A Distribution-Moment Approximation for Coupled Dynamics of the Airway Wall and Airway Smooth Muscle

Rampadarath, Anand; Donovan, Graham M.

doi:10.1016/j.bpj.2017.11.020

Cited by 9 publications

(5 citation statements)

References 40 publications

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“…Asthma is a chronic airway disease characterized by bronchial hyper-responsiveness, lung inflammation, airway remodeling, and airway obstruction ( Meyer et al, 2014 ; Rampadarath and Donovan, 2018 ). As heterogeneous condition, asthma includes acute episodes that revert spontaneously or with treatment and chronic inflammation and/or structural changes that may be related to persistent symptoms and eventual reduction of pulmonary function.…”

Section: Introductionmentioning

confidence: 99%

Effect of Anti-IL17 Antibody Treatment Alone and in Combination With Rho-Kinase Inhibitor in a Murine Model of Asthma

et al. 2018

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Background: Interleukin-17 (IL-17) and Rho-kinase (ROCK) play an important role in regulating the expression of inflammatory mediators, immune cell recruitment, hyper-responsiveness, tissue remodeling, and oxidative stress. Modulation of IL-17 and ROCK proteins may represent a promising approach for the treatment of this disease.Objective: To study the effects of an anti-IL17 neutralizing antibody and ROCK inhibitor treatments, separately and in combination, in a murine model of chronic allergy-induced lung inflammation.Methods: Sixty-four BALBc mice, were divided into eight groups (n = 8): SAL (saline-instilled); OVA (exposed-ovalbumin); SAL-RHOi (saline and ROCK inhibitor), OVA-RHOi (exposed-ovalbumin and ROCK inhibitor); SAL-anti-IL17 (saline and anti-IL17); OVA-anti-IL17 (exposed-ovalbumin and anti-IL17); SAL-RHOi-anti-IL17 (saline, ROCK inhibitor and anti-IL17); and OVA-RHOi-anti-IL17 (exposed-ovalbumin, anti-IL17, and ROCK inhibitor). A 28-day protocol of albumin treatment was used for sensitization and induction of pulmonary inflammation. The anti-IL17A neutralizing antibody (7.5 μg per treatment) was administered by intraperitoneal injection and ROCK inhibitor (Y-27632) intranasally (10 mg/kg), 1 h prior to each ovalbumin challenge (days 22, 24, 26, and 28).Results: Treatment with the anti-IL17 neutralizing antibody and ROCK inhibitor attenuated the percentage of maximal increase of respiratory system resistance and respiratory system elastance after challenge with methacholine and the inflammatory response markers evaluated (CD4+, CD8+, ROCK1, ROCK2, IL-4, IL-5, IL-6, IL-10 IL-13, IL-17, TNF-α, TGF-β, NF-κB, dendritic cells, iNOS, MMP-9, MMP-12, TIMP-1, FOXP3, isoprostane, biglycan, decorin, fibronectin, collagen fibers content and gene expression of IL-17, VAChT, and arginase) compared to the OVA group (p < 0.05). Treatment with anti-IL17 and the ROCK inhibitor together resulted in potentiation in decreasing the percentage of resistance increase after challenge with methacholine, decreased the number of IL-5 positive cells in the airway, and reduced, IL-5, TGF-β, FOXP3, ROCK1 and ROCK2 positive cells in the alveolar septa compared to the OVA-RHOi and OVA-anti-IL17 groups (p < 0.05).Conclusion: Anti-IL17 treatment alone or in conjunction with the ROCK inhibitor, modulates airway responsiveness, inflammation, tissue remodeling, and oxidative stress in mice with chronic allergic lung inflammation.

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Section: Introductionmentioning

confidence: 99%

Effect of Anti-IL17 Antibody Treatment Alone and in Combination With Rho-Kinase Inhibitor in a Murine Model of Asthma

et al. 2018

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“…This approximation assumes a Gaussian displacement-distribution (other distributions could be assumed) of myosin heads to allow for the simplification of the differential equations and causes some additional error in force and velocity approximates but significantly reduces the computational cost. The distribution-moment approximation for the HHM model of smooth muscle has also been developed (Rampadarath 2018 ). Initial simulations of the distribution-moment model for a single lymphangion have been run but are beyond the scope of this paper.…”

