{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T16:02:23Z","timestamp":1787500943337,"version":"build-2736575974"},"reference-count":82,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,2,19]],"date-time":"2021-02-19T00:00:00Z","timestamp":1613692800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,2,19]],"date-time":"2021-02-19T00:00:00Z","timestamp":1613692800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"NIH\/NHLBI","award":["R01 HL095545"],"award-info":[{"award-number":["R01 HL095545"]}]},{"name":"NIH\/NHLBI","award":["R35 HL144481"],"award-info":[{"award-number":["R35 HL144481"]}]},{"DOI":"10.13039\/100001962","name":"Ataxia-Telangiectasia Children\u2019s Project","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100001962","id-type":"DOI","asserted-by":"crossref"}]},{"name":"NIH\/NCI","award":["T32 CA009676"],"award-info":[{"award-number":["T32 CA009676"]}]},{"name":"NIH\/NIGMS","award":["T32 GM007863"],"award-info":[{"award-number":["T32 GM007863"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Ataxia-telangiectasia (A-T) is an autosomal recessive, multisystem disorder characterized by cerebellar degeneration, cancer predisposition, and immune system defects. A major cause of mortality in A-T patients is severe pulmonary disease; however, the underlying causes of the lung complications are poorly understood, and there are currently no curative therapeutic interventions. In this study, we examined the lung phenotypes caused by ATM-deficient immune cells using a mouse model of A-T pulmonary disease. In response to acute lung injury, ATM-deficiency causes decreased survival, reduced blood oxygen saturation, elevated neutrophil recruitment, exaggerated and prolonged inflammatory responses and excessive lung injury compared to controls. We found that\n                    <jats:italic>ATM<\/jats:italic>\n                    null bone marrow adoptively transferred to WT recipients induces similar phenotypes that culminate in impaired lung function. Moreover, we demonstrated that activated ATM-deficient macrophages exhibit significantly elevated production of harmful reactive oxygen and nitrogen species and pro-inflammatory cytokines. These findings indicate that ATM-deficient immune cells play major roles in causing the lung pathologies in A-T. Based on these results, we examined the impact of inhibiting the aberrant inflammatory responses caused by ATM-deficiency with reparixin, a CXCR1\/CXCR2 chemokine receptor antagonist. We demonstrated that reparixin treatment reduces neutrophil recruitment, edema and tissue damage in\n                    <jats:italic>ATM<\/jats:italic>\n                    mutant lungs. Thus, our findings indicate that targeted inhibition of CXCR1\/CXCR2 attenuates pulmonary phenotypes caused by ATM-deficiency and suggest that this treatment approach represents a viable therapeutic strategy for A-T lung disease.\n                  <\/jats:p>","DOI":"10.1038\/s41598-021-83531-3","type":"journal-article","created":{"date-parts":[[2021,2,20]],"date-time":"2021-02-20T11:02:53Z","timestamp":1613818973000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Elevated inflammatory responses and targeted therapeutic intervention in a preclinical mouse model of ataxia-telangiectasia lung disease"],"prefix":"10.1038","volume":"11","author":[{"given":"Rudel A.","family":"Saunders","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas F.","family":"Michniacki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Courtney","family":"Hames","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hilary A.","family":"Moale","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carol","family":"Wilke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Molly E.","family":"Kuo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johnathan","family":"Nguyen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea J.","family":"Hartlerode","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bethany B.","family":"Moore","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"JoAnn M.","family":"Sekiguchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,2,19]]},"reference":[{"key":"83531_CR1","doi-asserted-by":"publisher","first-page":"1187","DOI":"10.1016\/j.dnarep.2004.04.010","volume":"3","author":"HH Chun","year":"2004","unstructured":"Chun, H. H. & Gatti, R. A. Ataxia-telangiectasia, an evolving phenotype. DNA Repair. (Amst) 3, 1187\u20131196. https:\/\/doi.org\/10.1016\/j.dnarep.2004.04.010 (2004).","journal-title":"DNA Repair. (Amst)"},{"key":"83531_CR2","first-page":"573","volume":"39","author":"M Swift","year":"1986","unstructured":"Swift, M. et al. The incidence and gene frequency of ataxia-telangiectasia in the United States. Am. J. Hum. Genet. 