Alleviation of secondary brain injury, posttraumatic inflammation, and brain edema formation by inhibition of factor XIIa

Abstract

BackgroundTraumatic brain injury (TBI) is a devastating neurological condition and a frequent cause of permanent disability. Posttraumatic inflammation and brain edema formation, two pathological key events contributing to secondary brain injury, are mediated by the contact-kinin system. Activation of this pathway in the plasma is triggered by activated factor XII. Hence, we set out to study in detail the influence of activated factor XII on the abovementioned pathophysiological features of TBI.MethodsUsing a cortical cryogenic lesion model in mice, we investigated the impact of genetic deficiency of factor XII and inhibition of activated factor XII with a single bolus injection of recombinant human albumin-fused Infestin-4 on the release of bradykinin, the brain lesion size, and contact-kinin system-dependent pathological events. We determined protein levels of bradykinin, intracellular adhesion molecule-1, CC-chemokine ligand 2, and interleukin-1β by enzyme-linked immunosorbent assays and mRNA levels of genes related to inflammation by quantitative real-time PCR. Brain lesion size was determined by tetrazolium chloride staining. Furthermore, protein levels of the tight junction protein occludin, integrity of the blood-brain barrier, and brain water content were assessed by Western blot analysis, extravasated Evans Blue dye, and the wet weight-dry weight method, respectively. Infiltration of neutrophils and microglia/activated macrophages into the injured brain lesions was quantified by immunohistological stainings.ResultsWe show that both genetic deficiency of factor XII and inhibition of activated factor XII in mice diminish brain injury-induced bradykinin release by the contact-kinin system and minimize brain lesion size, blood-brain barrier leakage, brain edema formation, and inflammation in our brain injury model.ConclusionsStimulation of bradykinin release by activated factor XII probably plays a prominent role in expanding secondary brain damage by promoting brain edema formation and inflammation. Pharmacological blocking of activated factor XII could be a useful therapeutic principle in the treatment of TBI-associated pathologic processes by alleviating posttraumatic inflammation and brain edema formation.

Inhibition of Lats1/p‐YAP1 pathway mitigates neuronal apoptosis and neurological deficits in a rat model of traumatic brain injury

“…Previous studies have revealed that TBI can induce some secondary events such as brain edema, hematoma, and local inflammation which often lead to neuronal cell apoptosis in the injured region and its surroundings . In our work, increased apoptosis has also been detected following TBI (Figure S1).…”

“…During TBI, neuronal cell death is not only a paramount contributor to neurological deficits but also a critical factor which seriously affecting the TBI patients’ quality of life. And the neuronal apoptosis after TBI often caused by some secondary events such as hemorrhage, brain edema, and local inflammation . Although there are a significant amount of studies about TBI, there are few effective clinical treatments for TBI patients .…”

“…And the neuronal apoptosis after TBI often caused by some secondary events such as hemorrhage, brain edema, and local inflammation. [2][3][4] Although there are a significant amount of studies about TBI, there are few effective clinical treatments for TBI patients. 5 Inadequate understanding of the pathogenesis of neuronal cell death in the damaged area and its surroundings is a major obstacle to the effective treatment of TBI.…”

Factor XII-Driven Inflammatory Reactions with Implications for Anaphylaxis

“…Blocking B1R reduces brain infarction and edema formation in mice, while B2R deficiency had no effect on stroke outcome in mice ( 30 ). Furthermore, murine models indicate a role of FXIIa and BK in CNS autoimmunity, including multiple sclerosis ( 31 ) and pharmacologic interference with BK formation and/or signaling might ameliorate secondary brain injury ( 32 ).…”

Effect of antihypertensive agents ACEI/ARB and CCB on hypertensive intracerebral hemorrhage and inflammatory cytokines, serum ferritin, and serum P

“…2 Actually, inflammatory factors play an important role in the formation of cerebral edema. 3 It has also been found that both angiotensin-converting enzyme inhibitor (ACEI)/angiotensin II receptor blocker (ARB) antihypertensive drugs and calcium channel blocker (CCB) antihypertensive drugs enable to regulate the level of inflammatory cytokines such as serum interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α). 4 Pericranial edema in patients with hypertensive ICH can be reflected by serum ferritin (SF) and substance P (SP) levels.…”