A review of inflammatory mechanism in airway diseases.
by P. Aghasafari, U.Z. George, R. Pidaparti
in Inflammation Research, Vol. 68(1):59-74 (2019)
Abstract: In this review, we found that inflammatory response in COPD is determined by the activation of epithelial cells and macrophages in the respiratory tract. Epithelial cells and macrophages discharge transforming growth factor-β (TGF-β), which trigger fibroblast proliferation and tissue remodeling. Asthma leads to airway hyper-responsiveness, obstruction, mucus hyper-production, and airway-wall remodeling. Cytokines, allergens, chemokines, and infectious agents are the main stimuli that activate signaling pathways in epithelial cells in asthma. Mutation of the CF transmembrane conductance regulator (CFTR) gene results in CF. Mutations in CFTR influence the lung epithelial innate immune function that leads to exaggerated and ineffective airway inflammation that fails to abolish pulmonary pathogens. We present mechanistic computational models (based on ordinary differential equations, partial differential equations and agent-based models) that have been applied in studying the complex physiological and pathological mechanisms of chronic inflammation in different airway diseases.
Tissue geometry may govern lung branching mode selection.
by U.Z. George and S.R. Lubkin
in Journal of Theoretical Biology, Vol. 442:22-30 (2018)
Abstract: Lung branching morphogenesis proceeds in three stereotyped modes (domain, planar, and orthogonal branching). Much is known about the molecular players, including growth factors such as fibroblast growth factor 10 but it is unknown how these signals could actuate the different branching patterns. With the aim of identifying mechanisms that may determine the different branching modes, we developed a computational model of the epithelial lung bud and its surrounding mesenchyme. We studied transport of morphogens and localization of morphogen flux at lobe surfaces and lobe edges. We find that a single simple mechanism is theoretically capable of directing an epithelial tubule to elongate, bend, flatten, or bifurcate, depending solely on geometric ratios of the tissues in the vicinity of a growing tubule tip. Furthermore, the same simple mechanism is capable of generating orthogonal or planar branching, depending only on the same geometric ratios.
Quantifying stretch and secretion in the embryonic lung: Implications for morphogenesis.
by U.Z. George, K.K. Bokka, D. Warburton, S.R. Lubkin
in Mechanisms of Development Vol. 138:356-363 (2015)
Abstract: Branching in the embryonic lung is controlled by a variety of morphogens. Mechanics is also believed to play a significant role in lung branching. The relative roles and interactions of these two broad factors are challenging to determine. We considered three hypotheses for explaining why tracheal occlusion triples branching with no overall increase in size. Both hypotheses are based on tracheal occlusion blocking the exit of secretions. (H1) In- creased lumen pressure stretches tissues; stretch receptors at shoulders of growing tips increase local rate of branching. (H2) Blocking exit of secretions blocks advective transport of morphogens, leading to (H2a) increased overall concentration of morphogens or (H2b) increased flux of morphogens at specific locations. We constructed and analyzed computational models of tissue stretch and solute transport in a 3D lung geometry. Observed tissue stresses and stretches were predominantly in locations unrelated to subsequent branch locations, suggesting that tissue stretch (H1) is not the mechanism of enhancement of branching. Morphogen concentration in the mesenchyme (H2a) increased with tracheal occlusion, consistent with previously reported results. Morphogen flux at the epithelial surface (H2b) completely changed its distribution pattern when the trachea was occluded, tripling the number of locations at which it was elevated. Our results are consistent with the hypothesis that tracheal occlusion blocks outflow of secretions, leading to a higher number of high-flux locations at branching tips, in turn leading to a large increase in number of branching locations.
Numerical Analysis of the Effect of T-tubule Location on Calcium Transient in Ventricular Myocytes.
by U.Z. George, J. Wang, Z. Yu
in Biomed Mater Eng. Vol. 24(1):1299-306 (2014)
Abstract: Intracellular calcium (Ca2+) signaling in cardiac myocytes is vital for proper functioning of the heart. Understanding the intracellular Ca2+ dynamics would give an insight into the functions of normal and diseased hearts. In the current study, spatiotemporal Ca2+ dynamics is investigated in ventricular myocytes by considering Ca2+ release and re-uptake via sarcolemma and transverse tubules (T-tubules), Ca2+ diffusion and buffering in the cytosol, and the blockade of Ca2+ activities associated with the sarcoplasmic reticulum. This study is carried out using a three dimensional (3D) geometric model of a branch of T-tubule extracted from the electron microscopy (EM) images of a partial ventricular myocyte. Mathematical modeling is done by using a system of partial differential equations involving Ca2+ , buffers, and membrane channels. Numerical simulation results suggest that a lack of T-tubule structure at the vicinity of the cell surface could increase the peak time of Ca2+ concentration in myocytes. The results also show that T-tubules and mobile buffers play an important role in the regulation of Ca2+ transient in ventricular myocytes.
Mathematical modelling and numerical simulations of actin dynamics in the eukaryotic cell.
by U.Z. George, A. Stéphanou, A. Madzvamuse
in Journal of Mathematical Biology Vol. 66(3):547-593 (2013)
Abstract: The aim of this article is to study cell deformation and cell movement by considering both the mechanical and biochemical properties of the cortical network of actin filaments and its concentration. Actin is a polymer that can exist either in filamentous form (F-actin) or in monometric form (G-actin) (Chen et al. in Trends Biochem Sci 25:19-23, 2000) and the filamentous form is arranged in a paired helix of two protofilaments (Ananthakrishnan et al. in Recent Res Devel Biophys 5:39-69, 2006). By assuming that cell deformations are a result of the cortical actin dynamics in the cell cytoskeleton, we consider a continuum mathematical model that couples the mechanics of the network of actin filaments with its bio-chemical dynamics. Numerical treatment of the model is carried out using the moving grid finite element method (Madzvamuse et al. in J Comput Phys 190:478-500, 2003). Furthermore, by assuming slow deformations of the cell, we use linear stability theory to validate the numerical simulation results close to bifurcation points. Far from bifurcation points, we show that the mathematical model is able to describe the complex cell deformations typically observed in experimental results. Our numerical results illustrate cell expansion, cell contraction, cell translation and cell relocation as well as cell protrusions. In all these results, the contractile tonicity formed by the association of actin filaments to the myosin II motor proteins is identified as a key bifurcation parameter.
The moving grid finite element method applied to cell movement and deformation.
by U.Z. George, A. Madzvamuse
in Finite Elements in Analysis and Design Vol. 74:76-92 (2013)
Abstract: In this article we present a novel application of the moving grid finite element method  for solving a cytomechanical model that describes actin dynamics in order to generate cell movement and deformation. The cytomechanical model describes both the mechanical and biochemical properties of the cortical network of actin filaments and its concentration. Actin is a polymer that can exist either in filamentous form (F-actin) or in monometric form (G-actin)  and the filamentous form is arranged in a paired helix of two protofilaments . By assuming slow deformations of the cell, we validate numerical results by comparing qualitatively with predictions from linear stability theory close to bifurcation points. Far from bifurcation points, the mathematical model and computational algorithm are able to describe and generate the complex cell deformations typically observed in experiments. Our numerical results illustrate cell expansion, cell contraction, cell translation and cell relocation as well as cell protrusions. A key model bifurcation parameter identified is the contractile tonicity formed by the association of actin filaments to the myosin II motor proteins. The robustness, generality and applicability of the numerical methodology allows us to tackle similar problems in developmental biology, biomedicine and plant biology where similar mechanisms are routinely used.