Macrophage and tissue changes in the developmental phases of secondary lymphoedema and during conservative therapy with benzopyrone.

The normal role that the macrophage plays in tissue homeostasis is presented along with the morphological and functional changes that occur to the macrophage population as the lymphoedema progresses from the latent to the chronic phase and then with the treatment with a representative benzopyrone called coumarin. Underlying the lymphoedema, there is a chronic inflammation. It is this, in association with the accumulating protein and the subsequent alterations it produces in the tissues that attract monocytes and macrophages to the affected area. Despite the fact that macrophages are facultative anaerobes, and that larger numbers than normal accumulate, the tissue conditions result in a depression in their activity levels. Apart from these tissue conditions there is the possible production of deactivating proteins such as transforming growth factor beta 1 and 2. Evidence for this deactivation comes from enzymatic studies in which levels of typical macrophage enzymes are reduced and from morphological work which has shown a reduction in pseudopods and a tendency to accumulate large amounts of lipid in their vacuoles. As a consequence of this deactivation further protein accumulation occurs thereby osmotically attracting fluid. Also there is a tendency for the tissues to become fibrotic as the balance between collagen lysis and deposition shifts towards the latter since it has been shown that macrophages have an important role in collagen lysis. The administration of coumarin stimulates the macrophages resulting to their return to normal or supranormal activity levels within the lymphoedematous tissues. As well as this there is an increase in macrophage numbers. The reasons for stimulation are uncertain, however, alterations in the fine structure of the proteins and complement which make these more attractive for phagocytosis seem the most likely. The end result is an rapid enhanced breakup of the excess interstitial protein and the removal of the osmotically attracted fluid together with a more gradual removal of the deposits of fibrotic tissue by the non-stimulated macrophage. Clinically this manifests itself as a softening of the tissues, a reduction in circumference of the lymphoedematous extremity, a return to normal tissue remodelling processes and a range of subjective improvements for the patient.