{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,16]],"date-time":"2026-08-16T14:26:12Z","timestamp":1786890372018,"version":"build-2736575974"},"reference-count":19,"publisher":"SAGE Publications","issue":"8","license":[{"start":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T00:00:00Z","timestamp":1776902400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Journal of Ocular Pharmacology and Therapeutics"],"published-print":{"date-parts":[[2026,10,1]]},"abstract":"<jats:sec>\n                    <jats:title>Purpose:<\/jats:title>\n                    <jats:p>This study investigated the effects of benzalkonium chloride (BAK), a commonly used ophthalmic preservative, on corneal epithelial barrier function.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>Separate animals were assigned to the control and BAK groups. Rabbits received a topical instillation of 0.02% BAK solution every 5 min for a total of 5 doses (20 min). Corneal resistance (CR) was quantitatively measured at 30, 60, and 120 min after the final instillation using a corneal resistance device (CRD). Corneal epithelial damage was evaluated using fluorescein staining, histopathological analysis using hematoxylin and eosin (HE) staining, and immunofluorescence staining for the tight junction protein Zonula occludens-1 (ZO-1). The results were compared with those of the saline-treated control eyes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      In the BAK-treated group, CR measured using the CRD method was 82.50 \u00b1 8.92%, 74.17 \u00b1 10.19%, and 76.67 \u00b1 8.35% (\n                      <jats:italic toggle=\"yes\">n<\/jats:italic>\n                      = 6) at 30, 60, and 120 min after the final instillation, respectively. These values were significantly lower than those of the control group at the corresponding time points (100.00 \u00b1 3.34%, 99.17 \u00b1 3.96%, and 101.67 \u00b1 4.08%, respectively;\n                      <jats:italic toggle=\"yes\">n<\/jats:italic>\n                      = 6) (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      &lt; 0.0125). Fluorescein staining revealed mild superficial punctate keratopathy in most BAK-treated eyes, whereas the control eyes remained intact. HE staining revealed partial loss of superficial epithelial cells in the BAK group. Immunofluorescence analysis demonstrated that ZO-1 was continuously expressed along the corneal epithelial cell borders in control corneas, whereas ZO-1 expression was discontinuous and fragmented in corneas after BAK exposure. In addition, semiquantitative evaluation of the tissue sections indicated that BAK exposure altered ZO-1 localization.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>BAK disrupts the tight junctions of the corneal epithelium, thereby reducing barrier function. These findings emphasize the importance of evaluating preservative toxicity in ophthalmic formulations to ensure safety of the ocular surface. Although this is a pilot study, it provides important insights into the physiological mechanisms of BAK-induced corneal epithelial damage.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/10807683261441060","type":"journal-article","created":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T01:36:43Z","timestamp":1776994603000},"page":"492-497","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["Investigation of Corneal Epithelial Tight Junction Disruption and Barrier Function Impairment Induced by Benzalkonium Chloride"],"prefix":"10.1177","volume":"42","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5593-0067","authenticated-orcid":false,"given":"Masamichi","family":"Fukuda","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, Kanazawa Medical University, Ishikawa, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Sasaki","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Kanazawa Medical University, Ishikawa, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Kiyoi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Kanazawa Medical University, Ishikawa, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hidetoshi","family":"Ishida","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Kanazawa Medical University, Ishikawa, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makoto","family":"Sasaki","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Kanazawa Medical University, Ishikawa, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eri","family":"Kubo","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Kanazawa Medical University, Ishikawa, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takayoshi","family":"Masuoka","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Kanazawa Medical University, Ishikawa, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Sasaki","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Kanazawa Medical University, Ishikawa, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,4,23]]},"reference":[{"issue":"6","key":"e_1_3_7_2_1","first-page":"549","article-title":"Studies of antibacterial activity of benzalkonium chloride as preservative for ophthalmic solutions","volume":"29","author":"Saji M","year":"2003","unstructured":"1.Saji M, , Tanaka Y, , Suzuki K, et al. Studies of antibacterial activity of benzalkonium chloride as preservative for ophthalmic solutions. Jpn J Pharm Health Care Sci 2003;29(6):549\u2013556.","journal-title":"Jpn J Pharm Health Care Sci"},{"issue":"5","key":"e_1_3_7_3_1","first-page":"314","article-title":"Effects of benzalkonium chloride on growth and survival of Chang conjunctival cells","volume":"213","author":"De Saint Jean M","year":"1999","unstructured":"2.De Saint Jean M, , Baudouin C, , Labb\u00e9 A. Effects of benzalkonium chloride on growth and survival of Chang conjunctival cells. Ophthalmologica 1999;213(5):314\u2013318.","journal-title":"Ophthalmologica"},{"issue":"3","key":"e_1_3_7_4_1","first-page":"1","article-title":"Ocular surface inflammatory disorders and topical preservatives: Impact of benzalkonium chloride","volume":"218","author":"Baudouin C","year":"2004","unstructured":"3.Baudouin C, , Messmer EM, , Aragona P. Ocular surface inflammatory disorders and topical preservatives: Impact of benzalkonium chloride. Ophthalmologica 2004;218(3):1\u201310.","journal-title":"Ophthalmologica"},{"key":"e_1_3_7_5_1","doi-asserted-by":"publisher","DOI":"10.1089\/jop.2008.0140"},{"issue":"2","key":"e_1_3_7_6_1","first-page":"e55716","article-title":"Corneal alterations induced by topical application of benzalkonium chloride in rabbit","volume":"8","author":"Chen W","year":"2013","unstructured":"5.Chen W, , Li Z, , Hu J, et al. Corneal alterations induced by topical application of benzalkonium chloride in rabbit. PLoS One 2013;8(2):e55716.","journal-title":"PLoS One"},{"key":"e_1_3_7_7_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a002584"},{"issue":"21","key":"e_1_3_7_8_1","first-page":"363","article-title":"Tight junctions\/adherens junctions: Basic structure and function","volume":"120","author":"Niessen CM","year":"2007","unstructured":"7.Niessen CM. Tight junctions\/adherens junctions: Basic structure and function. J Cell Sci 2007;120(21):363\u2013368.","journal-title":"J Cell Sci"},{"issue":"4","key":"e_1_3_7_9_1","first-page":"203","article-title":"Tight junction proteins and their roles in ocular surface epithelial barrier function","volume":"3","author":"Barar J","year":"2008","unstructured":"8.Barar J, , Mohammadi G, , Ghahremani MH. Tight junction proteins and their roles in ocular surface epithelial barrier function. 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