Section: Discussionmentioning

confidence: 99%

A multiscale sliding filament model of lymphatic muscle pumping

Morris

Zawieja

Moore

2021

Biomech Model Mechanobiol

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The lymphatics maintain fluid balance by returning interstitial fluid to veins via contraction/compression of vessel segments with check valves. Disruption of lymphatic pumping can result in a condition called lymphedema with interstitial fluid accumulation. Lymphedema treatments are often ineffective, which is partially attributable to insufficient understanding of specialized lymphatic muscle lining the vessels. This muscle exhibits cardiac-like phasic contractions and smooth muscle-like tonic contractions to generate and regulate flow. To understand the relationship between this sub-cellular contractile machinery and organ-level pumping, we have developed a multiscale computational model of phasic and tonic contractions in lymphatic muscle and coupled it to a lymphangion pumping model. Our model uses the sliding filament model (Huxley in Prog Biophys Biophys Chem 7:255–318, 1957) and its adaptation for smooth muscle (Mijailovich in Biophys J 79(5):2667–2681, 2000). Multiple structural arrangements of contractile components and viscoelastic elements were trialed but only one provided physiologic results. We then coupled this model with our previous lumped parameter model of the lymphangion to relate results to experiments. We show that the model produces similar pressure, diameter, and flow tracings to experiments on rat mesenteric lymphatics. This model provides the first estimates of lymphatic muscle contraction energetics and the ability to assess the potential effects of sub-cellular level phenomena such as calcium oscillations on lymphangion outflow. The maximum efficiency value predicted (40%) is at the upper end of estimates for other muscle types. Spontaneous calcium oscillations during diastole were found to increase outflow up to approximately 50% in the range of frequencies and amplitudes tested.

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“…Isolated finitethickness airway models that use the HHM model suffers from significant computational cost (e.g., (Hiorns et al, 2014;Hiorns et al, 2016)); furthermore the cost becomes prohibitive for whole lung branching networks. To provide computationally efficient ways of coupling muscle cell contraction to tissue behaviour, simplified models, first proposed by Zahalak (Zahalak, 1981) for the Huxley model for striated muscle, have been developed for ASM and corresponding HHM models by Rampadarath and Donovan (Rampadarath and Donovan, 2018). The idea behind this is that an ansatz is made regarding the form of probability distribution functions (PDFs) of the cross-bridge distributions, enabling the reduction of the governing PDEs to a system of ODEs in terms of the distribution-moments of the PDF.…”

Section: Area Of Interest Model-generated Hypothesis Referencesmentioning

confidence: 99%

The role of mathematical models in designing mechanopharmacological therapies for asthma

Irons

Brook

2022

Front. Syst. Biol.

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Healthy lung function depends on a complex system of interactions which regulate the mechanical and biochemical environment of individual cells to the whole organ. Perturbations from these regulated processes give rise to significant lung dysfunction such as chronic inflammation, airway hyperresponsiveness and airway remodelling characteristic of asthma. Importantly, there is ongoing mechanobiological feedback where mechanical factors including airway stiffness and oscillatory loading have considerable influence over cell behavior. The recently proposed area of mechanopharmacology recognises these interactions and aims to highlight the need to consider mechanobiology when identifying and assessing pharmacological targets. However, these multiscale interactions can be difficult to study experimentally due to the need for measurements across a wide range of spatial and temporal scales. On the other hand, integrative multiscale mathematical models have begun to show success in simulating the interactions between different mechanobiological mechanisms or cell/tissue-types across multiple scales. When appropriately informed by experimental data, these models have the potential to serve as extremely useful predictive tools, where physical mechanisms and emergent behaviours can be probed or hypothesised and, more importantly, exploited to propose new mechanopharmacological therapies for asthma and other respiratory diseases. In this review, we first demonstrate via an exemplar, how a multiscale mathematical model of acute bronchoconstriction in an airway could be exploited to propose new mechanopharmacological therapies. We then review current mathematical modelling approaches in respiratory disease and highlight hypotheses generated by such models that could have significant implications for therapies in asthma, but that have not yet been the subject of experimental attention or investigation. Finally we highlight modelling approaches that have shown promise in other biological systems that could be brought to bear in developing mathematical models for optimisation of mechanopharmacological therapies in asthma, with discussion of how they could complement and accelerate current experimental approaches.

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A Distribution-Moment Approximation for Coupled Dynamics of the Airway Wall and Airway Smooth Muscle

Cited by 9 publications

References 40 publications

Effect of Anti-IL17 Antibody Treatment Alone and in Combination With Rho-Kinase Inhibitor in a Murine Model of Asthma

Effect of Anti-IL17 Antibody Treatment Alone and in Combination With Rho-Kinase Inhibitor in a Murine Model of Asthma

A multiscale sliding filament model of lymphatic muscle pumping

The role of mathematical models in designing mechanopharmacological therapies for asthma

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