{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T21:16:06Z","timestamp":1790457366632,"version":"4.1.0"},"reference-count":57,"publisher":"American Physiological Society","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Lung Cellular and Molecular Physiology"],"published-print":{"date-parts":[[2008,3]]},"abstract":"<jats:p>Ferritin is a protein principally known for its role in iron storage. We have previously shown that ferritin can bind high-molecular-weight kininogen (HK). Upon proteolytic cleavage by the protease kallikrein, HK releases the proinflammatory peptide bradykinin (BK) and other biologically active products, such as two-chain high-molecular-weight kininogen, HKa. At inflammatory sites, HK is oxidized, which renders it a poor substrate for kallikrein. However, oxidized HK remains a good substrate for elastase and tryptase, thereby providing an alternative cleavage mechanism for HK during inflammation. Here we report that ferritin can retard the cleavage of both native HK and oxidized HK by elastase and tryptase. Initial rates of cleavage were reduced 45\u201375% in the presence of ferritin. Ferritin is not a substrate for elastase or tryptase and does not interfere with the ability of either protease to digest a synthetic substrate, suggesting that ferritin may impede HK cleavage through direct interaction with HK. Immunoprecipitation and solid phase binding studies reveal that ferritin and HK bind directly with a K<jats:sub>d<\/jats:sub>of 134 nM. To test whether ferritin regulates HK cleavage in vivo, we used THP-1 cells, a human monocyte\/macrophage cell line that has been used to model pulmonary inflammatory cells. We observed that ferritin impedes the cleavage of HK by secretory proteases in stimulated macrophages. Furthermore, ferritin, HK, and elastase are all present in or on alveolar macrophages in a mouse model of pulmonary inflammation. Collectively, these results implicate ferritin in the modulation of HK cleavage at sites of inflammation.<\/jats:p>","DOI":"10.1152\/ajplung.00347.2007","type":"journal-article","created":{"date-parts":[[2008,1,12]],"date-time":"2008-01-12T02:18:46Z","timestamp":1200104326000},"page":"L505-L515","source":"Crossref","is-referenced-by-count":46,"title":["Cleavage of high-molecular-weight kininogen by elastase and tryptase is inhibited by ferritin"],"prefix":"10.1152","volume":"294","author":[{"given":"Lan G.","family":"Coffman","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie C.","family":"Brown","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Johnson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Narayanan","family":"Parthasarathy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"Ralph B.","family":"D'Agostino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark O.","family":"Lively","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyang","family":"Hua","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen L.","family":"Tilley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Werner","family":"Muller-Esterl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark C.","family":"Willingham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank M.","family":"Torti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzy V.","family":"Torti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"24","reference":[{"key":"R1","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2007.060831"},{"key":"R2","unstructured":"Barnes PJ.Effect of bradykinin on airway function.Agents Actions Suppl38: 432\u2013438, 1992."},{"key":"R3","unstructured":"Barnes PJ, Chung KF, Page CP.Inflammatory mediators of asthma: an update.Pharmacol Rev50: 515\u2013596, 1998."