39, 573\u2013583 (1986).","journal-title":"Am. J. Hum. Genet."},{"key":"83531_CR3","doi-asserted-by":"publisher","first-page":"772","DOI":"10.1038\/sj.embor.7400210","volume":"5","author":"PJ McKinnon","year":"2004","unstructured":"McKinnon, P. J. ATM and ataxia telangiectasia. EMBO Rep. 5, 772\u2013776. https:\/\/doi.org\/10.1038\/sj.embor.7400210 (2004).","journal-title":"EMBO Rep."},{"key":"83531_CR4","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1385\/NMM:8:4:495","volume":"8","author":"PO Frappart","year":"2006","unstructured":"Frappart, P. O. & McKinnon, P. J. Ataxia-telangiectasia and related diseases. Neuromol. Med. 8, 495\u2013511. https:\/\/doi.org\/10.1385\/NMM:8:4:495 (2006).","journal-title":"Neuromol. Med."},{"key":"83531_CR5","doi-asserted-by":"publisher","first-page":"610","DOI":"10.1136\/adc.2006.094268","volume":"91","author":"TO Crawford","year":"2006","unstructured":"Crawford, T. O., Skolasky, R. L., Fernandez, R., Rosquist, K. J. & Lederman, H. M. Survival probability in ataxia telangiectasia. Arch. Dis. Child 91, 610\u2013611. https:\/\/doi.org\/10.1136\/adc.2006.094268 (2006).","journal-title":"Arch. Dis. Child"},{"key":"83531_CR6","doi-asserted-by":"publisher","first-page":"1021","DOI":"10.1111\/j.1651-2227.2007.00338.x","volume":"96","author":"L Bott","year":"2007","unstructured":"Bott, L. et al. Lung disease in ataxia-telangiectasia. Acta Paediatr. 96, 1021\u20131024. https:\/\/doi.org\/10.1111\/j.1651-2227.2007.00338.x (2007).","journal-title":"Acta Paediatr."},{"key":"83531_CR7","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1126\/science.1192912","volume":"330","author":"Z Guo","year":"2010","unstructured":"Guo, Z., Kozlov, S., Lavin, M. F., Person, M. D. & Paull, T. T. ATM activation by oxidative stress. Science 330, 517\u2013521. https:\/\/doi.org\/10.1126\/science.1192912 (2010).","journal-title":"Science"},{"key":"83531_CR8","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1038\/nrc1011","volume":"3","author":"Y Shiloh","year":"2003","unstructured":"Shiloh, Y. ATM and related protein kinases: Safeguarding genome integrity. Nat. Rev. Cancer 3, 155\u2013168. https:\/\/doi.org\/10.1038\/nrc1011 (2003).","journal-title":"Nat. Rev. Cancer"},{"key":"83531_CR9","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1038\/nrm3546","volume":"14","author":"Y Shiloh","year":"2013","unstructured":"Shiloh, Y. & Ziv, Y. The ATM protein kinase: regulating the cellular response to genotoxic stress, and more. Nat. Rev. Mol. Cell Biol. 14, 197\u2013210 (2013).","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"83531_CR10","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1016\/j.tibs.2011.10.002","volume":"37","author":"S Ditch","year":"2012","unstructured":"Ditch, S. & Paull, T. T. The ATM protein kinase and cellular redox signaling: Beyond the DNA damage response. Trends Biochem. Sci. 37, 15\u201322. https:\/\/doi.org\/10.1016\/j.tibs.2011.10.002 (2012).","journal-title":"Trends Biochem. Sci."},{"key":"83531_CR11","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1016\/0304-3835(90)90089-G","volume":"54","author":"M Yi","year":"1990","unstructured":"Yi, M., Rosin, M. P. & Anderson, C. K. Response of fibroblast cultures from ataxia-telangiectasia patients to oxidative stress. Cancer Lett. 54, 43\u201350 (1990).","journal-title":"Cancer Lett."},{"key":"83531_CR12","doi-asserted-by":"publisher","first-page":"9915","DOI":"10.1073\/pnas.96.17.9915","volume":"96","author":"C Barlow","year":"1999","unstructured":"Barlow, C. et al. Loss of the ataxia-telangiectasia gene product causes oxidative damage in target organs. Proc. Natl. Acad. Sci. USA 96, 9915\u20139919 (1999).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"83531_CR13","first-page":"1849","volume":"61","author":"A Kamsler","year":"2001","unstructured":"Kamsler, A. et al. Increased oxidative stress in ataxia telangiectasia evidenced by alterations in redox state of brains from Atm-deficient mice. Cancer Res. 61, 1849\u20131854 (2001).","journal-title":"Cancer Res."},{"key":"83531_CR14","doi-asserted-by":"publisher","first-page":"997","DOI":"10.1038\/nature02989","volume":"431","author":"K Ito","year":"2004","unstructured":"Ito, K. et al. Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells. Nature 431, 997\u20131002. https:\/\/doi.org\/10.1038\/nature02989 (2004).","journal-title":"Nature"},{"key":"83531_CR15","doi-asserted-by":"publisher","first-page":"1490","DOI":"10.1182\/blood-2011-08-373639","volume":"119","author":"YA Valentin-Vega","year":"2012","unstructured":"Valentin-Vega, Y. A. et al. Mitochondrial dysfunction in ataxia-telangiectasia. Blood 119, 1490\u20131500. https:\/\/doi.org\/10.1182\/blood-2011-08-373639 (2012).","journal-title":"Blood"},{"key":"83531_CR16","doi-asserted-by":"publisher","first-page":"1","DOI":"10.7554\/eLife.07270","volume":"4","author":"WT Chen","year":"2015","unstructured":"Chen, W. T. et al. ATM regulation of IL-8 links oxidative stress to cancer cell migration and invasion. Elife 4, 1. https:\/\/doi.org\/10.7554\/eLife.07270 (2015).","journal-title":"Elife"},{"key":"83531_CR17","doi-asserted-by":"publisher","first-page":"2842","DOI":"10.1182\/blood-2015-05-645424","volume":"126","author":"CJ Harbort","year":"2015","unstructured":"Harbort, C. J. et al. Neutrophil oxidative burst activates ATM to regulate cytokine production and apoptosis. Blood 126, 2842\u20132851. https:\/\/doi.org\/10.1182\/blood-2015-05-645424 (2015).","journal-title":"Blood"},{"key":"83531_CR18","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1016\/j.immuni.2016.06.018","volume":"45","author":"SF Erttmann","year":"2016","unstructured":"Erttmann, S. F. et al. Loss of the DNA damage repair kinase ATM impairs inflammasome-dependent anti-bacterial innate immunity. Immunity 45, 106\u2013118. https:\/\/doi.org\/10.1016\/j.immuni.2016.06.018 (2016).","journal-title":"Immunity"},{"key":"83531_CR19","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1002\/ppul.22817","volume":"49","author":"SA Schroeder","year":"2014","unstructured":"Schroeder, S. A. & Zielen, S. Infections of the respiratory system in patients with ataxia-telangiectasia. Pediatr. Pulmonol. 49, 389\u2013399. https:\/\/doi.org\/10.1002\/ppul.22817 (2014).","journal-title":"Pediatr. Pulmonol."},{"key":"83531_CR20","doi-asserted-by":"publisher","first-page":"682","DOI":"10.1016\/j.jpeds.2009.12.007","volume":"156","author":"SA McGrath-Morrow","year":"2010","unstructured":"McGrath-Morrow, S. A. et al. Elevated serum IL-8 levels in ataxia telangiectasia. J. Pediatr. 156, 682\u2013684. https:\/\/doi.org\/10.1016\/j.jpeds.2009.12.007 (2010).","journal-title":"J. Pediatr."},{"key":"83531_CR21","doi-asserted-by":"publisher","first-page":"256","DOI":"10.1016\/j.jpeds.2016.01.002","volume":"171","author":"SA McGrath-Morrow","year":"2016","unstructured":"McGrath-Morrow, S. A., Collaco, J. M., Detrick, B. & Lederman, H. M. Serum interleukin-6 levels and pulmonary function in ataxia-telangiectasia. J. Pediatr. 171, 256\u2013261. https:\/\/doi.org\/10.1016\/j.jpeds.2016.01.002 (2016).","journal-title":"J. Pediatr."},{"key":"83531_CR22","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1093\/bmb\/ldm012","volume":"81\u201382","author":"MF Lavin","year":"2007","unstructured":"Lavin, M. F., Gueven, N., Bottle, S. & Gatti, R. A. Current and potential therapeutic strategies for the treatment of ataxia-telangiectasia. Br. Med. Bull. 81\u201382, 129\u2013147. https:\/\/doi.org\/10.1093\/bmb\/ldm012 (2007).","journal-title":"Br. Med. Bull."},{"key":"83531_CR23","doi-asserted-by":"publisher","first-page":"11791","DOI":"10.1073\/pnas.0402090101","volume":"101","author":"R Bertini","year":"2004","unstructured":"Bertini, R. et al. Noncompetitive allosteric inhibitors of the inflammatory chemokine receptors CXCR1 and CXCR2: Prevention of reperfusion injury. Proc. Natl. Acad. Sci. USA 101, 11791\u201311796. https:\/\/doi.org\/10.1073\/pnas.0402090101 (2004).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"83531_CR24","doi-asserted-by":"publisher","first-page":"1703","DOI":"10.1172\/JCI15849","volume":"110","author":"JA Belperio","year":"2002","unstructured":"Belperio, J. A. et al. Critical role for CXCR2 and CXCR2 ligands during the pathogenesis of ventilator-induced lung injury. J. Clin. Invest. 110, 1703\u20131716. https:\/\/doi.org\/10.1172\/JCI15849 (2002).","journal-title":"J. Clin. Invest."},{"key":"83531_CR25","doi-asserted-by":"publisher","first-page":"695","DOI":"10.1172\/JCI27009","volume":"116","author":"J Reutershan","year":"2006","unstructured":"Reutershan, J. et al. Critical role of endothelial CXCR2 in LPS-induced neutrophil migration into the lung. J. Clin. Invest. 116, 695\u2013702. https:\/\/doi.org\/10.1172\/JCI27009 (2006).","journal-title":"J. Clin. Invest."},{"key":"83531_CR26","doi-asserted-by":"publisher","first-page":"686","DOI":"10.1038\/nri3739","volume":"14","author":"MJ Holtzman","year":"2014","unstructured":"Holtzman, M. J., Byers, D. E., Alexander-Brett, J. & Wang, X. The role of airway epithelial cells and innate immune cells in chronic respiratory disease. Nat. Rev. Immunol. 14, 686\u2013698. https:\/\/doi.org\/10.1038\/nri3739 (2014).","journal-title":"Nat. Rev. Immunol."},{"key":"83531_CR27","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1038\/bjp.2008.270","volume":"155","author":"A Zarbock","year":"2008","unstructured":"Zarbock, A., Allegretti, M. & Ley, K. Therapeutic inhibition of CXCR2 by Reparixin attenuates acute lung injury in mice. Br. J. Pharmacol. 