Jonathan W. Bourne

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.

Fibrillar collagens are an integral structural element of tissues throughout the body and help provide tensile strength. These collagens are highly resistant to degradation other than by a small number of collagenolytic enzymes. Examples of tensile mechanical forces in vivo include expansion and contraction of blood vessels, tension on tendons and ligaments, and compression and swelling of cartilage.

Collagens strengthen tissues throughout the body and are generally resistant to degradation, except by a small number of collagenolytic enzymes. As structural proteins, collagens often experience mechanical forces in vivo including expansion and contraction of blood vessels, tension on tendons and ligaments, and compression of cartilage.

Fibrillar collagens are a group of structural proteins that self assemble into a complex ordered structure of interconnected molecules to form supramolecular fibril structures. These collagens have three subgroups based on sequence similarity, of which clade A includes the most abundant fibrillar collagens, types I, II, and III. The fibrous hierarchical structures starts with individual collagen molecules that are crosslinked by enzymes to other collagen molecules to form micro fibrils, which aggregate and link to form sub fibrils, then larger fibrils and in some tissues continuing to assemble into larger levels of fascicles and above.

Collagen degradation is a mechanism for normal musculoskeletal development and extracellular matrix (ECM) maintenance, and in response to trauma, disease and inflammation. Matrix metalloproteinases (MMP-1, 8, and 13, the collagenases) are the primary enzymes that act to degrade collagen. These MMPs gain access to the collagen triple helix by binding to the enzyme’s attachment domain along the α-chains, followed by separation (unwinding) of the α-chains to expose the 3/4–1/4 cleavage site, and then cleavage of the α-chain by the enzyme’s catalytic domain [3, 5].