Abstract
Phospholipids occurring in cell membranes and lipoproteins are converted into oxidized phospholipids (OxPL) by oxidative stress promoting atherosclerotic plaque formation. Here, OxPL were characterized as novel targets in acute and chronic inflammatory pain. Oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (OxPAPC) and its derivatives were identified in inflamed tissue by mass spectrometry and binding assays. They elicited calcium influx, hyperalgesia and induced pro-nociceptive peptide release. Genetic, pharmacological and mass spectrometric evidence in vivo as well as in vitro confirmed the role of transient receptor potential channels (TRPA1 and TRPV1) as OxPAPC targets. Treatment with the monoclonal antibody E06 or with apolipoprotein A-I mimetic peptide D-4F, capturing OxPAPC in atherosclerosis, prevented inflammatory hyperalgesia, and in vitro TRPA1 activation. Administration of D-4F or E06 to rats profoundly ameliorated mechanical hyperalgesia and inflammation in collagen-induced arthritis. These data reveal a clinically relevant role for OxPAPC in inflammation offering therapy for acute and chronic inflammatory pain treatment by scavenging OxPAPC.
Highlights
Hallmarks of inflammation – occurring, for example, acutely in wounds after surgery or chronically in rheumatoid arthritis - are pain and hyperalgesia
As oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (OxPAPC) is generated by reactive oxygen species (ROS) in the inflamed tissue in other diseases we evaluated whether OxPAPC elicits hyperalgesia when injected in the rat paw
Our results show experimental evidence that antagonism of the action of Oxidized phospholipids (OxPL) is a potent strategy to target inflammatory pain in rodents
Summary
Hallmarks of inflammation – occurring, for example, acutely in wounds after surgery or chronically in rheumatoid arthritis - are pain and hyperalgesia. Oxidized phospholipids (OxPL) are generated from the plasma membrane and from circulating lipoproteins through either enzymatic or non-enzymatic mechanisms. They are highly reactive and promote pro- and anti-inflammatory pathways. The ApoA-I mimetic peptide D-4F reduces plaque size in early vascular lesions as well as the pro-inflammatory reactions of low density lipoproteins (LDL). It might improve symptoms of other autoimmune diseases such as scleroderma, collagen-induced arthritis or systemic lupus[15, 16]. OxPL in turn are generated by ROS and present in inflamed tissues[9]
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