155, 357\u2013364. https:\/\/doi.org\/10.1038\/bjp.2008.270 (2008).","journal-title":"Br. J. Pharmacol."},{"key":"83531_CR28","doi-asserted-by":"publisher","first-page":"e12385","DOI":"10.1111\/xen.12385","volume":"25","author":"BM French","year":"2018","unstructured":"French, B. M. et al. Interleukin-8 mediates neutrophil-endothelial interactions in pig-to-human xenogeneic models. Xenotransplantation 25, e12385. https:\/\/doi.org\/10.1111\/xen.12385 (2018).","journal-title":"Xenotransplantation"},{"key":"83531_CR29","doi-asserted-by":"publisher","first-page":"L127","DOI":"10.1152\/ajplung.00200.2017","volume":"314","author":"L Yang","year":"2018","unstructured":"Yang, L. et al. IL-8 mediates idiopathic pulmonary fibrosis mesenchymal progenitor cell fibrogenicity. Am. J. Physiol. Lung Cell Mol. Physiol. 314, L127\u2013L136. https:\/\/doi.org\/10.1152\/ajplung.00200.2017 (2018).","journal-title":"Am. J. Physiol. Lung Cell Mol. Physiol."},{"key":"83531_CR30","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1111\/cei.12488","volume":"180","author":"P Opfermann","year":"2015","unstructured":"Opfermann, P. et al. A pilot study on reparixin, a CXCR1\/2 antagonist, to assess safety and efficacy in attenuating ischaemia-reperfusion injury and inflammation after on-pump coronary artery bypass graft surgery. Clin. Exp. Immunol. 180, 131\u2013142. https:\/\/doi.org\/10.1111\/cei.12488 (2015).","journal-title":"Clin. Exp. Immunol."},{"key":"83531_CR31","doi-asserted-by":"publisher","first-page":"3647","DOI":"10.1172\/JCI63089","volume":"122","author":"A Citro","year":"2012","unstructured":"Citro, A. et al. CXCR1\/2 inhibition enhances pancreatic islet survival after transplantation. J. Clin. Invest. 122, 3647\u20133651. https:\/\/doi.org\/10.1172\/JCI63089 (2012).","journal-title":"J. Clin. Invest."},{"key":"83531_CR32","doi-asserted-by":"publisher","first-page":"5358","DOI":"10.1158\/1078-0432.CCR-16-2748","volume":"23","author":"AF Schott","year":"2017","unstructured":"Schott, A. F. et al. Phase Ib pilot study to evaluate reparixin in combination with weekly paclitaxel in patients with HER-2-negative metastatic breast cancer. Clin. Cancer Res. 23, 5358\u20135365. https:\/\/doi.org\/10.1158\/1078-0432.CCR-16-2748 (2017).","journal-title":"Clin. Cancer Res."},{"key":"83531_CR33","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1097\/MCP.0b013e328349ac2b","volume":"17","author":"MA Mouratis","year":"2011","unstructured":"Mouratis, M. A. & Aidinis, V. Modeling pulmonary fibrosis with bleomycin. Curr. Opin. Pulm. Med. 17, 355\u2013361. https:\/\/doi.org\/10.1097\/MCP.0b013e328349ac2b (2011).","journal-title":"Curr. Opin. Pulm. Med."},{"key":"83531_CR34","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1007\/978-1-4939-7113-8_2","volume":"1627","author":"T Liu","year":"2017","unstructured":"Liu, T., De Los Santos, F. G. & Phan, S. H. The bleomycin model of pulmonary fibrosis. Methods Mol. Biol. 1627, 27\u201342. https:\/\/doi.org\/10.1007\/978-1-4939-7113-8_2 (2017).","journal-title":"Methods Mol. Biol."},{"key":"83531_CR35","doi-asserted-by":"publisher","first-page":"L152","DOI":"10.1152\/ajplung.00313.2007","volume":"294","author":"BB Moore","year":"2008","unstructured":"Moore, B. B. & Hogaboam, C. M. Murine models of pulmonary fibrosis. Am. J. Physiol. Lung Cell. Mol. Physiol. 294, L152\u2013L160. https:\/\/doi.org\/10.1152\/ajplung.00313.2007 (2008).","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"83531_CR36","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1186\/s13023-016-0543-7","volume":"11","author":"C Rothblum-Oviatt","year":"2016","unstructured":"Rothblum-Oviatt, C. et al. Ataxia telangiectasia: A review. Orphanet. J. Rare Dis. 11, 159. https:\/\/doi.org\/10.1186\/s13023-016-0543-7 (2016).","journal-title":"Orphanet. J. Rare Dis."},{"key":"83531_CR37","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1093\/hmg\/8.1.69","volume":"8","author":"N Sandoval","year":"1999","unstructured":"Sandoval, N. et al. Characterization of ATM gene mutations in 66 ataxia telangiectasia families. Hum. Mol. Genet. 8, 69\u201379 (1999).","journal-title":"Hum. Mol. Genet."},{"key":"83531_CR38","doi-asserted-by":"publisher","first-page":"9302","DOI":"10.1073\/pnas.0803520105","volume":"105","author":"S Zha","year":"2008","unstructured":"Zha, S., Sekiguchi, J., Brush, J. W., Bassing, C. H. & Alt, F. W. Complementary functions of ATM and H2AX in development and suppression of genomic instability. Proc. Natl. Acad. Sci. USA 105, 9302\u20139306. https:\/\/doi.org\/10.1073\/pnas.0803520105 (2008).