Mast cells(MCs)play an important role in the immune system.Through connective tissues,mechanical stimuli activate intracellular calcium signaling pathways,induce a variety of mediators including leukotriene C4(LTC4)release,and affect MCs’microenvironment.This paper focuses on MCs’intracellular calcium dynamics and LTC4 release responding to mechanical stimuli,explores signaling pathways in MCs and the effect of interstitial fluid flow on the transport of biological messengers and feedback in the MCs network.We use a mathematical model to show that(i)mechanical stimuli including shear stress induced by interstitial fluid flow can activate mechano-sensitive(MS)ion channels on MCs’membrane and allow Ca^(2+)entry,which increases intracellular Ca^(2+)concentration and leads to LTC4 release;(ii)LTC4 in the extracellular space(ECS)acts on surface cysteinyl leukotriene receptors(LTC4R)on adjacent cells,leading to Ca^(2+)influx through Ca^(2+)release-activated Ca^(2+)(CRAC)channels.An elevated intracellular Ca^(2+)concentration further stimulates LTC4 release and creates a positive feedback in the MCs network.The findings of this study may facilitate our understanding of the mechanotransduction process in MCs induced by mechanical stimuli,contribute to understanding of interstitial flow-related mechanobiology in MCs network,and provide a methodology for quantitatively analyzing physical treatment methods including acupuncture and massage in traditional Chinese medicine(TCM).
In micropipette aspiration experiment,increasing mechanical stress applied to cell membrane induced degranulation of mast cell as well as a current that could be inhibited by an inhibitor, which is specific for the transient receptor potential vanilloid(TRPVs) channels. To determine the sensitivity of TRPVs to membrane strain and tension, and to gain new insights into the activation mechanism of TRPVs, finite element models of mast cell and molecular dynamic simulations of human aquaporin-1are presented. During the finite element simulations, the cell membrane sustained to micropipette aspiration was simulated, and the strain distribution along membrane thickness direction was obtained. Besides, combining the finite element models of osteoblast aspirated into micropipette and other compared models, we examined the relationship between cell mechanical attributes and mechanical stimulations and presented a new perspective to determine the cell equivalent elastic modulus. Considering the indetermination of TRPV crystal structure, human aquaporin-1, one kind of the channel membrane proteins,substituting for TRPV, has been studied with molecular dynamic(MD) simulations, under different external lateral tensions which have been obtained in mast cell finite element simulations, to investigate the mechanical stimulation effects on the membrane channels. The simulations show that human aquaporin-1 undergoes significant conformational change and expands in accordance with lateral tension, which not only confirms the tendency of the previous electrophysiological experiments but also leads us to a better understanding of TRPVs. The multi-scale study combining finite element simulation and MD simulation is a significant breakthrough in the field of mechanical mechanism in cell system.
Mast cells(MCs) play an important role in the immune system. It is known that mechanical stimuli can induce intracellular Ca2+signal and release a variety of mediators, including leukotriene C4(LTC4), leading to other cellular and physiological changes. In this paper, we present a mathematical model to explore signalling pathways in MCs, by including cellular mechanisms for intracellular Ca2t increase and LTC4release in response to mechanical stimuli, thapsigargin(TG, SERCA pump inhibitor), and LTC4 stimuli. We show that(i) mechanical stimuli activate mechano-sensitive ion channels and induce inward ion fluxes and Ca2?entry which increases intracellular Ca2+concentration and releases LTC4;(ii) TG inhibits SERCA pumps, empties the internal Ca2+ stores,which activates Ca2+release-activated Ca2+channels and results in sustained intracellular Ca2+increase; and(iii)LTC4activates receptors on MCs surface and increases intracellular Ca2+concentration. Our results are consistent with experimental observations, and furthermore, they also reveal that mechanical stimuli can increase intracellular Ca2+even when LTC4release is blocked, which suggests a feed forward loop involved in LTC4production. This study may facilitate our understanding of the mechanotransduction process in MCs and provide a useful modeling tool for quantitatively analyzing immune mechanisms involving MCs.
In this paper,we present the analytic solutions of several continuum porous media models that describe the interstitial fluid flow in the interosseous membrane.We first compare the results of the Brinkman,Stokes and Darcy systems in describing the isotropic interstitial fluid flows.Our calculations show that the Stokes equations can well approximate the Brinkman equations when the Darcy number Da 0.2,while the Darcy model is an appropriate approximation to the Brinkman model in the interosseous membrane when4Da2 10.Yet,in most cases,the anisotropy dominates the interstitial fluid.Therefore,we build an anisotropic Darcy model and show that an isotropic model can be used as a suitable approximation when the ratio between the transverse and longitudinal permeabilities is no larger than 20.Lastly,we take the blood flow in capillaries into consideration as well and introduce the coupled Stokes-Darcy system to describe the cases comprising both the capillary and the interstitial domain.Our results reveal that the profile of the interface exchange flow is not exactly in the linear form as was widely adopted in the numerical simulation,instead,the flux near the artery and the vein is more significant,which in turn results in the increase of the maximum horizontal velocity in the interstitial space while the outflow rate remains the same.
OBJECTIVE: Based on comparison between fundamental theories of Traditional Chinese Medicine (TCM) and Western Medicine (WM) and modern scientific research on meridians, we find that "Qi" in TCM is closely related to tissue fluid. In this study, the essence of Qi is explored in the view of circulation of blood and interstitial fluid. METHODS: Because the concept of Qi is complicated, Qi deficiency syndrome (QDS) is chosen to probe the relationship between of Qi deficiency and Qi-blood circulation (QBC). We analyze Qi-blood theory in terms of WM, set up a hemodynamic model to describe QBC, and review clinical research on QDS in the view of blood-interstitial fluid circulation. RESULTS: QDS is caused by imbalances of substance exchanges between blood and interstitial fluid, leading to an increase in the interstitial liquid volume or a decrease in nutrients and retention ofmetabolic wastes in interstitial fluid. CONCLUSION: This study describes the essence of Qi, providing support for further research on theories of Qiand Qi-blood circulation inTCM.
