title: Zonulin as prehaptoglobin2 regulates lung permeability and activates the complement system.
abstract: Zonulin is a protein involved in the regulation of tight junctions (TJ) in epithelial or endothelial cells. Zonulin is known to affect TJ in gut epithelial cells, but little is known about its influences in other organs. Prehaptoglobin2 has been identified as zonulin and is related to serine proteases (MASPs, C1qrs) that activate the complement system. The current study focused on the role of zonulin in development of acute lung injury (ALI) in C57BL/6 male mice following intrapulmonary deposition of IgG immune complexes. A zonulin antagonist (AT-1001) and a related peptide with permeability agonist activities (AT-1002) were employed and given intratracheally or intravenously. Also, zonulin was blocked in lung with a neutralizing antibody. In a dose-dependent manner, AT-1001 or zonulin neutralizing antibody attenuated the intensity of ALI (as quantitated by albumin leak, neutrophil accumulation, and proinflammatory cytokines). A similar pattern was found using the bacterial lipopolysaccharide model of ALI. Using confocal microscopy on sections of injured lungs, staining patterns for TJ proteins were discontinuous, reduced, and fragmented. As expected, the leak of blood products into the alveolar space confirmed the passage of 3 and 20 kDa dextran, and albumin. In contrast to AT-1001, application of the zonulin agonist AT-1002 intensified ALI. Zonulin both in vitro and in vivo induced generation of complement C3a and C5a. Collectively, these data suggest that zonulin facilitates development of ALI both by enhancing albumin leak and complement activation as well as increased buildup of neutrophils and cytokines during development of ALI.
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI, USA. drittirsch@gmail.com
authors.forename: Daniel
authors.initials: D
authors.lastname: Rittirsch
authors.forename: Michael A
authors.initials: MA
authors.lastname: Flierl
authors.forename: Brian A
authors.initials: BA
authors.lastname: Nadeau
authors.forename: Danielle E
authors.initials: DE
authors.lastname: Day
authors.forename: Markus S
authors.initials: MS
authors.lastname: Huber-Lang
authors.forename: Jamison J
authors.initials: JJ
authors.lastname: Grailer
authors.forename: Firas S
authors.initials: FS
authors.lastname: Zetoune
authors.forename: Anuska V
authors.initials: AV
authors.lastname: Andjelkovic
authors.forename: Alessio
authors.initials: A
authors.lastname: Fasano
authors.forename: Peter A
authors.initials: PA
authors.lastname: Ward
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000936:Antigen-Antibody Complex / Q000494:pharmacology; D002772:Cholera Toxin / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D003167:Complement Activation / Q000187:drug effects; D003165:Complement System Proteins / Q000819:agonists* / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects; D006242:Haptoglobins; D007074:Immunoglobulin G / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D009842:Oligopeptides / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D010539:Permeability / Q000187:drug effects; D011498:Protein Precursors / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects; D019108:Tight Junctions / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D014132:Trachea / Q000187:drug effects / Q000276:immunology / Q000473:pathology
chemical_list: D000936:Antigen-Antibody Complex; D016207:Cytokines; D006242:Haptoglobins; D007074:Immunoglobulin G; D009842:Oligopeptides; D010455:Peptides; D011498:Protein Precursors; C408043:zonulin; D003165:Complement System Proteins; D002772:Cholera Toxin; C525167:larazotide acetate
keywords: C3a; C5a; acute lung injury; inflammation; tight junctions
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