Membrane-Stretch-Induced Cell Death in Deep Tissue Injury: Computer Model Studies

摘要

Deep tissue injury (DTI) is a serious pressure ulcer, involving a mass of necrotic soft tissue under bony prominences as a consequence of sustained tissue deformations. Though several processes are thought to participate in the onset and development of DTI (e.g., cellular deformation, ischemia, and ischemia-reperfusion), the specific mechanisms responsible for it are currently unknown. Recent work indicated that pathological processes at the cell level, which relate to cell deformation, are involvedin the etiology. We hypothesized that sustained tissue deformations can lead to elevated intracellular concentration of cell metabolites, e.g., calcium ion (Ca~(2+) ), due to a stretch-induced increase in the local permeability of plasma membranes. Thismay ultimately lead to cell death due to intracellular cytotoxic concentrations of metabolites. In order to investigate this hypothesis, computational models were developed, for determining compression-induced membrane stretches and trends of times for reaching intracellular cytotoxic Ca~(2+) levels due to uncontrolled Ca~(2+) influx through stretched membranes. The simulations indicated that elevated compressive cell deformations exceeding 25% induce large tensional strains (>5%, and up to 11.5%) in membranes. These are likely to increase Ca~(2+) influx from the extracellular space into the cytosol through the stretched sites. Consistent with this assumption, the Ca~(2+) transport model showed high sensitivity of times for cell death to changes in membrane resistance. These results may open a new path in pressure ulcer research, by indicating how global tissue deformations are transformed to plasma membrane deformations, which in turn, affect transport properties and eventually, cell viability.