Pulmonary intravascular macrophages: prime suspects as cellular mediators of porcine CARPA

Abstract

Pigs provide a highly sensitive and quantitative in vivo model for complement (C) activation-related pseudoallergy (CARPA), a hypersensitivity reaction caused by some state-of-art nanomedicines. In an effort to understand the mechanism of the pigs' unique sensitivity for CARPA, this review focuses on pulmonary intravascular macrophages (PIMs), which are abundantly present in the lung of pigs. These cells represent a macrophage subpopulation whose unique qualities explain the characteristic symptoms of CARPA in this species, most importantly the rapidly (within minutes) developing pulmonary vasoconstriction, leading to elevation of pulmonary arterial pressure. The unique qualities of PIM cells include the following; 1) they are strongly adhered to the capillary walls via desmosomelike intercellular adhesion plaques, which secure stable and lasting direct exposition of the bulk of these cells to the blood stream; 2) their ruffled surface engaged in intense phagocytic activity ensures efficient binding and phagocytosis of nanoparticles; 3) PIM cells express anaphylatoxin receptors, this way C activation can trigger these cells, 4) they also express pattern recognition molecules on their surface, whose engagement with certain coated nanoparticles may also activate these cells or act in synergy with anaphylatoxins and, finally 5) their high metabolic activity and capability for immediate secretion of vasoactive mediators upon stimulation explain the circulatory blockage and other robust physiological effects that their stimulation may cause. These qualities taken together with reports on liposome uptake by PIM cells during CARPA and the possible presence of these cells in human lung suggests that PIM cells may be a potential therapeutic target against CARPA.

Lessons learned from the porcine CARPA model: constant and variable responses to different nanomedicines and administration protocols

“…Namely, PIM cells are directly exposed to blood and their function is to screen out from blood particulate pathogens. They can be activated both by anaphylatoxins and via particle binding to their surface receptors, and they respond to activation with massive secretion of vasoactive mediators (78). These features are necessary and at the same time enough to explain the characteristic changes of PAP during CARPA in pigs.…”

“…Among the hemodynamic symptoms, the rise of PAP is the most prominent and reproducible measure of CARPA in the porcine model, which is invariably present with all RNMs. The transient, massive pulmonary hypertension is most likely due to the presence of pulmonary intravascular macrophages (PIM cells) in the lung of pigs, a theory based on the speed (seconds) and prominence (maximal possible) of pulmonary changes in this species taken together with the known properties and functions of PIM cells (78). Namely, PIM cells are directly exposed to blood and their function is to screen out from blood particulate pathogens.…”

“…One theory, referred to as "double hit" hypothesis, points to allergy-mediating cells (mast cells/basophils/PIM cells as anatomic sites of tachyphylaxis, and suggests that tachyphylactogenic RNMs trigger CARPA both via C activation and via direct binding to these allergy mediating cells, and the two signals together trigger these cells to release vasoactive mediators. If one of these mechanisms is not working for some reason at the time of repeated treatments, because a mediator gets consumed or a signal transduction pathway gets exhausted, tachyphylaxis will ensue (7,78). …”

Complement activation as a bioequivalence issue relevant to the development of generic liposomes and other nanoparticulate drugs

“…The pulmonary reaction in pigs has been attributed to the presence of special intravascular macrophages (PIM cells) in the lung of these animals [75], as these cells are directly exposed to blood and their function is to screen blood from particulate pathogens. They can be activated both by anaphylatoxins and via particle binding to their surface receptors, and they respond to activation with massive secretion of vasoactive mediators [75].…”

“…They can be activated both by anaphylatoxins and via particle binding to their surface receptors, and they respond to activation with massive secretion of vasoactive mediators [75]. The changes in SAP are more variable; it can drop, rise, display no change or undulate.…”