Role of the kallikrein–kinin system in traumatic brain injury

Abstract

Traumatic brain injury (TBI) is a major cause of mortality and morbidity worldwide. Despite improvements in acute intensive care, there are currently no specific therapies to ameliorate the effects of TBI. Successful therapeutic strategies for TBI should target multiple pathophysiologic mechanisms that occur at different stages of brain injury. The kallikrein–kinin system is a promising therapeutic target for TBI as it mediates key pathologic events of traumatic brain damage, such as edema formation, inflammation, and thrombosis. Selective and specific kinin receptor antagonists and inhibitors of plasma kallikrein and coagulation factor XII have been developed, and have already shown therapeutic efficacy in animal models of stroke and TBI. However, conflicting preclinical evaluation, as well as limited and inconclusive data from clinical trials in TBI, suggests that caution should be taken before transferring observations made in animals to humans. This review summarizes current evidence on the pathologic significance of the kallikrein–kinin system during TBI in animal models and, where available, the experimental findings are compared with human data.

Novel Innate Immune Genes Regulating the Macrophage Response to Gram Positive Bacteria

“…Bradykinin 1 receptor (Bdkrb1) has a well-established role in the regulation of inflammation, particularly in the brain (Albert-Weissenberger et al 2014), cardiovascular system (Couture et al 2014), and the lung (Yang et al 2014). Bradykinin receptor genes encode two G-protein-coupled receptors, inducible BDKRB1, and constitutive BDKRB2, that respond to endogenous kinin ligands as well as cytokines via the NF-kB pathway in the case of inducible BDKRB1 (Couture et al 2014).…”

Demyelinating and Thrombotic Diseases of the Central Nervous System: Common Pathogenic and Triggering Factors

“…The inhibition of plasma kallikrein, a key constituent of the proinflammatory contact-kinin system, is effective in wild-type mice up to 3 h post stroke ( 46 ). In fact, the contact-kinin system, representing an interface between inflammatory and thrombotic systems, was found activated in different neurological diseases, such as in traumatic brain injury showing a microvascular thrombosis along with edema and immune cell infiltration ( 47 ). The data reported in this work would suggest that the concept of thrombo-inflammation is also appropriate for the inflammatory-demyelinating diseases, albeit with quantitatively varying expression.…”

Mechanisms of Global Cerebral Edema Formation in Aneurysmal Subarachnoid Hemorrhage

“…79 Bradykinin receptor activation induces edema and increases vascular permeability both through inflammatory mechanisms and direct endothelial signaling. Studies of patients following aSAH demonstrate increased levels of bradykinin in plasma and CSF.…”