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The Plasma Kallikrein-Kinin System: A Hematological Target for Environmental Contaminants

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Purpose of Review The increasing occurrence of emerging chemicals of concern in the environment has caused high public attention. Assessing their hematologic toxicities is of high priority, as the blood circulation system is usually essential in transporting these exogenous substances to diverse target tissues in vivo. The plasma kallikrein-kinin system (KKS) is one of the most abundant protease enzyme systems and regulates a series of crucial hematologic functions. As a vulnerable target, the KKS may sensitively respond to circulatory pollutants, and combing the current studies on the interaction of the environmental contaminants with the KKS would help understand the toxicological or pathological significance of this system. Recent Findings The current studies have revealed that some environmental contaminants, such as small molecular organic chemicals, engineered nanoparticles (NPs), and atmospheric fine particulate matter (PM), can directly interact with the KKS, causing the autoactivation of the Hageman factor XII (FXII), the subsequent cascade cleavage of the plasma prekallikrein (PPK), and high molecular kininogen (HK). The consequent downstream hematological effects and other related toxicities can be concomitantly induced via the crosstalk with the KKS. In addition, multiple approaches, based on in vitro, ex vivo, and in vivo experimental models, have been developed to characterize the binding of exogenous substances with FXII, conformational changes of the protein, the cascade activation of the KKS, and downstream toxicological or pathological responses. Summary As a vulnerable target, the plasma KKS sensitively responds to the exposure of environmental pollutants and is promising for biomonitoring hematotoxicity in future studies.
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Vol.:(0123456789)
Current Pollution Reports (2024) 10:513–531
https://doi.org/10.1007/s40726-024-00308-8
REVIEW
The Plasma Kallikrein‑Kinin System: AHematological Target
forEnvironmental Contaminants
YurouGao1,2· YuzhuZhang1· ZhiwenLi1,2· QianS.Liu1· QunfangZhou1,3,4· GuibinJiang1,3
Accepted: 7 April 2024 / Published online: 7 May 2024
© The Author(s), under exclusive licence to Springer Nature Switzerland AG 2024
Abstract
Purpose of Review The increasing occurrence of emerging chemicals of concern in the environment has caused high public
attention. Assessing their hematologic toxicities is of high priority, as the blood circulation system is usually essential in
transporting these exogenous substances to diverse target tissues invivo. The plasma kallikrein-kinin system (KKS) is one of
the most abundant protease enzyme systems and regulates a series of crucial hematologic functions. As a vulnerable target,
the KKS may sensitively respond to circulatory pollutants, and combing the current studies on the interaction of the envi-
ronmental contaminants with the KKS would help understand the toxicological or pathological significance of this system.
Recent Findings The current studies have revealed that some environmental contaminants, such as small molecular organic
chemicals, engineered nanoparticles (NPs), and atmospheric fine particulate matter (PM), can directly interact with the KKS,
causing the autoactivation of the Hageman factor XII (FXII), the subsequent cascade cleavage of the plasma prekallikrein
(PPK), and high molecular kininogen (HK). The consequent downstream hematological effects and other related toxicities
can be concomitantly induced via the crosstalk with the KKS. In addition, multiple approaches, based on invitro, exvivo, and
invivo experimental models, have been developed to characterize the binding of exogenous substances with FXII, confor-
mational changes of the protein, the cascade activation of the KKS, and downstream toxicological or pathological responses.
Summary As a vulnerable target, the plasma KKS sensitively responds to the exposure of environmental pollutants and is
promising for biomonitoring hematotoxicity in future studies.
Keywords Plasma kallikrein-kinin system· Environmental pollutants· Hematologic toxicity· Plasma KKS activation
Introduction
Numerous functional enzyme cascade systems exist in the
plasma, and these proteasomes work together via reciprocal
interactions and crosstalk to regulate blood homeostasis. The
plasma kallikrein-kinin system (KKS), also known as the
contact system, is abundantly present in the blood circulative
system [1]. It consists of a series of serine proteases, includ-
ing Hageman factor (FXII), plasma prekallikrein (PPK), and
high molecular weight kininogen (HK). The plasma KKS
may interact with other plasma enzyme systems by trigger-
ing cascade reactions, consequently regulating numerous
physiological processes, such as blood pressure, inflam-
mation, vascular permeability, thrombosis, oxidative stress,
angiogenesis, coagulation, fibrinolysis, etc. [27]. The above
physio-pathological processes are closely regulated by the
activation of the KKS, which is highly susceptible to the
negatively charged surface of endogenous or exogenous
substances. Upon contacting the zymogen of FXII, this pro-
tein is autoactivated through conformational conversion and
subsequently self-cleaved to form FXIIa, thus triggering the
cascade activation of plasma KKS [2], characterized by the
sequential cleavage of PPK to plasma kallikrein (PK) and
HK to bradykinin (BK), respectively. The resultant short
* Qunfang Zhou
zhouqf@rcees.ac.cn
1 State Key Laboratory ofEnvironmental Chemistry
andEcotoxicology, Research Center forEco-Environmental
Sciences, Chinese Academy ofSciences, Beijing100085,
China
2 Sino-Danish College, University ofChinese Academy
ofSciences, Beijing100049, China
3 School ofEnvironment, Hangzhou Institute forAdvanced
Study, University ofChinese Academy ofSciences,
Hangzhou310000, China
4 Institute ofEnvironment andHealth, Jianghan University,
Wuhan430056, China
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