A dynamical model of TGF-β activation in asthmatic airways.

Excessive activation of the regulatory cytokine transforming growth factor $\beta $ (TGF-$\beta $) via contraction of airway smooth muscle (ASM) is associated with the development of asthma. In this study, we develop an ordinary differential equation model that describes the change in density of the key airway wall constituents, ASM and extracellular matrix (ECM), and their interplay with subcellular signalling pathways leading to the activation of TGF-$\beta $. We identify bistable parameter regimes where there are two positive steady states, corresponding to either reduced or elevated TGF-$\beta $ concentration, with the latter leading additionally to increased ASM and ECM density.

A computational cardiopulmonary physiology simulator accurately predicts individual patient responses to changes in mechanical ventilator settings.

We present new results validating the capability of a high-fidelity computational simulator to accurately predict the responses of individual patients with acute respiratory distress syndrome to changes in mechanical ventilator settings. 26 pairs of data-points comprising arterial blood gasses collected before and after changes in inspiratory pressure, PEEP, FiO, and I:E ratio from six mechanically ventilated patients were used for this study. Parallelized global optimization algorithms running on a high-performance computing cluster were used to match the simulator to each initial data point.

Modeling Mechanical Ventilation In Silico-Potential and Pitfalls.

Computer simulation offers a fresh approach to traditional medical research that is particularly well suited to investigating issues related to mechanical ventilation. Patients receiving mechanical ventilation are routinely monitored in great detail, providing extensive high-quality data-streams for model design and configuration. Models based on such data can incorporate very complex system dynamics that can be validated against patient responses for use as investigational surrogates.

The Critical Importance of Spatial and Temporal Scales in Designing and Interpreting Immune Cell Migration Assays.

Intravital microscopy and other direct-imaging techniques have allowed for a characterisation of leukocyte migration that has revolutionised the field of immunology, resulting in an unprecedented understanding of the mechanisms of immune response and adaptive immunity. However, there is an assumption within the field that modern imaging techniques permit imaging parameters where the resulting cell track accurately captures a cell's motion. This notion is almost entirely untested, and the relationship between what could be observed at a given scale and the underlying cell behaviour is undefined.

Reduced biomechanical models for precision-cut lung-slice stretching experiments.

Precision-cut lung-slices (PCLS), in which viable airways embedded within lung parenchyma are stretched or induced to contract, are a widely used ex vivo assay to investigate bronchoconstriction and, more recently, mechanical activation of pro-remodelling cytokines in asthmatic airways. We develop a nonlinear fibre-reinforced biomechanical model accounting for smooth muscle contraction and extracellular matrix strain-stiffening. Through numerical simulation, we describe the stresses and contractile responses of an airway within a PCLS of finite thickness, exposing the importance of smooth muscle contraction on the local stress state within the airway.

Switching behaviour in vascular smooth muscle cell-matrix adhesion during oscillatory loading.

Integrins regulate mechanotransduction between smooth muscle cells (SMCs) and the extracellular matrix (ECM). SMCs resident in the walls of airways or blood vessels are continuously exposed to dynamic mechanical forces due to breathing or pulsatile blood flow. However, the resulting effects of these forces on integrin dynamics and associated cell-matrix adhesion are not well understood.

An Integrated Pipeline for Combining Data and Mathematical Models Using a Bayesian Parameter Inference Approach to Characterize Spatio-temporal Chemokine Gradient Formation.

All protective and pathogenic immune and inflammatory responses rely heavily on leukocyte migration and localization. Chemokines are secreted chemoattractants that orchestrate the positioning and migration of leukocytes through concentration gradients. The mechanisms underlying chemokine gradient establishment and control include physical as well as biological phenomena.

DP antagonism reduces airway smooth muscle mass in asthma by decreasing eosinophilia and myofibroblast recruitment.

Increased airway smooth muscle mass, a feature of airway remodeling in asthma, is the strongest predictor of airflow limitation and contributes to asthma-associated morbidity and mortality. No current drug therapy for asthma is known to affect airway smooth muscle mass. Although there is increasing evidence that prostaglandin D type 2 receptor (DP) is expressed in airway structural and inflammatory cells, few studies have addressed the expression and function of DP in airway smooth muscle cells.

Small airway hyperresponsiveness in COPD: relationship between structure and function in lung slices.

The direct relationship between pulmonary structural changes and airway hyperresponsiveness (AHR) in chronic obstructive pulmonary disease (COPD) is unclear. We investigated AHR in relation to airway and parenchymal structural changes in a guinea pig model of COPD and in COPD patients. Precision-cut lung slices (PCLS) were prepared from guinea pigs challenged with lipopolysaccharide or saline two times weekly for 12 wk.

Chemokine Transport Dynamics and Emerging Recognition of Their Role in Immune Function.

Leukocyte migration is critically important during all protective and pathological immune and inflammatory responses. Chemokines play fundamental roles in this process, and chemokine concentration gradients stimulate the directional migration of leukocytes. The formation and regulation of these gradients is poorly understood.

A theoretical model of inflammation- and mechanotransduction-driven asthmatic airway remodelling.

Inflammation, airway hyper-responsiveness and airway remodelling are well-established hallmarks of asthma, but their inter-relationships remain elusive. In order to obtain a better understanding of their inter-dependence, we develop a mechanochemical morphoelastic model of the airway wall accounting for local volume changes in airway smooth muscle (ASM) and extracellular matrix in response to transient inflammatory or contractile agonist challenges. We use constrained mixture theory, together with a multiplicative decomposition of growth from the elastic deformation, to model the airway wall as a nonlinear fibre-reinforced elastic cylinder.

