{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T11:38:18Z","timestamp":1791459498709,"version":"4.3.4"},"reference-count":35,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2022,3,14]],"date-time":"2022-03-14T00:00:00Z","timestamp":1647216000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,5,26]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The ability to monitor for general drug-induced tissue injury (DITI) or systemic inflammation in any tissue using blood-based accessible biomarkers would provide a valuable tool in early exploratory animal studies to understand potential drug liabilities. Here we describe the evaluation of 4 biomarkers of tissue remodeling and inflammation (\u03b12-macroglobulin [A2M], \u03b11-acid glycoprotein [AGP], neutrophil gelatinase-associated lipocalin [NGAL], and tissue inhibitor of metalloproteinases [TIMP-1]) as well as the traditional serum parameter albumin as potential blood-based biomarkers of DITI and systemic inflammatory response (SIR). Biomarker performance was assessed in 51 short-term rat in vivo studies with various end-organ toxicities or SIR and receiver operating characteristic curves were generated to compare relative performances. All 4 biomarkers performed well in their ability to detect DITI and SIR with an area under the curve (AUC) of 0.82\u20130.78, however TIMP-1 achieved the best sensitivity (at 95% specificity) of 61%; AGP, NGAL, and A2M sensitivity was 51%\u201352%. AUC for albumin was 0.72 with sensitivity of 39%. A2M was the best performer in studies with only SIR (AUC 0.91). In the subset of studies with drug-induced vascular injury, TIMP-1 performed best with an AUC of 0.96. Poor performance of all tested biomarkers was observed in samples with CNS toxicity. In summary, TIMP-1, A2M, AGP, and NGAL demonstrated performance as sensitive accessible biomarkers of DITI and SIR, supporting their potential application as universal accessible tissue toxicity biomarkers to quickly identify dose levels associated with drug-induced injury in early exploratory rat safety and other studies.<\/jats:p>","DOI":"10.1093\/toxsci\/kfac030","type":"journal-article","created":{"date-parts":[[2022,3,10]],"date-time":"2022-03-10T20:11:11Z","timestamp":1646943071000},"page":"219-233","source":"Crossref","is-referenced-by-count":10,"title":["Universal Accessible Biomarkers of Drug-Induced Tissue Injury and Systemic Inflammation in Rat: Performance Assessment of TIMP-1, A2M, AGP, NGAL, and Albumin"],"prefix":"10.1093","volume":"187","author":[{"given":"Katerina","family":"Vlasakova","sequence":"first","affiliation":[{"name":"Merck & Co., Inc. , Nonclinical Drug Safety, West Point, Pennsylvania 19486, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Bourque","sequence":"additional","affiliation":[{"name":"Merck & Co., Inc. , Nonclinical Drug Safety, West Point, Pennsylvania 19486, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendy J","family":"Bailey","sequence":"additional","affiliation":[{"name":"Merck & Co., Inc. , Nonclinical Drug Safety, West Point, Pennsylvania 19486, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shetal","family":"Patel","sequence":"additional","affiliation":[{"name":"Merck & Co., Inc. , Nonclinical Drug Safety, West Point, Pennsylvania 19486, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth G","family":"Besteman","sequence":"additional","affiliation":[{"name":"Merck & Co., Inc. , Nonclinical Drug Safety, West Point, Pennsylvania 19486, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raymond J","family":"Gonzalez","sequence":"additional","affiliation":[{"name":"Merck & Co., Inc. , Nonclinical Drug Safety, West Point, Pennsylvania 19486, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank D","family":"Sistare","sequence":"additional","affiliation":[{"name":"Merck & Co., Inc. , Nonclinical Drug Safety, West Point, Pennsylvania 19486, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Warren E","family":"Glaab","sequence":"additional","affiliation":[{"name":"Merck & Co., Inc. , Nonclinical Drug Safety, West Point, Pennsylvania 19486, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,3,14]]},"reference":[{"key":"2022053118094969100_kfac030-B1","doi-asserted-by":"crossref","first-page":"565","DOI":"10.3109\/1354750X.2015.1123354","article-title":"The potential of lipocalin-2\/NGAL as biomarker for inflammatory and metabolic diseases","volume":"20","author":"Abella","year":"2015","journal-title":"Biomarkers"},{"key":"2022053118094969100_kfac030-B2","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1186\/s12931-016-0379-7","article-title":"Acute lung injury induced by whole gastric fluid: Hepatic acute phase response contributes to increase lung antiprotease protection","volume":"17","author":"Ayala","year":"2016","journal-title":"Respir. 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