Avaliação dos efeitos de dendropsofina 1, um peptídeo natural antimicrobiano, e de dois peptídeos análogos sobre a inflamação crônica induzida por implante de esponja sintética em camundongos

Abstract

Inflammation is a biological process aimed at restoring homeostasis after harmful stimuli. Through these events, the immune system removes injury-causing agents and promotes tissue repair. Although inflammatory events are essential for life, failure in their resolution may result in the development of chronic-degenerative diseases. Chronic inflammation is present in many disorders, such as diabetes mellitus, rheumatoid arthritis, cancer, and hard-to-heal wounds. In fact, many of the leading causes of death and major burdens on healthcare systems are diseases in which a persistent inflammatory state is present. Under these conditions, there is exacerbated activity of one or more components of chronic inflammation, namely inflammatory mediators, fibrogenesis, and/or angiogenesis. Continuous tissue damage and unsuccessful attempts at repair coexist in chronic inflammation. Thus, cytokines produced at the inflammatory site influence angiogenesis and extracellular matrix (ECM) deposition. Consequently, fibrosis may develop and local tissue function may be lost.

Given this scenario, there is a clear need to search for biologically active compounds capable of keeping inflammation under control without completely silencing it; compounds that enable the return to homeostasis while minimizing functional loss. Antimicrobial peptides (AMPs) are a diverse group of bioactive proteins that constitute the first line of defense of various organisms against pathogens. Amphibian skin, for example, is an important reservoir of AMPs. In addition to exerting direct antimicrobial activity, these peptides may inhibit the expression of pro-inflammatory cytokines and chemokines, act as chemotactic molecules, activate immune cells, and modulate fibrogenic and vascular components of inflammation.

The present study highlights the activity of a peptide isolated from the skin secretion of Dendropsophus columbianus, a tree frog endemic to Colombia, and two of its synthetic analogs. In 2018, the native peptide, named dendropsophin 1 (Dc1), was isolated, and subsequently the analogs Dc1.2 and Dc1.2.2 were synthesized. These peptides have documented antimicrobial activity; however, since their in vivo immunomodulatory action had not yet been elucidated, we evaluated the effects of their daily administration in a mouse model of chronic inflammation induced by polyester-polyurethane sponge implants. The sponge matrices induce a chronic foreign body-type inflammatory response and form fibrovascular tissue. Therefore, this model makes it possible to simultaneously evaluate inflammatory markers, angiogenesis, and fibrogenesis in vivo. To date, this is the first study to analyze the effects of dendropsophin 1 and its analogs in this context, and it demonstrates the therapeutic potential of this peptide for the treatment of conditions that require tissue repair and inflammatory control.