Effect of Loading History on Airway Smooth Muscle Cell-Matrix Adhesions.

Integrin-mediated adhesions between airway smooth muscle (ASM) cells and the extracellular matrix (ECM) regulate how contractile forces generated within the cell are transmitted to its external environment. Environmental cues are known to influence the formation, size, and survival of cell-matrix adhesions, but it is not yet known how they are affected by dynamic fluctuations associated with tidal breathing in the intact airway. Here, we develop two closely related theoretical models to study adhesion dynamics in response to oscillatory loading of the ECM, representing the dynamic environment of ASM cells in vivo.

, and study challenges the impact of bronchial thermoplasty on acute airway smooth muscle mass loss.

Bronchial thermoplasty is a treatment for asthma. It is currently unclear whether its histopathological impact is sufficiently explained by the proportion of airway wall that is exposed to temperatures necessary to affect cell survival.Airway smooth muscle and bronchial epithelial cells were exposed to media (37-70°C) for 10 s to mimic thermoplasty.

Repeated airway constrictions in mice do not alter respiratory function.

It is suggested that the frequent strain the airways undergo in asthma because of repeated airway smooth muscle (ASM)-mediated constrictions contributes to airway wall remodeling. However, the effects of repeated constrictions on airway remodeling, as well as the ensuing impact of this presumptive remodeling on respiratory mechanics, have never been investigated in subjects without asthma. In this study, we set out to determine whether repeated constrictions lead to features that are reminiscent of asthma in mice without asthma.

A Novel Computational Model Predicts Key Regulators of Chemokine Gradient Formation in Lymph Nodes and Site-Specific Roles for CCL19 and ACKR4.

The chemokine receptor CCR7 drives leukocyte migration into and within lymph nodes (LNs). It is activated by chemokines CCL19 and CCL21, which are scavenged by the atypical chemokine receptor ACKR4. CCR7-dependent navigation is determined by the distribution of extracellular CCL19 and CCL21, which form concentration gradients at specific microanatomical locations.

Corrigendum: Airway and Parenchymal Strains during Bronchoconstriction in the Precision Cut Lung Slice.

[This corrects the article on p. 309 in vol. 7, PMID: 27559314.

Mathematical modelling of cytokines, MMPs and fibronectin fragments in osteoarthritic cartilage.

Osteoarthritis (OA) is a degenerative disease which causes pain and stiffness in joints. OA progresses through excessive degradation of joint cartilage, eventually leading to significant joint degeneration and loss of function. Cytokines, a group of cell signalling proteins, present in raised concentrations in OA joints, can be classified into pro-inflammatory and anti-inflammatory groups.

Airway and Parenchymal Strains during Bronchoconstriction in the Precision Cut Lung Slice.

The precision-cut lung slice (PCLS) is a powerful tool for studying airway reactivity, but biomechanical measurements to date have largely focused on changes in airway caliber. Here we describe an image processing tool that reveals the associated spatio-temporal changes in airway and parenchymal strains. Displacements of sub-regions within the PCLS are tracked in phase-contrast movies acquired after addition of contractile and relaxing drugs.

Ryanodine receptor sensitization results in abnormal calcium signaling in airway smooth muscle cells.

Intracellular Ca(2+) dynamics of airway smooth muscle cells (ASMCs) are believed to play a major role in airway hyperresponsiveness and remodeling in asthma. Prior studies have underscored a prominent role for inositol 1,4,5-triphosphate (IP3) receptors in normal agonist-induced Ca(2+) oscillations, whereas ryanodine receptors (RyRs) appear to remain closed during such Ca(2+) oscillations, which mediate ASMC contraction. Nevertheless, RyRs have been hypothesized to play a role in hyperresponsive Ca(2+) signaling.

Nonlinear compliance modulates dynamic bronchoconstriction in a multiscale airway model.

The role of breathing and deep inspirations (DI) in modulating airway hyperresponsiveness remains poorly understood. In particular, DIs are potent bronchodilators of constricted airways in nonasthmatic subjects but not in asthmatic subjects. Additionally, length fluctuations (mimicking DIs) have been shown to reduce mean contractile force when applied to airway smooth muscle (ASM) cells and tissue strips.

Airway smooth muscle in asthma: linking contraction and mechanotransduction to disease pathogenesis and remodelling.

Asthma is an obstructive airway disease, with a heterogeneous and multifactorial pathogenesis. Although generally considered to be a disease principally driven by chronic inflammation, it is becoming increasingly recognised that the immune component of the pathology poorly correlates with the clinical symptoms of asthma, thus highlighting a potentially central role for non-immune cells. In this context airway smooth muscle (ASM) may be a key player, as it comprises a significant proportion of the airway wall and is the ultimate effector of acute airway narrowing.

STI-GMaS: an open-source environment for simulation of sexually-transmitted infections.

Background: Sexually-transmitted pathogens often have severe reproductive health implications if treatment is delayed or absent, especially in females. The complex processes of disease progression, namely replication and ascension of the infection through the genital tract, span both extracellular and intracellular physiological scales, and in females can vary over the distinct phases of the menstrual cycle. The complexity of these processes, coupled with the common impossibility of obtaining comprehensive and sequential clinical data from individual human patients, makes mathematical and computational modelling valuable tools in developing our understanding of the infection, with a view to identifying new interventions.