Massive neutrophil infiltration into the airways is a hallmark of the chronic inflammatory response in cystic fibrosis (CF) and occurs even in the absence of bacterial or other infections. Such inflammatory responses significantly contribute to progressive lung disease (PLD) that accounts for most of the morbidity and mortality in CF. We hypothesize that CF neutrophil activity results in part from the pulmonary hemodynamics in CF patients being more pro-inflammatory than in healthy individuals. Our objective is to analyze the influence of disturbed patterns of blood flow in the lungs of CF patients on the resulting levels of physiological force that regulate neutrophil adhesion to the vasculature using an integrated analytical and experimental approach. First, computational fluid dynamics (CFD) is being used to characterize detailed hemodynamics in models representing pre-capillary pulmonary vessels under normal and CF-patient conditions in children.
Second, a range of parameters identified in the modeling studies will be used for in vitro cell adhesion experiments analyzing the influence of altered hemodynamics as well as vascular endothelium-expressed adhesion receptor densities on neutrophil adhesion to the inflamed vascular endothelium in flow. This innovative research will inform the CF field and lay the groundwork for subsequent investigations on the role of neutrophilic inflammation in PLD.
Edwards, E., Thomas, S.N., “P-Selectin and ICAM-1 Synergy in Mediating THP-1 Monocyte Adhesion in Hemodynamic Flow is Length Dependent”, Integrative Biology, Volume 9, Issue 4, April 2017, Pages 313–327, https://doi.org/10.1039/c7ib00020k