block a critical step downstream of the signaling pathway induced by LPS after TNF-alpha production.

Mitogen-activated Protein Kinases Mediate Activator Protein-1-dependent Human Inducible Nitric-oxide Synthase Promoter Activation

“…The importance of early gene activation was stressed in animal models of sepsis, in which tyrphostins decreased mortality only when administered before, or soon after, the initiation of sepsis (16,17,19). The JAK2 inhibitor AG490 attenuated CM stimulation of hiNOS promoter activity.…”

“…MAPKs are signaling proteins rapidly activated by tyrosine phosphorylation, and tyrosine kinase inhibitors have been studied as potential therapeutic targets in inflammatory and proliferative disorders (15)(16)(17)(18)(19). Activation of MAPK pathways by LPS and cytokines (20,21) represents a potential signaling mechanism for NO production during the inflammatory response.…”

The tyrosine kinase inhibitor AG126 restores receptor signaling and blocks release functions in activated microglia (brain macrophages) by preventing a chronic rise in the intracellular calcium level

“…Hence, they offer substantial drug development potential (Levitzki and Gazit 1995). Tyrphostin AG126 has been reported as a promising antiinflammatory agent in a variety of models in which it reduced release of inflammatory mediators (Novogrodsky et al 1994;Prinz et al 1999), oxidative stress-induced neuronal cell death , phagocytic activity (Spitzer and Zhang 1996), leukocyte invasion (Hanisch et al 2001), expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) (Cuzzocrea et al 2000) and the lethal outcome of septic shock (Novogrodsky et al 1994;Vanichkin et al 1996). However, the mechanisms by which AG126 evolves these broad anti-inflammatory and protective effects are mostly unknown.…”

The Tyrosine Kinase Inhibitor Tyrphostin AG126 Reduces the Development of Acute and Chronic Inflammation

“…Thus, inhibitors of tyrosine kinase activity should reduce the formation and/or effects of pro-inflammatory cytokines, eg, tumor necrosis factor-␣ (TNF-␣) and interleukin-1 (IL-1), the expression of iNOS and COX-2, and the activation of the transcription factor nuclear factor-B (NF-B). [22][23][24][25][26][27] Although all of these effects of inhibitors of tyrosine kinase should be anti-inflammatory in nature, there are no studies investigating the effects of tyrosine kinase inhibitors in animal models of acute and chronic inflammation.…”