Abstract
The reasons for poor healing of pressure injuries are poorly understood. Vascular ulcers are worsened by extracellular release of hemoglobin, so we examined the impact of myoglobin (Mb) iron in murine muscle pressure injuries (mPI). Tests used Mb-knockout or treatment with deferoxamine iron chelator (DFO).
Unlike acute injuries (from cardiotoxin), mPI regenerated poorly with a lack of viable immune cells, failure of phagocytosis, and abnormal deposition of iron. However, Mb-knockout or DFO-treated mPI displayed a reversal of the pathology: decreased tissue death, decreased iron deposition, decrease in markers of oxidative damage, and higher numbers of intact immune cells. Subsequently, DFO treatment improved myofiber regeneration and morphology.
We conclude that myoglobin iron contributes to tissue death in mPI. Remarkably, a large fraction of muscle death in untreated mPI occurred later than, and was preventable by, DFO treatment, even though treatment started 12 hours after pressure was removed. This demonstrates an opportunity for post-pressure prevention to salvage tissue viability.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
↵* Prof. Tucker-Kellogg, 8 College Road, Singapore 169857. +65 8123 3490. Lisa.Tucker-kellogg{at}duke-nus.edu.sg
The authors have declared that no conflict of interest exists.
The method of quantifying fluorescence intensity was replaced, causing changes in plots 2G, 2M, 3F, 4E, 4J, 4Q, 5F, 6E, 6J, 6N, 7K, 7N and the methods text. All conclusions are unchanged except for a lack of statistical significance in 2M. Text in the section 'Effects of iron chelation therapy on immune...' includes new results from immuno-fluorescence staining of MerTK, associated with macrophage survival and phagocytic function, and Suppl. Fig 10 shows the staining results. Figs 1E and 2L show different representatives from the cohorts, and all images of all samples have been provided. All primary datafiles for each of the 106 frames in the main figures have been uploaded to a public repository, specified in the Supplemental Text. Figs 5-8 now show a dotted line for the baseline control (uninjured control for Figs 5-7, and cardiotoxin control for Fig 8), and therefore the statistical test was changed. Text in 'Statistical analyses' clarifies which cohorts used which statistical tests. All conclusions are unchanged. Fig 5 has duplicates removed. Figs 6 A-J now show a greater number of Day 3 mice while Day 7 mice have been removed. Text in 'Magnet-induced pressure injury causes delayed healing and ...' clarifies multiple cohorts and hypotheses. The list of co-authors, author affiliations, author contributions, and acknowledgements have changed. The References and Supplement were updated.
