Brain death-induced lung injury is complement dependent, with a primary role for the classical/lectin pathway

Abstract

In brain‐dead donors immunological activation occurs, which deteriorates donor lung quality. Whether the complement system is activated and which pathways are herein involved, remain unknown. We aimed to investigate whether brain death (BD)‐induced lung injury is complement dependent and dissected the contribution of the complement activation pathways. BD was induced and sustained for 3 hours in wild‐type (WT) and complement deficient mice. C3−/− mice represented total complement deficiency, C4−/− mice represented deficiency of the classical and lectin pathway, and factor properdin (P)−/− mice represented alternative pathway deficiency. Systemic and local complement levels, histological lung injury, and pulmonary inflammation were assessed. Systemic and local complement levels were reduced in C3−/− mice. In addition, histological lung injury and inflammation were attenuated, as corroborated by influx of neutrophils and gene expressions of interleukin (IL)‐6, IL‐8–like KC, TNF‐α, E‐selectin, and MCP‐1. In C4−/− mice, complement was reduced on both systemic and local levels and histological lung injury and inflammatory status were ameliorated. In P−/− mice, histological lung injury was attenuated, though systemic and local complement levels, IL‐6 and KC gene expressions, and neutrophil influx were not affected. We demonstrated that BD‐induced lung injury is complement dependent, with a primary role for the classical/lectin activation pathway.

Long–term lung inflammation is reduced by estradiol treatment in brain dead female rats

“…In our study, we found that estradiol could reduce complement activity until the C3 level, which is explained by the existence of an estradiol-responsive element in the promoter region (19). A lower complement system activity will increase lung transplant success (12,13). Indeed, by reducing C3, estradiol may inhibit actions of the active fragments such as C3a and C5a, which cause tissue damage by microvascular changes in flow and permeability, leukocyte extravasation, and migration (20).…”

“…Thus, understanding the long-term role of estradiol in female lung donors can contribute to therapeutic donor management aiming to improve transplant outcomes. In this sense, the evaluation of estradiol's influence on the complement system activity, which increases BD-induced lung injury and worsens transplant outcomes (12,13), as well as on the inflammatory response with activated neutrophil and macrophage release of inflammatory mediators, is relevant. Therefore, in this study, we investigated the effect of estradiol on BD-induced lung inflammation, focusing on the long-term inflammatory repercussions and complementary elements as a means to understand estradiol as a possible therapeutic tool for lung transplantation.…”

Complement activation in wasp venom-induced acute kidney injury

“…Complement activation involves the activation of C3 through three pathways: the classical (CP), alternative (AP), and lectin pathways (LP). All three pathways lead to C3 activation [ 13 ], followed by the formation of C5b-9, also known as the membrane attack complex. C5b-9 forms lytic pores on the outer membranes of target cells, leading to host cell lysis [ 14 ].…”