Abstract
The mechanism of penicillin immediate hypersensitivity reactions has not been completely elucidated. These reactions are generally considered to be mediated by IgE, but penicillin-specific IgE could not be detected in most cases. This study demonstrated that penicillin was able to cause vascular hyperpermeability in a mouse model mimicking clinical symptoms of penicillin immediate hypersensitivity reactions. The first exposure to penicillin also induced immediate edema and exudative reactions in ears and lungs of mice in a dose-dependent manner. Vasodilation was noted in microvessels in ears. These reactions were unlikely to be immune-mediated reactions, because no penicillin-specific IgE was produced. Furthermore, penicillin treatment directly elicited rapid histamine release. Penicillin also led to F-actin reorganization in human umbilical vein endothelial cells and increased the permeability of the endothelial monolayer. Activation of the RhoA/ROCK signaling pathway was observed in ears and lungs of mice and in endothelial cells after treatment with penicillin. Both an anti-histamine agent and a ROCK inhibitor attenuated penicillin immediate hypersensitivity reactions in mice. This study presents a novel mechanism of penicillin immediate hypersensitivity reactions and suggests a potential preventive approach against these reactions.
Highlights
Penicillin causes immunoglobulin E (IgE)-mediated immediate allergic hypersensitivity reactions (AHRs) with serious consequences such as urticaria, pruritus, angioedema, bronchospasm, and anaphylaxis
We demonstrate that histamine release and the RhoA/Rho-associated kinase (ROCK) signaling pathway play important roles in penicillin non-allergic hypersensitivity reactions (NAHRs), and the results suggest that an anti-histamine agent and a ROCK inhibitor might be useful for the prevention and treatment of some penicillin hypersensitivity reactions
We demonstrated that the first exposure of mice to penicillin through intravenous injection rapidly provoked significant vascular hyperpermeability
Summary
Penicillin causes immunoglobulin E (IgE)-mediated immediate allergic hypersensitivity reactions (AHRs) with serious consequences such as urticaria, pruritus, angioedema, bronchospasm, and anaphylaxis. NAHRs mimic IgE-mediated AHRs with identical clinical symptoms, including angioedema, urticaria, bronchospasm, gastrointestinal signs, and anaphylaxis[15]. Because clinical signs of penicillin immediate hypersensitivity reactions including angioedema, urticaria, bronchospasm, and anaphylaxis are closely related to endothelial hyperpermeability, we hypothesize that the RhoA/ROCK signaling pathway is involved in penicillin hypersensitivity reactions. This study is the first to investigate whether penicillin treatment might induce IgE-independent vascular hyperpermeability in a mouse model which mimics the typical clinical symptoms of immediate allergic reactions to penicillin. We demonstrate that histamine release and the RhoA/ROCK signaling pathway play important roles in penicillin NAHRs, and the results suggest that an anti-histamine agent and a ROCK inhibitor might be useful for the prevention and treatment of some penicillin hypersensitivity reactions
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