SAPHIR - a multi-scale, multi-resolution modeling environment targeting blood pressure regulation and fluid homeostasis.

International audienceWe present progress on a comprehensive, modular, interactive modeling environment centered on overall regulation of blood pressure and body fluid homeostasis. We call the project SAPHIR, for "a Systems Approach for PHysiological Integration of Renal, cardiac, and respiratory functions". The project uses state-of-the-art multi-scale simulation methods. The basic core model will give succinct input-output (reduced-dimension) descriptions of all relevant organ systems and regulatory processes, and it will be modular, multi-resolution, and extensible, in the sense that detailed submodules of any process(es) can be "plugged-in" to the basic model in order to explore, eg. system-level implications of local perturbations. The goal is to keep the basic core model compact enough to insure fast execution time (in view of eventual use in the clinic) and yet to allow elaborate detailed modules of target tissues or organs in order to focus on the problem area while maintaining the system-level regulatory compensations

The role of γδ T cells in airway epithelial injury and bronchial responsiveness after chlorine gas exposure in mice

BACKGROUND: Acute exposure to chlorine (Cl(2)) gas causes epithelial injury and airway dysfunction. γδ T cells are present in the mucosal surface of the airways and may contribute to the injury/repair response of the epithelium. METHODS: C57Bl/6J (wild type) and TCR-δ(-/- )mice exposed to Cl(2 )(400 ppm) for 5 minutes underwent measurements of airway responses to i.v. methacholine (MCh) at 1, 3, and 5 days after exposure. Bronchoalveolar lavage was performed to determine epithelial and leukocyte counts, and protein content. Tissue repair was assessed by proliferating cell nuclear antigen (PCNA) immunoreactivity and by expression of keratinocyte growth factor (KGF) mRNA by real-time PCR. RESULTS: Wild type mice developed a greater degree of airway hyperresponsiveness to MCh at 1 day post exposure to Cl(2 )compared with TCR-δ(-/- )mice. Epithelial cell counts in BAL after Cl(2 )exposure were greater in TCR-δ(-/- )mice, but macrophages showed a later peak and granulocyte numbers were lower in TCR-δ(-/- )than in wild type mice. Both groups had increased levels of total protein content in BAL after Cl(2 )exposure that resolved after 3 and 5 days, respectively. Epithelial proliferating cell nuclear antigen staining was increased at 1 and 3 days post exposure and was similar in the two groups. KGF mRNA was constitutively expressed in both groups and did not increase significantly after Cl(2 )but expression was lower in TCR-δ(-/- )mice. CONCLUSION: The severity of airway epithelial injury after Cl(2 )is greater in TCR-δ(-/- )mice but the inflammatory response and the change in airway responsiveness to methacholine are reduced. The rates of epithelial regeneration are comparable in both groups

From channelopathies to hypertension: A multi-mode modeling approach for exploration of heterogeneous systems spanning many scales and involving multiple organ systems

Despite the development of ever more sophisticated models at many scales, from the level of gene regulation or intra-cellular signal transduction or cellular metabolism, through models of tissue function, epithelial transport, or even whole organ physiology, there is presently, to our knowledge, no comprehensive, organism-level modeling environment that allows exploration of the whole chain of regulatory influences brought into play by a local perturbation such as a defect in a cell membrane ion transport protein. To fill this need, we are developing a comprehensive, modular, interactive modeling environment centered on overall regulation of blood pressure and body fluids. We rely on state-of-the-art multi-scale, multi-mode simulation methods. The core model will give succinct input-output (reduced-dimension) descriptions of all relevant organ systems and regulatory processes, and it will be modular, multi-resolution, and extensible, in the sense that detailed sub-modules of any process(es) can be "plugged-in" to the basic model in order to explore, e.g., system-level implications of local perturbations. The goal is to keep the basic core model compact enough to insure fast execution time (in view of eventual use in the clinic) and yet to allow elaborate detailed modules of target tissues or organs in order to focus on the problem area while maintaining the system-level regulatory compensations. We will present the core model, inspired by Guyton's classic 1972 model of overall regulation of blood pressure, and several aspects of the renal, cardiac, and lung modules to be included in the initial development

On-line monitoring of lung mechanics during spontaneous breathing: a physiological study.

Monitoring the mechanics of breathing in patients with advanced chronic obstructive lung diseases prior to lung transplantation is useful to characterize changes in the mechanical properties of the lungs. On-line methods of monitoring immediately process the data for clinical decisions. However, the few available methods are so far limited to monitor respiratory mechanics in ventilator-dependent patients. We investigated whether on-line monitoring of the lung mechanics, including intrinsic PEEP, was feasible in spontaneously breathing patients.In 9 stable patients with chronic obstructive pulmonary disease (COPD) and 11 with cystic fibrosis (CF) undergoing the procedure for the lung transplantation waiting list, we applied 2 methods of on-line monitoring (modified recursive least squares, RLS and modified multiple linear regression methods, SLS) of intrinsic PEEP (P(0)), dynamic lung elastance (E(Ldyn)) and inspiratory resistance (R(Linsp)), and compared them with an off-line graphical analysis (GA), our reference technique.In CF patients, there was no difference between methods, while in COPD, the median values of E(Ldyn) and R(Linsp) were significantly different between GA/SLS and GA/RLS, respectively (Dunn's, p0.98) and R(Linsp) (R>0.93). Moreover, Bland-Altman plots showed that the mean differences were consistently low and the intervals of agreement reasonable.Our study suggests that on-line methods are reliable for monitoring lung mechanics in spontaneous breathing patients with severe lung diseases and could help clinicians in their decision-making process

SAPHIR : a collaborative multi-scale, multi-resolution Core Model Environment for the Physiome--with a prototype core model of blood pressure regulation and fluid homeostasis

International audienceWe present the current state of the SAPHIR project, a multi-resolution core modeling environment (CME) in the spirit of the IUPS Physiome, with application to a prototype core model based on a modular implementation of the classic systems model by Guyton et al. (1972 Ann. Rev. Physiol. 34:13–44) and its extension by Ikeda et al. (1979 Annals Biomed. Engin. 7:135–166). This core model targets short- and long-term regulation of blood pressure and homeostasis of body fluids and major solutes. The aim is to provide a collaborative modeling environment enabling plug-and-play construction of integrated systems models with lumped-parameter sub-models at the organ/tissue level yet also allowing focus on cell- or molecular-level detailed models embedded in the larger core model. Thus, in silico exploration of gene-to-organ-to-organism scenarios is possible while keeping computation time manageable. The CME is built on the M2SL toolbox, a multi-scale, multi-resolution, multi-mode open source package developed in C++ by one of us (AH). Associated with the CME is an ontology-based database allowing exploration of the modules, parameter values, and equations.In parallel with the CME implementation of the core model, we also present stand-alone implementations in Berkeley Madonna (Ikeda model) and Simulink (Guyton model)