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We argue here that I\u2013R injury also underpins elements of the pathology of a variety of chronic, inflammatory diseases, including rheumatoid arthritis, ME\/CFS and, our chief focus and most proximally, Long COVID. Ischaemia may be initiated via fibrin amyloid microclot blockage of capillaries, for instance as exercise is started; reperfusion is a necessary corollary when it finishes. We rehearse the mechanistic evidence for these occurrences here, in terms of their manifestation as oxidative stress, hyperinflammation, mast cell activation, the production of marker metabolites and related activities. Such microclot-based phenomena can explain both the breathlessness\/fatigue and the post-exertional malaise that may be observed in these conditions, as well as many other observables. The recognition of these processes implies, mechanistically, that therapeutic benefit is potentially to be had from antioxidants, from anti-inflammatories, from iron chelators, and via suitable, safe fibrinolytics, and\/or anti-clotting agents. We review the considerable existing evidence that is consistent with this, and with the biochemical mechanisms involved.<\/jats:p>","DOI":"10.1042\/bcj20220154","type":"journal-article","created":{"date-parts":[[2022,9,2]],"date-time":"2022-09-02T15:50:43Z","timestamp":1662133843000},"page":"1653-1708","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":72,"title":["The potential role of ischaemia\u2013reperfusion injury in chronic, relapsing diseases such as rheumatoid arthritis, Long COVID, and ME\/CFS: evidence, mechanisms, and therapeutic implications"],"prefix":"10.1042","volume":"479","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5838-7963","authenticated-orcid":false,"given":"Douglas B.","family":"Kell","sequence":"first","affiliation":[{"name":"1Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool, Liverpool L69 7ZB, U.K."},{"name":"2The Novo Nordisk Foundation Centre for Biosustainability, Technical University of Denmark, Kemitorvet 200, 2800 Kgs Lyngby, Denmark"},{"name":"3Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Stellenbosch, Private Bag X1 Matieland 7602, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9108-2384","authenticated-orcid":false,"given":"Etheresia","family":"Pretorius","sequence":"additional","affiliation":[{"name":"1Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool, Liverpool L69 7ZB, U.K."},{"name":"3Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Stellenbosch, Private Bag X1 Matieland 7602, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2022,8,31]]},"reference":[{"key":"2022101008571672500_BCJ-2022-0154CC1","doi-asserted-by":"publisher","first-page":"1650","DOI":"10.1159\/000489241","article-title":"Current mechanistic concepts in ischemia and reperfusion injury","volume":"46","year":"2018","journal-title":"Cell. 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