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. This could be explained by RyRs being "sensitized" to open more frequently by certain compounds. We investigate the implications of RyR sensitization on Ca(2+) dynamics in ASMC using a combination of mathematical modeling and experiments with mouse precision-cut lung slices. Caffeine is used to increase the sensitivity of RyRs to cytosolic Ca(2+) concentration ([Ca(2+)]i) and sarcoplasmic reticulum Ca(2+) ([Ca(2+)]SR). In ASMCs, high caffeine concentrations (>10 mM) induce a sustained elevation of [Ca(2+)]i. Our mathematical model accounts for this by the activation of store-operated Ca(2+) entry that results from a large increase in the RyR sensitivity to [Ca(2+)]SR and the associated Ca(2+) release, which leads to a reduction of [Ca(2+)]SR. Importantly, our model also predicts that: (1) moderate RyR sensitization induces slow Ca(2+) oscillations, a result experimentally confirmed with low concentrations of caffeine; and (2) high RyR sensitization suppresses fast, agonist-induced Ca(2+) oscillations by inducing substantial store-operated Ca(2+) entry and elevated [Ca(2+)]i. These results suggest that RyR sensitization could play a role in ASMC proliferation (by inducing slow Ca(2+) oscillations) and in airway hyperresponsiveness (by inducing greater mean [Ca(2+)]i for similar levels of contractile agonist).

The role of inflammation resolution speed in airway smooth muscle mass accumulation in asthma: insight from a theoretical model.

Despite a large amount of in vitro data, the dynamics of airway smooth muscle (ASM) mass increase in the airways of patients with asthma is not well understood. Here, we present a novel mathematical model that describes qualitatively the growth dynamics of ASM cells over short and long terms in the normal and inflammatory environments typically observed in asthma. The degree of ASM accumulation can be explained by an increase in the rate at which ASM cells switch between non-proliferative and proliferative states, driven by episodic inflammatory events. Our model explores the idea that remodelling due to ASM hyperplasia increases with the frequency and magnitude of these inflammatory events, relative to certain sensitivity thresholds. It highlights the importance of inflammation resolution speed by showing that when resolution is slow, even a series of small exacerbation events can result in significant remodelling, which persists after the inflammatory episodes. In addition, we demonstrate how the uncertainty in long-term outcome may be quantified and used to design an optimal low-risk individual anti-proliferative treatment strategy. The model shows that the rate of clearance of ASM proliferation and recruitment factors after an acute inflammatory event is a potentially important, and hitherto unrecognised, target for anti-remodelling therapy in asthma. It also suggests new ways of quantifying inflammation severity that could improve prediction of the extent of ASM accumulation. This ASM growth model should prove useful for designing new experiments or as a building block of more detailed multi-cellular tissue-level models.

Activation of store-operated calcium entry in airway smooth muscle cells: insight from a mathematical model.

Intracellular Ca(2+) dynamics of airway smooth muscle cells (ASMC) mediate ASMC contraction and proliferation, and thus play a key role in airway hyper-responsiveness (AHR) and remodelling in asthma. We evaluate the importance of store-operated Ca(2+) entry (SOCE) in these Ca(2+) dynamics by constructing a mathematical model of ASMC Ca(2+) signaling based on experimental data from lung slices. The model confirms that SOCE is elicited upon sufficient Ca(2+) depletion of the sarcoplasmic reticulum (SR), while receptor-operated [Ca(2+) entry (ROCE) is inhibited in such conditions. It also shows that SOCE can sustain agonist-induced Ca(2+) oscillations in the absence of other [Ca(2+) influx. SOCE up-regulation may thus contribute to AHR by increasing the Ca(2+) oscillation frequency that in turn regulates ASMC contraction. The model also provides an explanation for the failure of the SERCA pump blocker CPA to clamp the cytosolic Ca(2+) of ASMC in lung slices, by showing that CPA is unable to maintain the SR empty of Ca(2+). This prediction is confirmed by experimental data from mouse lung slices, and strongly suggests that CPA only partially inhibits SERCA in ASMC.

Spatiotemporal organization of Ca dynamics: a modeling-based approach.

Calcium is a ubiquitous second messenger that mediates vital physiological responses such as fertilization, secretion, gene expression, or apoptosis. Given this variety of processes mediated by Ca(2+), these signals are highly organized both in time and space to ensure reliability and specificity. This review deals with the spatiotemporal organization of the Ca(2+) signaling pathway in electrically nonexcitable cells in which InsP(3) receptors are by far the most important Ca(2+) channels. We focus on the aspects of this highly regulated dynamical system for which an interplay between experiments and modeling is particularly fruitful. In particular, the importance of the relative densities of the different InsP(3) receptor subtypes will be discussed on the basis of a modeling approach linking the steady-state behaviors of these channels in electrophysiological experiments with their behavior in a cellular environment. Also, the interplay between InsP(3) metabolism and Ca(2+) oscillations will be considered. Finally, we discuss the relationships between stochastic openings of the Ca(2+) releasing channels at the microscopic level and the coordinated, regular behavior observed at the whole cell level on the basis of a combined experimental and modeling approach.