Methods and compositions for treating inflammation
Disclosed herein are methods and compositions for treating neutrophil-mediated inflammation by targeting, in any combination, the pro-inflammatory MRP2/HXA3 pathway and/or the anti-inflammatory P-gp/endocannabinoid pathway and/or the anti-inflammatory MRP 1/L-AMEND pathway, comprising administering to the subject a therapeutically effective amount of (a) one or more first compound that inhibits the activity and/or level of one or more of multidrug resistance protein 2 (MRP2) and hepoxilin A3 (HXA3) synthase, and/or (b) one or more second compound that increases the level and/or activity of one or more N-acylethanolamines (NAEs), and/or (c) one or more third compound that increases the level and/or activity of multidrug resistance protein 1 (MRP1), wherein the therapeutic amount of the first, second, and third compounds reduces migration of neutrophils into the target tissue.
1 . A compound having the formula:
wherein X is a C 6 linker and POLY is a polymer.
2 . The compound of claim 1 , wherein said C 6 linker is selected from the group consisting of a substituted or unsubstituted alkylene, a cycloakylene, a cycloalkylalkylene, a heteroalkylene, an alkenylene, and a heteroalkenylene group.
3 . The compound of claim 1 , wherein POLY is a polymer selected from the group consisting of: dextran, polyethylene glycol (PEG), periodate-oxidized dextran, polysialic acids (PSAs), hyaluronic acid (HA), dextrin, hydroxyethyl-starch (HES), poly(2-ethyl 2-oxazoline) (PEOZ), polyglutamic acid (PGA), polylactic acid (PLA), polylactic-co-glycolic (PLGA), poly(D,L-lactide-co-glycolide) (PLA/PLGA), poly(hydroxyalkylmethaacrylamide), polyglycerol, 25 polyamidoamine (PAMAM), polyethylenimine (PEI), polypeptides, and any combination thereof.
4 . A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier.
5 . A method for treating or preventing inflammation in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of claim 1 .
6 . The method of claim 5 , wherein the treatment reduces the number of neutrophils migrating in a basolateral-to-apical direction.