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"83531_CR39","doi-asserted-by":"publisher","first-page":"645","DOI":"10.1016\/j.redox.2017.11.006","volume":"14","author":"R Duecker","year":"2018","unstructured":"Duecker, R. et al. Oxidative stress-driven pulmonary inflammation and fibrosis in a mouse model of human ataxia-telangiectasia. Redox. Biol. 14, 645\u2013655. https:\/\/doi.org\/10.1016\/j.redox.2017.11.006 (2018).","journal-title":"Redox. Biol."},{"key":"83531_CR40","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1186\/1471-2466-14-93","volume":"14","author":"O Eickmeier","year":"2014","unstructured":"Eickmeier, O. et al. Altered mucosal immune response after acute lung injury in a murine model of Ataxia Telangiectasia. BMC Pulm. Med. 14, 93. https:\/\/doi.org\/10.1186\/1471-2466-14-93 (2014).","journal-title":"BMC Pulm. Med."},{"key":"83531_CR41","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1083\/jcb.201204098","volume":"198","author":"K Yamamoto","year":"2012","unstructured":"Yamamoto, K. et al. Kinase-dead ATM protein causes genomic instability and early embryonic lethality in mice. J. Cell Biol. 198, 305\u2013313. https:\/\/doi.org\/10.1083\/jcb.201204098 (2012).","journal-title":"J. Cell Biol."},{"key":"83531_CR42","doi-asserted-by":"publisher","first-page":"3336","DOI":"10.1073\/pnas.050584897","volume":"97","author":"PR Borghesani","year":"2000","unstructured":"Borghesani, P. R. et al. Abnormal development of Purkinje cells and lymphocytes in Atm mutant mice. Proc. Natl. Acad. Sci. USA 97, 3336\u20133341. https:\/\/doi.org\/10.1073\/pnas.050584897 (2000).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"83531_CR43","doi-asserted-by":"publisher","first-page":"222","DOI":"10.1038\/nature05112","volume":"443","author":"M Pellegrini","year":"2006","unstructured":"Pellegrini, M. et al. Autophosphorylation at serine 1987 is dispensable for murine Atm activation in vivo. Nature 443, 222\u2013225. https:\/\/doi.org\/10.1038\/nature05112 (2006).","journal-title":"Nature"},{"key":"83531_CR44","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1016\/S0092-8674(00)80086-0","volume":"86","author":"C Barlow","year":"1996","unstructured":"Barlow, C. et al. Atm-deficient mice: A paradigm of ataxia telangiectasia. Cell 86, 159\u2013171 (1996).","journal-title":"Cell"},{"key":"83531_CR45","doi-asserted-by":"publisher","first-page":"1713","DOI":"10.1002\/humu.23778","volume":"40","author":"A Fievet","year":"2019","unstructured":"Fievet, A. et al. Functional classification of ATM variants in ataxia-telangiectasia patients. Hum. Mutat. 40, 1713\u20131730. https:\/\/doi.org\/10.1002\/humu.23778 (2019).","journal-title":"Hum. Mutat."},{"key":"83531_CR46","doi-asserted-by":"publisher","first-page":"612","DOI":"10.1016\/j.dnarep.2013.04.014","volume":"12","author":"MF Lavin","year":"2013","unstructured":"Lavin, M. F. The appropriateness of the mouse model for ataxia-telangiectasia: Neurological defects but no neurodegeneration. DNA Repair. (Amst) 12, 612\u2013619. https:\/\/doi.org\/10.1016\/j.dnarep.2013.04.014 (2013).","journal-title":"DNA Repair. (Amst)"},{"key":"83531_CR47","doi-asserted-by":"publisher","first-page":"1928","DOI":"10.4161\/cc.10.12.16011","volume":"10","author":"EJ Gapud","year":"2011","unstructured":"Gapud, E. J. & Sleckman, B. P. Unique and redundant functions of ATM and DNA-PKcs during V(D)J recombination. Cell Cycle 10, 1928\u20131935. https:\/\/doi.org\/10.4161\/cc.10.12.16011 (2011).","journal-title":"Cell Cycle"},{"key":"83531_CR48","doi-asserted-by":"publisher","first-page":"1736","DOI":"10.1183\/09031936.96.09081736","volume":"9","author":"M Drent","year":"1996","unstructured":"Drent, M., Cobben, N. A., Henderson, R. F., Wouters, E. F. & van Dieijen-Visser, M. Usefulness of lactate dehydrogenase and its isoenzymes as indicators of lung damage or inflammation. Eur. Respir. J. 9, 1736\u20131742. https:\/\/doi.org\/10.1183\/09031936.96.09081736 (1996).","journal-title":"Eur. Respir. J."},{"key":"83531_CR49","doi-asserted-by":"publisher","first-page":"8","DOI":"10.3164\/jcbn.11-006FR","volume":"48","author":"MJ Davies","year":"2011","unstructured":"Davies, M. J. Myeloperoxidase-derived oxidation: Mechanisms of biological damage and its prevention. J. Clin. Biochem. Nutr. 48, 8\u201319. https:\/\/doi.org\/10.3164\/jcbn.11-006FR (2011).","journal-title":"J. Clin. Biochem. Nutr."},{"key":"83531_CR50","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1016\/0272-0590(85)90072-7","volume":"5","author":"HP Witschi","year":"1985","unstructured":"Witschi, H. P., Tryka, A. F. & Lindenschmidt, R. C. The many faces of an increase in lung collagen. Fund. Appl. Toxicol. 5, 240\u2013250 (1985).","journal-title":"Fund. Appl. Toxicol."