Neuroinflammatory Mechanisms of Connective Tissue Fibrosis: Targeting Neurogenic and Mast Cell Contributions

Abstract

The pathogenesis of fibrogenic wound and connective tissue healing is complex and incompletely understood. Common observations across a vast array of human and animal models of fibroproliferative conditions suggest neuroinflammatory mechanisms are important upstream fibrogenic events. As detailed in this review, mast cell hyperplasia is a common observation in fibrotic tissue. Recent investigations in human and preclinical models of hypertrophic wound healing and post-traumatic joint fibrosis provides evidence that fibrogenesis is governed by a maladaptive neuropeptide-mast cell-myofibroblast signaling pathway. The blockade and manipulation of these factors is providing promising evidence that if timed correctly, the fibrogenic process can be appropriately regulated. Clinically, abnormal fibrogenic healing responses are not ubiquitous to all patients and the identification of those at-risk remains an area of priority. Ultimately, an integrated appreciation of the common pathobiology shared by many fibrogenic connective tissue conditions may provide a scientific framework to facilitate the development of novel antifibrotic prevention and treatment strategies.

Curbing Inflammation in Multiple Sclerosis and Endometriosis: Should Mast Cells Be Targeted?

“…Interestingly, the profile of postinjury changes in the rabbit was very similar to those detected in tissue from humans with elbow contractures [ 14 , 15 ]. Of note was the consistent pattern of increased nerve elements, mast cells, and myofibroblasts in the abnormal phenotype of healing (reviewed in [ 18 , 19 ]). These abnormal healing patterns have led to the concept of “a nerve-mast cell-myofibroblast axis” in such conditions (reviewed in [ 18 , 19 ]), with neuroinflammation a potential key element of dysregulated responses to injury (reviewed in [ 18 – 20 ]).…”

PrEvention of posttraumatic contractuRes with Ketotifen 2 (PERK 2) – protocol for a multicenter randomized clinical trial

“…It has been used in the treatment of chronic asthma for over 40 years in humans. Post-market surveillance has confirmed the safety of KF (11,Bassler). Through a preclinical rabbit model of post-traumatic joint contractures, we have shown that KF, decreased contracture severity concomitant with decreased numbers of myofibroblasts, mast cells, neuropeptide containing nerve fibres, and measures of fibrosis in the joint capsule in a dose-dependent fashion [12][13][14].…”

“…Eligible participants will be randomized in equal proportions to receiving KF 2 mg, KF 5 mg, or a PL. This trial follows from the feasibility PERK 1 RCT (Clinicaltrials.gov, NCT01902017) where a dose of 5 mg was used, which is larger than the recommended dose of Ketotifen for the treatment of chronic asthma (1-2 mg twice daily) [11]. In choosing the second dose, the higher end of the recommended dose (2 mg) was selected balancing the effectiveness to prevent contractures and decreasing the chance for side effects (sedation).…”

“…Over the last 20 years, our laboratory research has implicated a myofibroblast-mast cell-neuropeptide axis of fibrosis in post-traumatic joint contractures [11]. Ketotifen Fumarate (KF) is a medication that has anti-anaphylactic properties, due to the prevention of the synthesis and/or release of growth factors and mediators from mast cells.…”

Phytotherapeutische Behandlungsmöglichkeiten bei Endometriose-Erkrankungen

“…Die biochemische Dysbalance führt oft zu Funktionsstö-rungen wie chronischen Schmerzen sowie Tubentransport-und Einnistungsproblemen. Anatomische Strukturveränderungen können, müssen jedoch nicht eine Folge sein [8,19]. Mit meinen Erfahrungen übereinstim-mend, können schon minimale Ände-rungen in der Exposition zu deutlichen Veränderungen in der Endometriose-Aktivität führen [13].…”