Dataset Information

A mechanochemical model for auto-regulation of lung airway surface layer volume.

ABSTRACT: We develop a proof-of-principle model for auto-regulation of water volume in the lung airway surface layer (ASL) by coupling biochemical kinetics, transient ASL volume, and homeostatic mechanical stresses. The model is based on the hypothesis that ASL volume is sensed through soluble mediators and phasic stresses generated by beating cilia and air drag forces. Model parameters are fit based on the available data on human bronchial epithelial cell cultures. Simulations then demonstrate that homeostatic volume regulation is a natural consequence of the processes described. The model maintains ASL volume within a physiological range that modulates with phasic stress frequency and amplitude. Next, we show that the model successfully reproduces the responses of cell cultures to significant isotonic and hypotonic challenges, and to hypertonic saline, an effective therapy for mucus hydration in cystic fibrosis patients. These results compel an advanced airway hydration model with therapeutic value that will necessitate detailed kinetics of multiple molecular pathways, feedback to ASL viscoelasticity properties, and stress signaling from the ASL to the cilia and epithelial cells.

SUBMITTER: Herschlag G

PROVIDER: S-EPMC3631568 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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A mechanochemical model for auto-regulation of lung airway surface layer volume.

Herschlag Gregory G Garcia Guilherme J M GJ Button Brian B Tarran Robert R Lindley Brandon B Reinhardt Benjamin B Elston Timothy C TC Forest M Gregory MG

Journal of theoretical biology 20130213

We develop a proof-of-principle model for auto-regulation of water volume in the lung airway surface layer (ASL) by coupling biochemical kinetics, transient ASL volume, and homeostatic mechanical stresses. The model is based on the hypothesis that ASL volume is sensed through soluble mediators and phasic stresses generated by beating cilia and air drag forces. Model parameters are fit based on the available data on human bronchial epithelial cell cultures. Simulations then demonstrate that homeo ...[more]

PMID: 23415939

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Project description:BACKGROUND: TATA Binding Protein (TBP) is required for transcription initiation by all three eukaryotic RNA polymerases. It participates in transcriptional initiation at the majority of eukaryotic gene promoters, either by direct association to the TATA box upstream of the transcription start site or by indirectly localizing to the promoter through other proteins. TBP exists in solution in a dimeric form but binds to DNA as a monomer. Here, we present the first mathematical model for auto-catalytic TBP expression and use it to study the role of dimerization in maintaining the steady state TBP level. RESULTS: We show that the autogenous regulation of TBP results in a system that is capable of exhibiting three steady states: an unstable low TBP state, one stable state corresponding to a physiological TBP concentration, and another stable steady state corresponding to unviable cells where no TBP is expressed. Our model predicts that a basal level of TBP is required to establish the transcription of the TBP gene, and hence for cell viability. It also predicts that, for the condition corresponding to a typical mammalian cell, the high-TBP state and cell viability is sensitive to variation in DNA binding strength. We use the model to explore the effect of the dimer in buffering the response to changes in TBP levels, and show that for some physiological conditions the dimer is not important in buffering against perturbations. CONCLUSIONS: Results on the necessity of a minimum basal TBP level support the in vivo observations that TBP is maternally inherited, providing the small amount of TBP required to establish its ubiquitous expression. The model shows that the system is sensitive to variations in parameters indicating that it is vulnerable to mutations in TBP. A reduction in TBP-DNA binding constant can lead the system to a regime where the unviable state is the only steady state. Contrary to the current hypotheses, we show that under some physiological conditions the dimer is not very important in restoring the system to steady state. This model demonstrates the use of mathematical modelling to investigate system behaviour and generate hypotheses governing the dynamics of such nonlinear biological systems.

Project description:Rationale: Airway remodeling in chronic obstructive pulmonary disease (COPD) is due to luminal narrowing and/or loss of airways. Existing computed tomographic metrics of airway disease reflect only components of these processes. With progressive airway narrowing, the ratio of the airway luminal surface area to volume (SA/V) should increase, and with predominant airway loss, SA/V should decrease.Objectives: To phenotype airway remodeling in COPD.Methods: We analyzed the airway trees of 4,325 subjects with COPD Global Initiative for Chronic Obstructive Lung Disease stages 0 to 4 and 73 nonsmokers enrolled in the multicenter COPDGene (Genetic Epidemiology of COPD) cohort. Surface area and volume measurements were estimated for the subtracheal airway tree to derive SA/V. We performed multivariable regression analyses to test associations between SA/V and lung function, 6-minute-walk distance, St. George's Respiratory Questionnaire, change in FEV1, and mortality, adjusting for demographics, total airway count, airway wall thickness, and emphysema. On the basis of the change in SA/V over 5 years, we categorized subjects into predominant airway narrowing [positive ∆(SA/V) more than 0] and predominant airway loss [negative ∆(SA/V) less than 0] and compared survival between the two groups.Measurements and Main Results: Airway SA/V was independently associated with FEV1/FVC (β = 0.12; 95% confidence interval [CI], 0.09-0.14; P < 0.001) and FEV1% predicted (β = 20.10; 95% CI, 15.13-25.08; P < 0.001). Airway SA/V was also independently associated with 6-minute-walk distance, respiratory quality of life, and lung function decline. Compared with subjects with predominant airway narrowing (n = 2,914; 66.3%), those with predominant airway loss (n = 1,484; 33.7%) had worse survival (adjusted hazard ratio for all-cause mortality = 1.58; 95% CI, 1.18-2.13; P = 0.002).Conclusions: Computed tomography-based airway SA/V is an imaging biomarker of airway remodeling and provides differential information on predominant airway narrowing and loss in COPD. SA/V is associated with respiratory morbidity, lung function decline, and survival.

Dataset Information

A mechanochemical model for auto-regulation of lung airway surface layer volume.

Publications

A mechanochemical model for auto-regulation of lung airway surface layer volume.

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