title: Progranulin deficiency leads to severe inflammation, lung injury and cell death in a mouse model of endotoxic shock.
abstract: Progranulin (PGRN) is a crucial secreted growth factor involved in various kinds of physiologic and disease processes and often has a protective role in inflammatory diseases. This study was designed to investigate the protective effects of PGRN on endotoxic shock in a mouse model of PGRN deficiency. After lipopolysaccharide (LPS) injection to induce endotoxic shock in mice, PGRN levels were induced in wild-type (WT) mice at 6 and 24 hrs. Survival rate analysis, haematoxylin and eosin staining, immunohistochemical staining, enzyme-linked immunosorbent assay and in situ terminal deoxynucleotidyl transferase-mediated uridine triphosphate nick-end labelling assay were used to reveal the susceptibility, lung injury, inflammatory cell infiltration, production of inflammatory mediators and lung cell death in mice after LPS injection. PGRN-deficient (Grn(-/-) ) mice were highly susceptible to LPS-induced endotoxic shock, with decreased survival, severe lung injury, increased production of pro-inflammatory mediators, and inflammatory cell infiltration and apoptotic death in the lung. Additionally, recombinant PGRN (rPGRN) administration before LPS stimulation ameliorated the survival of and abnormalities in both WT and Grn(-/-) mice. Altogether, these findings indicate that PGRN may be a novel biologic agent with therapeutic potential for endotoxic shock probably by inhibiting LPS-induced systemic and local inflammation in mice for treating endotoxic shock.
authors.affiliation: Department of Hematology, Qilu Hospital, Shandong University, Jinan, Shandong, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Pathogenic Biology, Shandong University School of Medicine, Jinan, Shandong, China.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Pathology, Huai'an First People's Hospital, Huai'an, Jiangsu, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Pathogenic Biology, Shandong University School of Medicine, Jinan, Shandong, China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Mao
authors.affiliation: Department of Pathogenic Biology, Shandong University School of Medicine, Jinan, Shandong, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Feng
authors.affiliation: Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan, Shandong, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Pathogenic Biology, Shandong University School of Medicine, Jinan, Shandong, China.
authors.forename: Yizhe
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Department of Medical Microbiology, Weifang Medical University, Weifang, Shandong, China.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Pathogenic Biology, Shandong University School of Medicine, Jinan, Shandong, China.
authors.forename: Weiming
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Department of Pathogenic Biology, Shandong University School of Medicine, Jinan, Shandong, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Tang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D016207:Cytokines / Q000097:blood; D000077155:Granulins; D007249:Inflammation / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D055370:Lung Injury / Q000276:immunology / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000276:immunology; D000077153:Progranulins; D012772:Shock, Septic / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D016207:Cytokines; D000077155:Granulins; C120204:Grn protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D000077153:Progranulins
keywords: endotoxic shock; inflammation; lipopolysaccharide; progranulin