Deep Tissue Injury in Development of Pressure Ulcers: A Decrease of Inflammasome Activation and Changes in Human Skin Morphology in Response to Aging and Mechanical Load

Abstract

Molecular mechanisms leading to pressure ulcer development are scarce in spite of high mortality of patients. Development of pressure ulcers that is initially observed as deep tissue injury is multifactorial. We postulate that biomechanical forces and inflammasome activation, together with ischemia and aging, may play a role in pressure ulcer development. To test this we used a newly-developed bio-mechanical model in which ischemic young and aged human skin was subjected to a constant physiological compressive stress (load) of 300 kPa (determined by pressure plate analyses of a person in a reclining position) for 0.5–4 hours. Collagen orientation was assessed using polarized light, whereas inflammasome proteins were quantified by immunoblotting. Loaded skin showed marked changes in morphology and NLRP3 inflammasome protein expression. Sub-epidermal separations and altered orientation of collagen fibers were observed in aged skin at earlier time points. Aged skin showed significant decreases in the levels of NLRP3 inflammasome proteins. Loading did not alter NLRP3 inflammasome proteins expression in aged skin, whereas it significantly increased their levels in young skin. We conclude that aging contributes to rapid morphological changes and decrease in inflammasome proteins in response to tissue damage, suggesting that a decline in the innate inflammatory response in elderly skin could contribute to pressure ulcer pathogenesis. Observed morphological changes suggest that tissue damage upon loading may not be entirely preventable. Furthermore, newly developed model described here may be very useful in understanding the mechanisms of deep tissue injury that may lead towards development of pressure ulcers.

Using ultrasound elastography to monitor human soft tissue behaviour during prolonged loading: A clinical explorative study

“…Moreover, we observed loading dependent changes in skin stiffness (superficial ROIs). Continuous mechanical deformation of the skin leads to a variety of morphological and functional changes like altered orientation of collagen fibres [31], reduction of blood flow [32,33], and increase of skin temperature [19,26]. Empirical evidence suggests that increasing skin temperature is associated with increasing skin stiffness under loading [34].…”

Wound repair and regeneration: Mechanisms, signaling, and translation

“…IL-1β and TNFα are increased in chronic wounds, and this increase has been shown to lead to elevated metalloproteinases that excessively degrade the local ECM and thus impair cell migration (30). Recent studies have implicated the inflammasome, a multiprotein complex of the innate immune system responsible for activation and release of IL-1β from several skin cell types, in the development of chronic wounds (31, 32). In addition, continued presence of a high bacterial load in wounds results in a sustained influx of pro-inflammatory cells and increased inflammation also leading to delayed healing (Fig.…”

Pathogenesis of wound healing disorders in the elderly

“…The subsequent induction of metalloproteinases attenuates cell migration [ 25,26 ] . The infl ammasome -a protein complex located in the cytosol that activates proinfl ammatory protease enzymes and IL-1 β in human epidermal cells [ 27 ] -also plays a crucial role in wound physiology; its response to tissue damage deteriorates with age [ 28 ] . Remarkably, vascular endothelial growth factor receptor (VEGFR) type 1 signaling protects from disturbed wound healing in diabetes by inhibiting the production of IL-1 β by recruited macrophages, and regulating the equilibrium between different macrophage phenotypes [ 29 ] .…”