Quantitative studies of the pathway to acute carrageenan inflammation.

A 12-step scheme representing initiation and development of acute carrageenan inflammation in the rat has been devised. Simultaneous quantitative temporal measurement of the number of inflammatory cells mobilized and edema volume produced as carrageenan pleurisy developed helped elucidate several of the early steps, In the pleurisy a 20-min lag phase preceded both the mobilization of neutrophils and edema formation. Temporal histological studies suggested that the lag phase represents the time needed for the neutrophil chemotactic factor to be generated and/or released (steps 2 and 3) in addition to the time required for these cells to move through the walls of the capillaries into the pleural space (steps 4 and 5). The neutrophil chemotactic factor is unknown. The complement system is not involved since cobra venom factor-treated animals produced a normal edematous and cellular response to carrageenan in spite of severely depressed complement levels. The mobilized neutrophils are believed to phagocytize the carrageenan(step6). In this process lysosomal enzymes are released (step 7). Drug inhibition studies suggest that lysosomal enzymes are not the edemagenic agents in carrageenan inflammation. In the scheme these enzymes are responsible for activation of the prostaglandin biosynthetic chain (step 8). Prostaglandin biosynthesis (step 9) leads to the release of an intermediate (step 10), as yet unidentified, which is responsible for increased tissue permeability (step 11) and edema formation (step 12). Histamine, serotonin, bradykinin, arachidonic acid, and prostaglandin's E1 and E2 are not deemagenic in the rat pleural cavity and therefore cannot be responsible for edema formation. Aspirin and indomethacin reduce the edema produced by carrageenan in a dose-related manner without affecting the magnitude or the time course of neutrophil mobilization. These findings led to the concept that edema formation is not the result of inflammatory cell mobilization but is rather a consequence of cellular activity, presumably phagocytosis, after mobilization.