**1. Introduction**

*Bothrops* spp. snakes are responsible for the majority of snakebites in Latin America. Envenomation by these snakes induces severe pathological alterations at the site of venom injection, characterized by an intense local inflammatory reaction associated with myonecrosis, pain, and hemorrhage, potentially leading to permanent tissue damage and disability [1–6]. The local inflammatory response to bothropic envenomation involves a set of events including an increase in vascular permeability, edema formation, hyperalgesia, the activation and infiltration of immunocompetent cells, and a complex network of inflammatory mediators driving the inflammatory response [2]. These events are caused by the activation of critical host defense mechanisms of the victims by direct and indirect actions of

**Citation:** Moreira, V.; Leiguez, E.; Janovits, P.M.; Maia-Marques, R.; Fernandes, C.M.; Teixeira, C. Inflammatory Effects of *Bothrops* Phospholipases A2: Mechanisms Involved in Biosynthesis of Lipid Mediators and Lipid Accumulation. *Toxins* **2021**, *13*, 868. https:// doi.org/10.3390/toxins13120868

Received: 3 November 2021 Accepted: 30 November 2021 Published: 4 December 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

the toxins present in the snake venom. Proteomic studies of *Bothrops* snake venoms revealed that the phospholipases A2 (PLA2s) are ubiquitous components of these venoms and play an important role in the pathophysiology of envenoming by these snakes [7–11]. During envenomation, in addition to aiding prey digestion, these toxins have been described to display myotoxic, cytotoxic, hemolytic, hypotensive, anticoagulant, platelet aggregation inhibition/activation, and proinflammatory effects [12–14]. Regarding inflammation, in addition to exerting direct effects on cell membranes, these lipolytic enzymes can recruit mammalian PLA2s analogs of similar activity and trigger endogenous signaling systems that display and amplify the cell injury and host defense mechanisms triggered by the whole venom. This amplification is responsible for many acutely important consequences of *Bothrops* envenoming. Yet, as discussed below, studies with in vitro and in vivo models aiming to understand the inflammatory action of isolated venom PLA2s can contribute to the knowledge of the local inflammatory mechanisms induced by *Bothrops* snake venoms and those from the Viperidae family [3,15–17]. These studies might lead to the discovery of new therapeutic targets for a more efficient treatment of envenoming by viperid snakes, since the currently available antivenoms have low effectiveness to neutralize the local events promoted by their venoms [18]. Finally, due to the structural and functional similarities to mammalian group (G) IIA PLA2, the *Bothrops* PLA2s can constitute useful tools for studies on the roles of human GIIA PLA2s in inflammatory diseases. In this regard, the effectiveness of varespladib, an inhibitor of svPLA2s [19] in attenuating inflammatory events caused by Viperidae snake venoms has been demonstrated in mice experimental model [20].