},{"key":"83531_CR51","doi-asserted-by":"publisher","first-page":"L709","DOI":"10.1152\/ajplung.00341.2013","volume":"306","author":"NR Aggarwal","year":"2014","unstructured":"Aggarwal, N. R., King, L. S. & D\u2019Alessio, F. R. Diverse macrophage populations mediate acute lung inflammation and resolution. Am. J. Physiol. Lung Cell Mol. Physiol. 306, L709-725. https:\/\/doi.org\/10.1152\/ajplung.00341.2013 (2014).","journal-title":"Am. J. Physiol. Lung Cell Mol. Physiol."},{"key":"83531_CR52","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1093\/toxsci\/kfy309","volume":"168","author":"DL Laskin","year":"2019","unstructured":"Laskin, D. L., Malaviya, R. & Laskin, J. D. Role of macrophages in acute lung injury and chronic fibrosis induced by pulmonary toxicants. Toxicol. Sci. 168, 287\u2013301. https:\/\/doi.org\/10.1093\/toxsci\/kfy309 (2019).","journal-title":"Toxicol. Sci."},{"key":"83531_CR53","doi-asserted-by":"publisher","unstructured":"Jasper, A. E., McIver, W. J., Sapey, E. & Walton, G. M. Understanding the role of neutrophils in chronic inflammatory airway disease. F1000Res 8, 1. doi:https:\/\/doi.org\/10.12688\/f1000research.18411.1 (2019).","DOI":"10.12688\/f1000research.18411.1"},{"key":"83531_CR54","doi-asserted-by":"publisher","first-page":"672","DOI":"10.1002\/path.5221","volume":"247","author":"PM Potey","year":"2019","unstructured":"Potey, P. M., Rossi, A. G., Lucas, C. D. & Dorward, D. A. Neutrophils in the initiation and resolution of acute pulmonary inflammation: understanding biological function and therapeutic potential. J. Pathol. 247, 672\u2013685. https:\/\/doi.org\/10.1002\/path.5221 (2019).","journal-title":"J. Pathol."},{"key":"83531_CR55","doi-asserted-by":"publisher","first-page":"C510","DOI":"10.1152\/ajpcell.00181.2020","volume":"319","author":"JG Filep","year":"2020","unstructured":"Filep, J. G. & Ariel, A. Neutrophil heterogeneity and fate in inflamed tissues: Implications for the resolution of inflammation. Am. J. Physiol. Cell Physiol. 319, C510\u2013C532. https:\/\/doi.org\/10.1152\/ajpcell.00181.2020 (2020).","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"83531_CR56","doi-asserted-by":"publisher","first-page":"293","DOI":"10.2119\/molmed.2010.00138","volume":"17","author":"J Grommes","year":"2011","unstructured":"Grommes, J. & Soehnlein, O. Contribution of neutrophils to acute lung injury. Mol. Med. 17, 293\u2013307. https:\/\/doi.org\/10.2119\/molmed.2010.00138 (2011).","journal-title":"Mol. Med."},{"key":"83531_CR57","doi-asserted-by":"publisher","first-page":"1001","DOI":"10.1164\/rccm.201405-0992OC","volume":"191","author":"SI Rennard","year":"2015","unstructured":"Rennard, S. I. et al. CXCR2 antagonist MK-7123: A phase 2 proof-of-concept trial for chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 191, 1001\u20131011. https:\/\/doi.org\/10.1164\/rccm.201405-0992OC (2015).","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"83531_CR58","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1183\/13993003.01020-2018","volume":"52","author":"AL Lazaar","year":"2018","unstructured":"Lazaar, A. L. et al. Effect of the CXCR2 antagonist danirixin on symptoms and health status in COPD. Eur. Respir. J. 52, 1. https:\/\/doi.org\/10.1183\/13993003.01020-2018 (2018).","journal-title":"Eur. Respir. J."},{"key":"83531_CR59","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1016\/j.pharmthera.2008.10.005","volume":"121","author":"RW Chapman","year":"2009","unstructured":"Chapman, R. W. et al. CXCR2 antagonists for the treatment of pulmonary disease. Pharmacol. Ther. 121, 55\u201368. https:\/\/doi.org\/10.1016\/j.pharmthera.2008.10.005 (2009).","journal-title":"Pharmacol. Ther."},{"key":"83531_CR60","doi-asserted-by":"publisher","first-page":"566953","DOI":"10.3389\/fimmu.2020.566953","volume":"11","author":"MS Mattos","year":"2020","unstructured":"Mattos, M. S. et al. CXCR1 and CXCR2 inhibition by ladarixin improves neutrophil-dependent airway inflammation in mice. Front. Immunol. 11, 566953. https:\/\/doi.org\/10.3389\/fimmu.2020.566953 (2020).","journal-title":"Front. Immunol."},{"key":"83531_CR61","doi-asserted-by":"publisher","first-page":"5273201","DOI":"10.1155\/2017\/5273201","volume":"2017","author":"CK Mardh","year":"2017","unstructured":"Mardh, C. K. et al. Targets of neutrophil influx and weaponry: Therapeutic opportunities for chronic obstructive airway disease. J. Immunol. Res. 2017, 5273201. https:\/\/doi.org\/10.1155\/2017\/5273201 (2017).","journal-title":"J. Immunol. Res."},{"key":"83531_CR62","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/j.pupt.2015.08.002","volume":"34","author":"A Planaguma","year":"2015","unstructured":"Planaguma, A. et al. Combined anti CXC receptors 1 and 2 therapy is a promising anti-inflammatory treatment for respiratory diseases by reducing neutrophil migration and activation. Pulm. Pharmacol. Ther. 34, 37\u201345. https:\/\/doi.org\/10.1016\/j.pupt.2015.08.002 (2015).","journal-title":"Pulm. Pharmacol. Ther."