The effects of heparin and related molecules on vascular permeability and neutrophil accumulation in rabbit skin.

Unfractionated heparin (UH) has been shown to possess a wide range of properties which are potentially anti-inflammatory. Many of these studies, including effects of heparin on adhesion of inflammatory cells to endothelium, have been carried out in vitro. In the present study, we have used radioisotopic techniques to study the effect of UH, and related molecules, on in vivo inflammatory responses (plasma exudation (PE) and PMN accumulation) in rabbit skin induced by cationic proteins, mediators and antigen. Intradermal (i.d.) pretreatment with UH dose-dependently inhibited poly-L-lysine (PLL)-induced responses. The same treatment had no effect on antigen (extract of Alternaria tenuis, AT)-, formyl-methionyl-leucyl-phenylalanine (fMLP)- or leukotriene (LT) B(4)-induced responses, although i.d. dextran sulphate (DS) significantly inhibited responses to all of these mediators. High dose (10,000 u kg(-1)) intravenous UH significantly decreased cutaneous responses to fMLP and LTB(4). By comparison, the selectin inhibitor, fucoidin, and DS, were very effective inhibitors of these responses, and of responses to AT and PLL. In contrast to the weak effect in the in vivo studies, UH significantly inhibited in vitro homotypic aggregation of rabbit PMNs, showing that it can modify PMN function. Our data with i.d. UH confirm the important ability of this molecule to interact with and neutralize polycationic peptides in vivo, suggesting that this is a prime role of endogenous heparin. The lack of effect of exogenous heparin on acute inflammatory responses induced by allergen, suggests that cationic proteins are unlikely to be primary mediators of the allergen-induced PE or PMN accumulation.