INFLAMMATION ON AIRWAY CONSTRICTION AND ASTHMA

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The relation between airway inflammation and abnormal mechanical properties in asthmatics is poorly understood. In vivo stretching of airways can diminish the steady-state constriction response to a provocation and may be an important modulator of airway tone. Recent studies indicate that (a) with increased severity of asthma, there is a diminished capacity to dilate airways following a deep inspiration (DI); and (b) prohibiting a DI during a bronchial challenge causes healthy subjects to show asthmatic-like hyperresponsiveness. Could inflammation in asthmatics affect airway walls and parenchymal tethering to inhibit smooth muscle stretching? This question cannot be answered from isolated muscle preparations, and there is a paucity of data examining these mechanisms in situ, and with sufficient resolution to the peripheral constriction conditions. HYPOTHESIS 1: Inflammation inhibits airway smooth muscle stretching during a deep inspiration. To test this hypotheses we propose a method that can track airway resistance (Raw), an index of airway smooth muscle stretching, with high time resolution during and after a deep inspiration (DI). Degree of muscle stretch and reflex recovery of constriction will be evaluated as a function of the degree of airway inflammation (assayed independently) and the degree of constriction. Principal to understanding the asthmatic condition is to determine how airway constriction and inflammation act in concert to establish both the mean level and the heterogeneity (pattern) of peripheral constriction. We will show that particular forms of heterogeneous constriction can produce large increases in lung resistance and elastance (RL and EL) at typical breathing rates, despite relatively small increases in airway resistance, Raw. This is not intuitive, but important. Our evidence further suggests that by decoupling parenchyma from airways, airway inflammation in severe asthma predisposes the lung for this radical form of constriction. HYPOTHESIS 2: Inflammation can cause spontaneous asthmatic constriction conditions to be distinct from pharmacologically induced constriction conditions in a non-inflammatory environment. We will show that the pattern of constriction can often be inferred from the frequency dependence of RL and EL for frequencies surrounding typical breathing rates. We have developed a method to routinely acquire such data, even in flow-limited patients. We propose three studies and will perform a cellular assay for inflammation in each: Study 1 will induce asthmatic-like hyperresponsiveness in healthy subjects by prohibiting deep inspirations during a methacholine challenge and then track Raw and the constriction conditions (i.e., frequency dependence of RL and EL) during and after a DI. Study 2 will perform similar measurements on asthmatic volunteers with a wide range of pre-existing baseline inflammation. Study 3 will perform an antigen challenge on asthmatics and compare these measurements before and after a late-phase constriction in which substantial inflammation is "created". We will answer then: How does airway smooth muscle function in an asthmatic?; and Are hypotheses based on isolated muscle studies relevant to asthma? Thus, we will mold new paradigms on the causality link between inflammation and constriction.