Mechanical forces induce an asthma gene signature in healthy airway epithelial cells

Bronchospasm compresses the bronchial epithelium, and this compressive stress has been implicated in asthma pathogenesis. However, the molecular mechanisms by which this compressive stress alters pathways relevant to disease are not well understood. Using air-liquid interface cultures of primary human bronchial epithelial cells derived from non-asthmatic donors and asthmatic donors, we applied a compressive stress and then used a network approach to map resulting changes in the molecular interactome. In cells from non-asthmatic donors, compression by itself was sufficient to induce inflammatory, late repair, and fibrotic pathways. Remarkably, this molecular profile of non-asthmatic cells after compression recapitulated the profile of asthmatic cells before compression. Together, these results show that even in the absence of any inflammatory stimulus, mechanical compression alone is sufficient to induce an asthma-like molecular signature

Contribution of quasi-static tissue hysteresis to the dynamic alveolar pressure-volume loop

We obtained dynamic and flow-interrupted (quasi-static) pressure-volume loops from the lungs of anesthetized paralyzed open-chest mongrel dogs by measuring tracheal flow and pressure and alveolar pressure (PA) in three different regions using alveolar capsules. We used continuous tidal ventilation to obtain dynamic PA-volume loops and used the single-breath-interrupter technique to construct quasi-static pressure-volume loops for the same tidal volume (VT). We used three different VT's (15 and 20 ml/kg and inspiratory capacity) under control conditions and a VT of 15 ml/kg after methacholine-induced bronchoconstriction. We found that quasi-static hysteresis was negligible under control conditions for VT of 15 and 20 ml/kg. Quasi-static hysteresis became more important (36 +/- 11% of the corresponding dynamic PA-volume loop) during inspiratory capacity ventilation and after induced bronchoconstriction (27 +/- 12% of the corresponding dynamic PA-volume loop). We conclude that during tidal breathing near functional residual capacity "true" static hysteresis is negligible and that purely viscoelastic processes can explain lung mechanical behavior. For higher volume ventilation and after methacholine-induced constriction, quasi-static hysteresis accounted for a more important portion of dynamic tissue hysteresis. This suggests either that a more complex model, e.g., one including plastic processes, should be invoked or that the lung exhibits longer viscoelastic time constants as peak distending stresses become greater

Interpretation of interrupter resistance after histamine-induced constriction in the dog

The interrupter method for measuring respiratory system resistance involves interrupting flow at the airway opening and measuring the resultant changes in pressure. We have recently shown (J. Appl. Physiol. 65: 408-414, 1988) that in open-chest mongrel dogs, under control conditions, the initial rapid pressure change (ΔPinit) reflects conducting airway resistance and the subsequent gradual pressure change (ΔPdif) reflects stress recovery of the tissues. We questioned whether the same interpretation would apply after induced constriction. Accordingly, we performed interruption experiments on anesthetized, paralyzed, tracheostomized, open-chest mongrel dogs during passive expiration, measuring pressure at the trachea and in three different alveolar regions with alveolar capsules. We recorded measurements before and after the administration of increasing concentrations of histamine aerosol (0.1-30.0 mg/ml). We found a significant increase in the heterogeneity of alveolar pressures during the relaxed expiration with increasing concentrations of histamine. Despite the introduction of significant mechanical heterogeneities, ΔPinit still reflected the pressure drop as the result of the resistance of the conducting airways. ΔPdif, however, reflected a combination of the stress recovery of the tissues and pendelluft

Lung tissue resistance during contractile stimulation : structural damping decomposition

Research in the mechanics of soft tissue, and lung tissue in particular, has emphasized that dissipative processes depend predominantly on the viscous stress. A corollary is that dissipative losses may be expressed as a tissue viscous resistance, (Rti). An alternative approach is offered by the structural damping hypothesis, which holds that dissipative processes within soft tissue depend directly more on the elastic stress than on the viscous stress. This implies that dissipative and elastic processes within lung tissues are coupled at a fundamental level. We induced alterations of Rti by exposing canines to aerosols of the constrictors prostaglandin F2 alpha, histamine, and methacholine and by changing volume history. Using the structural damping paradigm, we could separate those alterations in Rti into the product of two distinct contributions: change in the coefficient of coupling of dissipation to elastance (eta) and change in the elastance itself (Edyn). Response of Edyn accounted for most of the response of resistance associated with contractile stimulation; it accounted for almost all the response associated with differences in volume history. The eta changed appreciably with constriction but accounted for little of the response of Rti with volume history. According to the structural damping hypothesis, induced changes in eta with constriction must reflect changes in the kinetics of the stress-bearing process, i.e., differences in cross-bridge kinetics within the target contractile cell and/or differences in the influence of the target cell on other stress-bearing systems. We conclude that, regardless of underlying processes, the structural damping analysis demonstrates a fundamental phenomenological simplification: when Edyn responds, Rti is obligated to respond to a similar degree