Investigating the therapeutic potential of the novel CXCL12 neutralizing ligand LIT-927 as a treatment for asthma

Abstract

Background: Chronic allergic airway disease is primarily characterized by airway remodeling, which severely compromises lung function. This remodeling process involves the thickening of airway smooth muscles, alterations in the vasculature, and a significant influx of inflammatory cells. Unfortunately, current therapeutic approaches often fall short in effectively addressing these structural changes. The core objective of this thesis is to investigate the therapeutic potential of LIT-927, a novel CXCL12-neutralizing ligand. This research will specifically focus on its influence on vascular and bronchial remodeling and its interactions with pericytes.

Methods: In this study, mice were exposed to a protocol of chronic airway inflammation induced by the common environmental aeroallergen, house dust mite (HDM). Phenotypic alterations in the lungs, in the presence of LIT-927, were assessed through flow cytometry and immunostaining. Additionally, the functional capabilities of pericytes were evaluated using in vitro migration assays.

Results: The administration of LIT-927 mitigated HDM-induced bronchial and vascular remodeling. In the context of chronic allergic inflammation, pericytes exhibited heightened expression of CXCR4, indicating an enhanced chemotactic response to CXCL12. Pericytes displayed increased CXCR4 expression in response to chronic allergic inflammation and demonstrated increased migration towards its cognate chemokine, CXCL12. This augmented migratory capacity was accompanied by the accumulation of pericytes in the airway wall, increased smooth muscle thickness, and respiratory distress symptoms. Notably, the uncoupling of pericytes from pulmonary vessels and their subsequent migration to the airway wall were effectively inhibited following topical treatment with the CXCL12 neutralizing ligand LIT-927.

Conclusion: This study highlights the pivotal role of the CXCL12/CXCR4 axis in promoting pulmonary pericyte accumulation and airway remodeling. Our findings position LIT-927 as a promising therapeutic agent for addressing tissue remodeling associated with chronic inflammation.

Date of Award	Sept 2023
Original language	English
Awarding Institution	Aston University
Supervisor	Jill Johnson (Supervisor) & Andrew Devitt (Supervisor)