},{"key":"83531_CR63","doi-asserted-by":"publisher","first-page":"779","DOI":"10.1111\/j.1476-5381.2009.00367.x","volume":"158","author":"SM Vieira","year":"2009","unstructured":"Vieira, S. M. et al. A crucial role for TNF-alpha in mediating neutrophil influx induced by endogenously generated or exogenous chemokines, KC\/CXCL1 and LIX\/CXCL5. Br. J. Pharmacol. 158, 779\u2013789. https:\/\/doi.org\/10.1111\/j.1476-5381.2009.00367.x (2009).","journal-title":"Br. J. Pharmacol."},{"key":"83531_CR64","doi-asserted-by":"publisher","first-page":"769","DOI":"10.1164\/rccm.200505-717OC","volume":"173","author":"NI Chaudhary","year":"2006","unstructured":"Chaudhary, N. I., Schnapp, A. & Park, J. E. Pharmacologic differentiation of inflammation and fibrosis in the rat bleomycin model. Am. J. Respir. Crit. Care Med. 173, 769\u2013776. https:\/\/doi.org\/10.1164\/rccm.200505-717OC (2006).","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"83531_CR65","doi-asserted-by":"publisher","first-page":"871","DOI":"10.1016\/j.cell.2010.02.029","volume":"140","author":"C Nathan","year":"2010","unstructured":"Nathan, C. & Ding, A. Nonresolving inflammation. Cell 140, 871\u2013882. https:\/\/doi.org\/10.1016\/j.cell.2010.02.029 (2010).","journal-title":"Cell"},{"key":"83531_CR66","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1007\/s00281-016-0560-6","volume":"38","author":"CT Robb","year":"2016","unstructured":"Robb, C. T., Regan, K. H., Dorward, D. A. & Rossi, A. G. Key mechanisms governing resolution of lung inflammation. Semin. Immunopathol. 38, 425\u2013448. https:\/\/doi.org\/10.1007\/s00281-016-0560-6 (2016).","journal-title":"Semin. Immunopathol."},{"key":"83531_CR67","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/S1568-7864(01)00007-6","volume":"1","author":"A Barzilai","year":"2002","unstructured":"Barzilai, A., Rotman, G. & Shiloh, Y. ATM deficiency and oxidative stress: A new dimension of defective response to DNA damage. DNA Repair. (Amst) 1, 3\u201325 (2002).","journal-title":"DNA Repair. (Amst)"},{"key":"83531_CR68","doi-asserted-by":"publisher","first-page":"1185","DOI":"10.1007\/s10875-013-9933-y","volume":"33","author":"S Montella","year":"2013","unstructured":"Montella, S. et al. Non invasive assessment of lung disease in ataxia telangiectasia by high-field magnetic resonance imaging. J. Clin. Immunol. 33, 1185\u20131191. https:\/\/doi.org\/10.1007\/s10875-013-9933-y (2013).","journal-title":"J. Clin. Immunol."},{"key":"83531_CR69","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1186\/1465-9921-7-125","volume":"7","author":"S Mukhopadhyay","year":"2006","unstructured":"Mukhopadhyay, S., Hoidal, J. R. & Mukherjee, T. K. Role of TNFalpha in pulmonary pathophysiology. Respir. Res. 7, 125. https:\/\/doi.org\/10.1186\/1465-9921-7-125 (2006).","journal-title":"Respir. Res."},{"key":"83531_CR70","doi-asserted-by":"publisher","first-page":"1363","DOI":"10.1164\/rccm.200410-1349OC","volume":"171","author":"LK Lundblad","year":"2005","unstructured":"Lundblad, L. K. et al. Tumor necrosis factor-alpha overexpression in lung disease: A single cause behind a complex phenotype. Am. J. Respir. Crit. Care Med. 171, 1363\u20131370. https:\/\/doi.org\/10.1164\/rccm.200410-1349OC (2005).","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"83531_CR71","doi-asserted-by":"publisher","first-page":"e108","DOI":"10.1371\/journal.pone.0000108","volume":"1","author":"N Oikonomou","year":"2006","unstructured":"Oikonomou, N. et al. Soluble TNF mediates the transition from pulmonary inflammation to fibrosis. PLoS ONE 1, e108. https:\/\/doi.org\/10.1371\/journal.pone.0000108 (2006).","journal-title":"PLoS ONE"},{"key":"83531_CR72","doi-asserted-by":"publisher","first-page":"3073","DOI":"10.1182\/blood-2008-03-143412","volume":"112","author":"GA Yanik","year":"2008","unstructured":"Yanik, G. A. et al. The impact of soluble tumor necrosis factor receptor etanercept on the treatment of idiopathic pneumonia syndrome after allogeneic hematopoietic stem cell transplantation. Blood 112, 3073\u20133081. https:\/\/doi.org\/10.1182\/blood-2008-03-143412 (2008).","journal-title":"Blood"},{"key":"83531_CR73","doi-asserted-by":"publisher","first-page":"40","DOI":"10.3389\/fonc.2019.00040","volume":"9","author":"PA Ruffini","year":"2019","unstructured":"Ruffini, P. A. The CXCL8-CXCR1\/2 axis as a therapeutic target in breast cancer stem-like cells. Front. Oncol. 9, 40. https:\/\/doi.org\/10.3389\/fonc.2019.00040 (2019).","journal-title":"Front. Oncol."