Role of airway recruitment and derecruitment in lung injury

Abstract

The mechanical forces generated during the ventilation of patients with acute lung injury causes significant lung damage and inflammation. Low-volume ventilation protocols are commonly used to prevent stretch-related injury that occurs at high lung volumes. However, the cyclic closure and reopening of pulmonary airways at low lung volumes, i.e., derecruitment and recruitment, also causes significant lung damage and inflammation. In this review, we provide an overview of how biomedical engineering techniques are being used to elucidate the complex physiological and biomechanical mechanisms responsible for cellular injury during recruitment/derecruitment. We focus on the development of multiscale, multiphysics computational models of cell deformation and injury during airway reopening. These models, and the corresponding in vitro experiments, have been used to both elucidate the basic mechanisms responsible for recruitment/derecruitment injury and to develop alternative therapies that make the epithelium more resistant to injury. For example, models and experiments indicate that fluidization of the cytoskeleton is cytoprotective and that changes in cytoskeletal structure and cell mechanics can be used to mitigate the mechanotransduction of oscillatory pressure into inflammatory signaling. The continued application of biomedical engineering techniques to the problem of recruitment/derecruitment injury may therefore lead to novel and more effective therapies.

FIGURE 1

Schematic diagram of recruitment dynamics and air-liquid motion in pulmonary airways (A) and alveoli (B); in both cases, the movement of air-liquid interfaces results in the application of complex hydrodynamic forces on the epithelial cells lining airway/alveolar walls.

FIGURE 2

(A) Effect of oscillatory pressure on NF-κB activation at different frequencies and pressure magnitudes, where * indicates statistically significant differences with unloaded controls (p < 0.01) and ^ indicates statistically significant differences (p < 0.05) between the ±12 cmH2O and ±10 or ±14 cm H2O pressure levels; (B) influence of intracellular (BAPTA-AM) and extracellular (EGTA) calcium chealators on pressure induced NF-κB activation, where * indicates statistically significant differences with unloaded controls (p < 0.01) and ^ represents statistically signifi-cant differences with activation in the no treatment group (p < 0.01); all data are mean ±95% confidence interval (reproduced from Huang et al.,Cell Mol Bioeng, 2010, Springer, used with persmission).

FIGURE 3

(A) Confocal microscopy of confluent (top) and subconfluent cells (bottom) alveolar epithelial cells; (B) 3D reconstruction of a representative cell [red circle in (A)] using cross-sectional boundary curves that define the cell's apical surface; (C) surface map of cell height in the monolayer; (D) finite element models showing solutions for effective strain in the membrane given equivalent loading conditions; results indicate that subconfluent cells developed higher strains than confluent cells (reproduced from Dailey et al.,J Appl Physiol, 2009, Am Physiol Soc, used with permission).

FIGURE 4

(A) Transient dynamic pressures applied to the epithelium during microbubble flows as a function of dimensionless velocity (Ca); (B) effective membrane strains in a representative cells at locations 1, 2, and 3 during transient microbubble flows; correlation of normalized membrane strain with the applied pressure gradient in cells models with a Maxwell (C) and power law (D) material model; only the power law models capture the strong correlation observed experimentally (reproduced from Dailey et al.,Biomech Mechanobiol Bioeng, 2010, Springer, used with persmission).

FIGURE 5

(A) Effect of Jasplakinolide and Latrunculin treatment on amount of cell necrosis in adhered cells following one or five reopening events; data are means ±SE, and * represents statistically significant differences compared with no treatment (p < 0.05); (B) optical tweezer measurements of the shear modulus as a function of oscillation frequency under no treatment, Jasplakinolide, and Latrunculin treatment; data indicates that Latrunculin cells are softer and more fluidlike (reproduced from Yalcin et al.,Am J Physiol Lung Cell Mol Physiol, 2009. Am Physiol Soc, used with permission).

FIGURE 6

(A) Effect of static pressure and cytoskeletal agents on NF-κB activation; (B) effect of cytoskeletal agents on NF-κB activation at an oscillation frequency of 0.18 Hz; all data are mean ±95% confidence interval and represent fold change in activation with respect to unloaded controls in each treatment group; * indicates statistically significant differences with unloaded controls (p < 0.05) ^ represents statistically significant differences with activation in the no treatment group (p < 0.05) (reproduced from Huang et al.,Cell Mol Bioeng, 2010, Springer, used with persmission).