Fibrosis: ultimate and proximate causes

Abstract

Fibrotic disorders account for an increasing burden of disease-associated morbidity and mortality worldwide. Although numerous risk factors have been recognized, the etiologies of many of these clinical syndromes have not been identified, and they are often termed idiopathic or cryptogenic. Here, we provide an evolutionary perspective on fibrosis aimed at elucidating its etiopathogenesis. By asking the ultimate question of "why" this process evolved in multicellular organisms, we hope to uncover proximate explanations for "how" it causes disease in humans. We posit that physiological fibrosis-like reactions evolved as an essential process in host defense against pathogens and in normal wound healing. Based on this premise, we reason that pathological fibrosis is related to one or more of the following: unidentified infectious or noninfectious antigens, autoimmunity, impaired regenerative responses, and the antagonistically pleiotropic action of genes involved in wound healing or development. The importance of genetic susceptibility, epigenetics, aging, and the modern-day environment are highlighted. Consideration of both ultimate and proximate causation goes beyond philosophical cogitations, as it will better inform pathobiological mechanisms of disease and aid in the prevention and treatment of fibrotic diseases.

Figure 1. Evolution of fibrosis.

In most multicellular organisms, fibrosis-like reactions serve a useful purpose by limiting pathogen invasion and promoting wound healing. Pathological fibrosis may result from the persistence of extrinsic (unidentified) infections and/or antigens or of intrinsic neoantigens that evoke chronic autoimmune reactions. Impaired tissue regenerative capacity and/or the action of antagonistically pleiotropic genes may trigger perpetual wound healing responses that cause progressive fibrosis. These pathological processes may be instigated by genetic or epigenetic alterations in reparative and immune cells in the setting of modern environmental challenges and in an aging population.