Inflammation, topical stress and the concept of pluricausal diseases

Abstract

Eleven experimental models of acute connective-tissue reactions were designed for comparative investigations in the rat: anaphylactoid edema, ischemic necrosis, formalin-induced pedal inflammation, various forms of calciphylaxis and calcergy, thrombohemorrhagic phenomena (THP), acute conditioned necrosis (ACN), and delayed tissue-clearance of dyes. Several of these reactions can only be produced by the conjoint application of two drugs (a “conditioner” and a “challenger”), both of which are inactive in themselves. Furthermore, the same lesion (calcification, necrosis, thrombosis) can be produced by several pairs of agents, as long as their members belong to appropriate categories. Even temporary ischemia, produced by the short-term application of a clip to a skin fold, though well tolerated in itself, can act as a challenger and elicit qualitatively different topical lesions (dye accumulation, thrombosis with hemorrhage, calcification, or necrosis) whose nature depends upon the conjoint application of conditioning factors. All these findings suggest that, despite chemical and pharmacologic differences, the members of any one group of conditioners and challengers have some latent pathogenic potencies in common and that they can be conveniently classified on this basis. The following drugs were found to block the manifestations of some of the above mentioned acute connective-tissue reactions: chlorpromazine, compound 48/80, cyproheptadine, dibenzylchloroethylamine, heparin, histamine, 5-hydroxytryptamine (5-HT), phenoxybenzamine, phentolamine, and polymyxin. The ischemic necrosis produced by long-term application of the skin clip is prevented by various systemic stressors (spinal-cord transection, restraint, starvation, forced muscular exercise); apparently, systemic stress can induce “cross-resistance” against the damaging effect of topical stress. 5-HT and mast-cell dischargers possess a pro-inflammatory effect upon the poditis elicited by the intrapedal injection of various irritants. These same compounds delay the tissue clearance of intracutaneously administered dyes; they also act as conditioners for the production of ACN by the subcutaneous administration of normally rapidly absorbed and well-tolerated irritants. Hence, the influence of mast-cell products upon inflammation, dye absorption, and necrosis is presumably due to a single mechanism: the retardation of tissue clearance. The implications of these findings for the pharmacologic analysis of acute connective-tissue reactions are briefly discussed.