Intravenous injection of nanopharmaceuticals can induce severe hypersensitivity reactions
(HSRs) resulting in anaphylactoid shock in a small percentage of patients, a phenomenon
explicitly reproducible in pigs. However, there is a debate in the literature on whether
the pig model of HSRs can be used as a safety test for the prediction of severe adverse
reactions in humans. Given the importance of using appropriate animal models for toxicity/safety
testing, the choice of the right species and model is a critical decision. In order
to facilitate the decision process and to expand the relevant information regarding
the pig or no pig dilemma, this review examines an ill-fated clinical development
program conducted by Baxter Corporation in the United States 24 years ago, when HemeAssist,
an αα (diaspirin) crosslinked hemoglobin-based O2 carrier (HBOC) was tested in trauma
patients. The study showed increased mortality in the treatment group relative to
controls and had to be stopped. This disappointing result had far-reaching consequences
and contributed to the setback in blood substitute research ever since. Importantly,
the increased mortality of trauma patients was predicted in pig experiments conducted
by US Army scientists, yet they were considered irrelevant to humans. Here we draw
attention to that the underlying cause of hemoglobin-induced aggravation of hemorrhagic
shock and severe HSRs have a common pathomechanism: cardiovascular distress due to
vasoconstrictive effects of hemoglobin (Hb) and reactogenic nanomedicines, manifested,
among others, in pulmonary hypertension. The main difference is that in the case of
Hb this effect is due to NO-binding, while nanomedicines can trigger the release of
proinflammatory mediators. Because of the higher sensitivity of cloven-hoof animals
to this kind of cardiopulmonary distress compared to rodents, these reactions can
be better reproduced in pigs than in murine or rat models. When deciding on the battery
of tests and the appropriate models to identify the potential hazard for nanomedicine-induced
severe HSR, the pros and cons of the various species must be considered carefully.