},{"key":"83531_CR74","doi-asserted-by":"publisher","first-page":"1139","DOI":"10.1097\/TP.0b013e3181efd018","volume":"90","author":"SM Coomes","year":"2010","unstructured":"Coomes, S. M. & Moore, B. B. Pleiotropic effects of transforming growth factor-beta in hematopoietic stem-cell transplantation. Transplantation 90, 1139\u20131144. https:\/\/doi.org\/10.1097\/TP.0b013e3181efd018 (2010).","journal-title":"Transplantation"},{"key":"83531_CR75","first-page":"173","volume":"111","author":"TP Green","year":"1988","unstructured":"Green, T. P., Johnson, D. E., Marchessault, R. P. & Gatto, C. W. Transvascular flux and tissue accrual of Evans blue: Effects of endotoxin and histamine. J. Lab. Clin. Med. 111, 173\u2013183 (1988).","journal-title":"J. Lab. Clin. Med."},{"key":"83531_CR76","doi-asserted-by":"publisher","first-page":"4368","DOI":"10.4049\/jimmunol.167.8.4368","volume":"167","author":"BB Moore","year":"2001","unstructured":"Moore, B. B. et al. Protection from pulmonary fibrosis in the absence of CCR2 signaling. J. Immunol. 167, 4368\u20134377. https:\/\/doi.org\/10.4049\/jimmunol.167.8.4368 (2001).","journal-title":"J. Immunol."},{"key":"83531_CR77","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1083\/jcb.119.3.493","volume":"119","author":"Y Gavrieli","year":"1992","unstructured":"Gavrieli, Y., Sherman, Y. & Ben-Sasson, S. A. Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J. Cell Biol. 119, 493\u2013501. https:\/\/doi.org\/10.1083\/jcb.119.3.493 (1992).","journal-title":"J. Cell Biol."},{"key":"83531_CR78","doi-asserted-by":"publisher","first-page":"639","DOI":"10.3892\/ijo.1.6.639","volume":"1","author":"W Gorczyca","year":"1992","unstructured":"Gorczyca, W., Bruno, S., Darzynkiewicz, R., Gong, J. & Darzynkiewicz, Z. DNA strand breaks occurring during apoptosis: Their early insitu detection by the terminal deoxynucleotidyl transferase and nick translation assays and prevention by serine protease inhibitors. Int. J. Oncol. 1, 639\u2013648. https:\/\/doi.org\/10.3892\/ijo.1.6.639 (1992).","journal-title":"Int. J. Oncol."},{"key":"83531_CR79","doi-asserted-by":"publisher","first-page":"7076","DOI":"10.4049\/jimmunol.177.10.7076","volume":"177","author":"JJ Lazarus","year":"2006","unstructured":"Lazarus, J. J., Meadows, M. J., Lintner, R. E. & Wooten, R. M. IL-10 deficiency promotes increased Borrelia burgdorferi clearance predominantly through enhanced innate immune responses. J. Immunol. 177, 7076\u20137085. https:\/\/doi.org\/10.4049\/jimmunol.177.10.7076 (2006).","journal-title":"J. Immunol."},{"key":"83531_CR80","doi-asserted-by":"publisher","first-page":"5142","DOI":"10.1128\/IAI.67.10.5142-5150.1999","volume":"67","author":"JP Brown","year":"1999","unstructured":"Brown, J. P., Zachary, J. F., Teuscher, C., Weis, J. J. & Wooten, R. M. Dual role of interleukin-10 in murine Lyme disease: regulation of arthritis severity and host defense. Infect. Immun. 67, 5142\u20135150 (1999).","journal-title":"Infect. Immun."},{"key":"83531_CR81","doi-asserted-by":"crossref","first-page":"2407","DOI":"10.4049\/jimmunol.141.7.2407","volume":"141","author":"AH Ding","year":"1988","unstructured":"Ding, A. H., Nathan, C. F. & Stuehr, D. J. Release of reactive nitrogen intermediates and reactive oxygen intermediates from mouse peritoneal macrophages: Comparison of activating cytokines and evidence for independent production. J. Immunol. 141, 2407\u20132412 (1988).","journal-title":"J. Immunol."},{"key":"83531_CR82","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1080\/15321810500403722","volume":"27","author":"HS Choi","year":"2006","unstructured":"Choi, H. S., Kim, J. W., Cha, Y. N. & Kim, C. A quantitative nitroblue tetrazolium assay for determining intracellular superoxide anion production in phagocytic cells. J. Immunoassay. Immunochem. 27, 31\u201344. https:\/\/doi.org\/10.1080\/15321810500403722 (2006).","journal-title":"J. Immunoassay. Immunochem."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-83531-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-83531-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-83531-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,21]],"date-time":"2023-10-21T11:53:56Z","timestamp":1697889236000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-83531-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,19]]},"references-count":82,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["83531"],"URL":"https:\/\/doi.org\/10.1038\/s41598-021-83531-3","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,19]]},"assertion":[{"value":"17 July 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 February 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 February 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"4268"}}