Inflammation induced by snake venoms optimizes envenomation

Snake envenomation activates the immune system through permeability-increasing factors that generate an acute vascular inflammatory response by opening large inflammation-activated pores (IAPs) in the microvasculature. These events facilitate the exudation of plasma from blood into body tissues. However we show that IAPs also allow macromolecules, including venom toxins, to flood directly into the bloodstream, even against an outflow of plasma solutes. Such inflammation-facilitated macromolecular absorption (IFMA) acts together with lymphatic absorption and has a physiological role in removing interstitial molecules, as evidenced by our dextran studies. IFMA will function in vascular absorption of interstitial molecules, potentially up to the radius of IAPs, which we determined to be 21 nm (95% confidence interval (CI) 18-24 nm). This absorption depends on factors, including the interstitial-vascular concentration gradient, the reflection coefficient of each molecule and microvascular pressure. Molecules absorbed will include snake venom toxins and various cellular breakdown products that arise during processes such as the inflammatory phase of wound healing. Most, if not all, venom toxins will be absorbed, as these typically have a hydrodynamic radius (r₀) of 1-6 nm, which is well below that of IAPs. Notably once in the circulation venoms cause distributed inflammation, enhancing venom toxin movement from the bloodstream into the tissues. These mechanisms markedly increase the absorption of often lethal snake toxins and ensure their dissemination throughout body tissues, facilitating prey capture and adding to make snakebite extremely dangerous to humans. These findings provide mechanistic insight into current empirical snakebite first aid and present directions that may improve these procedures. KEY POINTS: Snake venoms induce acute vascular inflammation, manifested by the opening of large pores termed inflammation-activated pores (IAPs), which we experimentally measure to have a radius of 21 nm. These pores mediate well-known exudation of plasma proteins but simultaneously provide a pathway for absorption of macromolecules, including venoms, a process that operates in parallel with the lymphatic system in clearing interstitial macromolecules. Although utilized in snakebite envenomation, such inflammation-facilitated macromolecular absorption (IFMA) is likely to have important physiological or pathophysiological roles, candidates including clearance of cellular breakdown products during the inflammatory phase of wound healing. Once in the vasculature venoms induce distributed inflammation of the IAPs, facilitating the exudation of venom toxins into tissues. The findings together with a model based on our experimental data provide new directions for improving snakebite first aid and present experimental evidence for a mechanism that operates to clear interstitial macromolecules.