},{"key":"R4","doi-asserted-by":"crossref","unstructured":"Campbell EJ, Silverman EK, Campbell MA.Elastase and cathepsin G of human monocytes. Quantification of cellular content, release in response to stimuli, and heterogeneity in elastase-mediated proteolytic activity.J Immunol143: 2961\u20132968, 1989.","DOI":"10.4049\/jimmunol.143.9.2961"},{"key":"R5","doi-asserted-by":"publisher","DOI":"10.3181\/00379727-203-43597"},{"key":"R6","doi-asserted-by":"publisher","DOI":"10.1096\/fj.01-0201com"},{"key":"R7","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M304344200"},{"key":"R8","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm\/145.4_Pt_1.900"},{"key":"R9","doi-asserted-by":"publisher","DOI":"10.1016\/S0065-2776(08)60837-8"},{"key":"R10","unstructured":"Colman RW.Contact activation pathway: inflammatory, fibrinolytic, anticoagulation, antiadhesive, and antiangiogenic activities. In:Hemostasis and Thrombosis: Basic Principles and Clinical Practice, edited by Colman RW, Hirsh J, Marder VJ, Salzman EW. Philadelphia: Lippincott, 1998, p. 1567\u20131583."},{"key":"R11","unstructured":"Colman RW, Schmaier AH.Contact system: a vascular biology modulator with anticoagulant, profibrinolytic, antiadhesive, and proinflammatory attributes.Blood90: 3819\u20133843, 1997."},{"key":"R12","doi-asserted-by":"publisher","DOI":"10.1016\/S0895-7061(99)00073-4"},{"key":"R13","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)63358-5"},{"key":"R14","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00206.2004"},{"key":"R15","doi-asserted-by":"publisher","DOI":"10.1084\/jem.188.1.157"},{"key":"R16","doi-asserted-by":"publisher","DOI":"10.1172\/JCI114151"},{"key":"R17","doi-asserted-by":"publisher","DOI":"10.1172\/JCI112567"},{"key":"R18","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.270.33.19256"},{"key":"R19","doi-asserted-by":"publisher","DOI":"10.1046\/j.1432-1033.2001.01888.x"},{"key":"R20","doi-asserted-by":"publisher","DOI":"10.1097\/00003246-198908000-00002"},{"key":"R21","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-291X(02)00490-4"},{"key":"R22","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.1998.274.1.L26"},{"key":"R23","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/151.6.1019"},{"key":"R24","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.0000240290.70852.c0"},{"key":"R25","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.50.33224"},{"key":"R26","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2005.05.006"},{"key":"R27","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0703774104"},{"key":"R28","doi-asserted-by":"publisher","DOI":"10.1042\/bj3070341"},{"key":"R29","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M304239200"},{"key":"R30","doi-asserted-by":"crossref","unstructured":"Maier M, Spragg J, Schwartz LB.Inactivation of human high molecular weight kininogen by human mast cell tryptase.J Immunol130: 2352\u20132356, 1983.","DOI":"10.4049\/jimmunol.130.5.2352"},{"key":"R31","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-6363(00)00184-X"},{"key":"R32","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.88.11.4946"},{"key":"R33","doi-asserted-by":"crossref","unstructured":"Nieziolek M, Kot M, Pyka K, Mak P, Kozik A.Properties of chemically oxidized kininogens.Acta Biochim Pol50: 753\u2013763, 2003.","DOI":"10.18388\/abp.2003_3666"},{"key":"R34","doi-asserted-by":"publisher","DOI":"10.1042\/bj20011637"},{"key":"R35","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2004.04.020"},{"key":"R36","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1522-2683(19991201)20:18<3551::AID-ELPS3551>3.0.CO;2-2"},{"key":"R37","unstructured":"Ponka P, Beaumont C, Richardson DR.Function and regulation of transferrin and ferritin.Semin Hematol35: 35\u201354, 1998."