Mast Cell Promotes the Development of Intracranial Aneurysm Rupture

And since this was tested in mice your stroke hospital needs to ensure human testing. 

Drugs That Work In Mice Often Fail When Tried In People

Mast Cell Promotes the Development of Intracranial Aneurysm Rupture

Hajime Furukawa

,

Kosuke Wada

,

Yoshiteru Tada

,

Atsushi Kuwabara

,

Hiroki Sato

,

Jinglu Ai

,

Michael T. Lawton

,

Tomoki Hashimoto

Originally published6 Oct 2020https://doi.org/10.1161/STROKEAHA.120.030834Stroke. 2020;51:3332–3339

Abstract

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Background and Purpose:

Inflammation has emerged as a key component of the pathophysiology of intracranial aneurysms. Mast cells have been detected in human intracranial aneurysm tissues, and their presence was associated with intramural microhemorrhage and wall degeneration. We hypothesized that mast cells play a critical role in the development of aneurysmal rupture, and that mast cells can be used as a therapeutic target for the prevention of aneurysm rupture.

Methods:

Intracranial aneurysms were induced in adult mice using a combination of induced systemic hypertension and a single injection of elastase into the cerebrospinal fluid. Aneurysm formation and rupture were assessed over 3 weeks. Roles of mast cells were assessed using a mast cell stabilizer (cromolyn), a mast cell activator (C48/80), and mice that are genetically lacking mature mast cells (Kit^W-sh/W-sh mice).

Results:

Pharmacological stabilization of mast cells with cromolyn markedly decreased the rupture rate of aneurysms (80% versus 19%, n=10 versus n =16) without affecting the aneurysm formation. The activation of mast cells with C48/80 significantly increased the rupture rate of aneurysms (25% versus 100%, n=4 versus n=5) without affecting the overall rate of aneurysm formation. Furthermore, the genetic deficiency of mast cells significantly prevented aneurysm rupture (80% versus 25%, n=10 versus n=8, wild-type versus Kit^W-sh/W-sh mice).

Conclusions:

These results suggest that mast cells play a key role in promoting aneurysm rupture but not formation. Stabilizers of mast cells may have a potential therapeutic value in preventing intracranial aneurysm rupture in patients.

Introduction

Rupture of intracranial aneurysms causes aneurysmal subarachnoid hemorrhage. The 30-day mortality rate after aneurysmal subarachnoid hemorrhage can be as high as 45%.¹ Therefore, surgical clipping or endovascular coiling are offered to patients with unruptured aneurysms for the prevention of aneurysmal rupture. Significant technical advancements and refinements have been made in these invasive treatments. However, the adverse outcome rates resulting from the clipping and coiling of unruptured aneurysms are still not negligible.² Therefore, pharmacological prevention of aneurysmal rupture may be an attractive alternative approach in patients with unruptured aneurysms.³

Inflammation is increasingly recognized as a critical component in the pathophysiology of intracranial aneurysms.^4–9 Observational studies have shown the presence of inflammatory cells and inflammatory markers in human intracranial aneurysm tissues and serum samples.^5,10 Mast cells have been detected in human intracranial aneurysm tissues,^7,11 and the presence of mast cells was associated with intramural microhemorrhage and wall degeneration of human intracranial aneurysms.¹¹

Mast cells, classically known as key regulators of allergic reactions, have emerged as integral players in cardiovascular diseases.^12–17 By releasing cytokines, including tryptase, chymases, cathepsins, and interleukins, mast cells can affect vascular inflammation and remodeling.^12,18–20 Blocking the cytokine release from mast cells reduces the development and progression of atherosclerosis and abdominal aortic aneurysm in animals.^14,16 Although previous studies suggested an association between mast cell activation and pathological remodeling of aneurysm walls,^21,22 the direct link between mast cell activation and the development of aneurysmal rupture has not been established. Therefore, we tested whether mast cells contribute to the development of aneurysmal rupture using the genetic and pharmacological tools in a mouse model of intracranial aneurysm.