Protection from endotoxic shock in mice by pharmacologic inhibition of phosphatidic acid.

Abstract

Certain phosphatidic/plasmanic/plasmenic acid (PA) species function as lipid intermediates in cell activation and may function directly as intracellular signaling molecules. PA can also be dephosphorylated to 1,2-diradyl-snglycerol by phosphatidate phosphohydrolase. Treatment of various cell types, including murine P388 monocytic leukemia cells, with bacterial lipopolysaccharide rapidly stimulates large increases in PA and PA-derived diradylglycerol. Pentoxifylline, 1-(5-oxohexyl)-3,7-dimethylxanthine, inhibits lipopolysaccharide-stimulated formation of PA in P388 cells at high concentrations (ICso = 500 FM). Lisofylline [1-(5R-hydroxyhexyl)-3,7-dimethylxanthine] is a unique metabolite of pentoxifylline in humans and is >800-fold more active as an inhibitor of PA formation than pentoxifylline (IC5s = 0.6 jL). Lisofylline does not inhibit lipopolysaccharide-induced activation of phosphatidylinositol-specific phospholipase C and generation of phosphatidylinositol-derived diradylgylcerol. Lisofylline but not pentoxifylline protects BALB/c mice from endotoxin lethality when administered 4 hr after lipopolysaccharide. This protective effect is independent of either agent's effect on suppression of plasma tumor necrosis factor a. These data suggest that inhibitors of PA formation may have significant clinical potential in the treatment of sepsis and septic shock.

Human Lysophosphatidic Acid Acyltransferase

“…In contrast, the product of LPA acylation is PA. A number of recent reports have suggested that PA may be a key intracellular messenger in a common signaling pathway activated by proinflammatory mediators such as IL-1␤, tumor necrosis factor-␣, platelet-activating factor, and lipid A (29,32,33). That this PA is generated by the action of LPAAT was demonstrated by the observation that small molecule inhibitors of the enzyme block PA formation in P388 monocytic leukemia cells stimulated with bacterial lipopolysaccharide (35) and in hypoxia-treated human neutrophils (36). The small molecule inhibitors also protected mice from lipopolysaccharide-mediated endotoxic shock and from lung injury in a model of hemorrhage and resuscitation (36).…”

Topical Combinations Aimed at Treating Microvascular Dysfunction Reduce Allodynia in Rat Models of CRPS-I and Neuropathic Pain

“…Also, clonidine's anti-allodynic effects were mimicked by apraclondine, which does not cross the blood brain barrier 83 . In addition, the many of the various anti-inflammatory activities of pentoxifylline and lisofylline are linked with their vascular effects 7,62,76,91 , as microvascular function is key to various processes involved in the inflammatory response, including plasma extravasation, platelet aggregration, leukocyte migration, cytokine activation, among others.…”

“…For example, clonidine acts at imidazoline receptors as well as α 2A receptors 88 , and pentoxiphylline is a non-specific PDE inhibitor that produces anti-inflammatory effects by interacting with various biological systems. Furthermore, although lisofylline is a phosphatidic acid inhibitor, it is a metabolite of pentoxifylline 62,76 , and shares many of pentoxifylline's PDE inhibitor activities, including inhibition of various cytokines 76 . However, topical administered clonidine is unlikely to have significant effects at brainstem imidazoline receptors, especially at the low concentrations we have used.…”

“…However, α 2A receptor agonists, NO donors and PDE inhibitors have been used systemically in patients or preclinical animal models to treat pain associated with angina 13,43,66 , PAD 19,52,82 , CRPS 18,40,63,74 , neuropathic pain 32,53,60 and PDN 16,24,48,84 indicating their usefulness in these syndromes. PA inhibitors have not been used to treat chronic pain, but should be equally or more effective than PDE inhibitors since they have anti-oxidant 7,34 , anticytokine 68,76 , anti-chemotaxic 70,91 , immunosuppressant 15,23 , and mitochondrial protective 12 effects, in addition to the vasodilator 61 , anti-ischemic 90 and anti-platelet aggregation 62 effects they share with PDE inhibitors.…”

“…Pentoxifylline is a PDE4 inhibitor commonly used to treated these ischemic disorders 44,77 . A major metabolite of pentoxifylline, lisofylline shares many of the actions of its prodrug 60,61,90 , but also inhibits the conversion of lysophophatidic acid to phosphatidic acid (PA), a pathway critical to the production of various cytokines 76 .…”