},{"key":"R38","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-5793(00)01141-8"},{"key":"R39","doi-asserted-by":"crossref","unstructured":"Ren S, Lawson AE, Carr M, Baumgarten CM, Schwartz LB.Human tryptase fibrinogenolysis is optimal at acidic pH and generates anticoagulant fragments in the presence of the anti-tryptase monoclonal antibody B12.J Immunol159: 3540\u20133548, 1997.","DOI":"10.4049\/jimmunol.159.7.3540"},{"key":"R40","doi-asserted-by":"publisher","DOI":"10.1126\/science.910131"},{"key":"R41","doi-asserted-by":"crossref","unstructured":"Schmaier AH, Kuo A, Lundberg D, Murray S, Cines DB.The expression of high molecular weight kininogen on human umbilical vein endothelial cells.J Biol Chem263: 16327\u201316333, 1988.","DOI":"10.1016\/S0021-9258(18)37596-3"},{"key":"R42","doi-asserted-by":"crossref","unstructured":"Schwartz LB, Bradford TR, Littman BH, Wintroub BU.The fibrinogenolytic activity of purified tryptase from human lung mast cells.J Immunol135: 2762\u20132767, 1985.","DOI":"10.4049\/jimmunol.135.4.2762"},{"key":"R43","unstructured":"Sharma JN, Thani RB.Therapeutic prospects for bradykinin receptor agonists in the treatment of cardiovascular diseases.IDrugs7: 926\u2013934, 2004."},{"key":"R44","doi-asserted-by":"crossref","unstructured":"Skidgel RA, Stanisavljevic S, Erdos EG.Kinin- and angiotensin- converting enzyme (ACE) inhibitor-mediated nitric oxide production in endothelial cells.Biol Chem387: 159\u2013165, 2006.","DOI":"10.1515\/BC.2006.021"},{"key":"R45","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2143(03)00008-8"},{"key":"R46","doi-asserted-by":"publisher","DOI":"10.1016\/j.peptides.2005.03.052"},{"key":"R47","doi-asserted-by":"crossref","unstructured":"Svensjo E, Batista PR, Brodskyn CI, Silva R, Lima AP, Schmitz V, Saraiva E, Pesquero JB, Mori MA, Muller-Esterl W, Scharfstein J.Interplay between parasite cysteine proteases and the host kinin system modulates microvascular leakage and macrophage infection by promastigotes of the Leishmania donovani complex.Microbes Infect8: 206\u2013200, 2005.","DOI":"10.1016\/j.micinf.2005.06.016"},{"key":"R48","doi-asserted-by":"publisher","DOI":"10.1136\/ard.61.8.741"},{"key":"R49","doi-asserted-by":"publisher","DOI":"10.1021\/bi972119z"},{"key":"R50","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V99.10.3505"},{"key":"R51","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.22.13630"},{"key":"R52","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2003.12.008"},{"key":"R53","doi-asserted-by":"crossref","unstructured":"Vogel R, Assfalg-Machleidt I, Esterl A, Machleidt W, Muller-Esterl W.Proteinase-sensitive regions in the heavy chain of low molecular weight kininogen map to the inter-domain junctions.J Biol Chem263: 12661\u201312668, 1988.","DOI":"10.1016\/S0021-9258(18)37804-9"},{"key":"R54","doi-asserted-by":"publisher","DOI":"10.1210\/en.2004-1096"},{"key":"R55","doi-asserted-by":"publisher","DOI":"10.1016\/0006-291X(90)91466-6"},{"key":"R56","doi-asserted-by":"crossref","unstructured":"Yang C, Wang J, Krutchinsky AN, Chait BT, Morrisett JD, Smith CV.Selective oxidation in vitro by myeloperoxidase of the N-terminal amine in apolipoprotein B-100.J Lipid Res42: 1891\u20131896, 2001.","DOI":"10.1016\/S0022-2275(20)31515-7"},{"key":"R57","doi-asserted-by":"crossref","unstructured":"Yarovaya GA, Blokhina TB, Neshkova Contact system EA.New concepts on activation mechanisms and bioregulatory functions.Biochemistry67: 13\u201324, 2002.","DOI":"10.1023\/A:1013991828598"}],"container-title":["American Journal of Physiology-Lung Cellular and Molecular Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.physiology.org\/doi\/pdf\/10.1152\/ajplung.00347.2007","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,15]],"date-time":"2023-05-15T20:10:21Z","timestamp":1684181421000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.physiology.org\/doi\/10.1152\/ajplung.00347.2007"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,3]]},"references-count":57,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2008,3]]}},"alternative-id":["10.1152\/ajplung.00347.2007"],"URL":"https:\/\/doi.org\/10.1152\/ajplung.00347.2007","relation":{},"ISSN":["1040-0605","1522-1504"],"issn-type":[{"value":"1040-0605","type":"print"},{"value":"1522-1504","type":"electronic"}],"subject":[],"published":{"date-parts":[[2008,3]]}}}