title: Delayed resolution of lung inflammation in Il-1rn-/- mice reflects elevated IL-17A/granulocyte colony-stimulating factor expression.
abstract: IL-1 has been associated with acute lung injury (ALI) in both humans and animal models, but further investigation of the precise mechanisms involved is needed, and may identify novel therapeutic targets. To discover the IL-1 mediators essential to the initiation and resolution phases of acute lung inflammation, knockout mice (with targeted deletions for either the IL-1 receptor-1, i.e., Il-1r1(-/-), or the IL-1 receptor antagonist, i.e., Il-1rn(-/-)) were exposed to aerosolized LPS, and indices of lung and systemic inflammation were examined over the subsequent 48 hours. The resultant cell counts, histology, protein, and RNA expression of key cytokines were measured. Il-1r1(-/-) mice exhibited decreased neutrophil influx, particularly at 4 and 48 hours after exposure to LPS, as well as reduced bronchoalveolar lavage (BAL) expression of chemokines and granulocyte colony-stimulating factor (G-CSF). On the contrary, Il-1rn(-/-) mice demonstrated increased BAL neutrophil counts, increased BAL total protein, and greater evidence of histologic injury, all most notably 2 days after LPS exposure. Il-1rn(-/-) mice also exhibited higher peripheral neutrophil counts and greater numbers of granulocyte receptor-1 cells in their bone marrow, potentially reflecting their elevated plasma G-CSF concentrations. Furthermore, IL-17A expression was increased in the BAL and lungs of Il-1rn(-/-) mice after exposure to LPS, likely because of increased numbers of γδ T cells in the Il-1rn(-/-) lungs. Blockade with IL-17A monoclonal antibody before LPS exposure decreased the resultant BAL neutrophil counts and lung G-CSF expression in Il-1rn(-/-) mice, 48 hours after exposure to LPS. In conclusion, Il-1rn(-/-) mice exhibit delayed resolution in acute lung inflammation after exposure to LPS, a process that appears to be mediated via the G-CSF/IL-17A axis.
authors.affiliation: Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Pearlman School of Medicine, University of Pennsylvania, Abramson Research Building, Rm. 414E, 3615 Civic Center Blvd., Philadelphia, PA 19104, USA. kristin.hudock@uphs.upenn.edu
authors.forename: Kristin M
authors.initials: KM
authors.lastname: Hudock
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Liu
authors.forename: Junjie
authors.initials: J
authors.lastname: Mei
authors.forename: Roberta C
authors.initials: RC
authors.lastname: Marino
authors.forename: Jason E
authors.initials: JE
authors.lastname: Hale
authors.forename: Ning
authors.initials: N
authors.lastname: Dai
authors.forename: G Scott
authors.initials: GS
authors.lastname: Worthen
mesh_terms: D055371:Acute Lung Injury / Q000097:blood / Q000276:immunology / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D019743:Chemokines, CXC / Q000378:metabolism; D015870:Gene Expression; D016179:Granulocyte Colony-Stimulating Factor / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D053590:Interleukin 1 Receptor Antagonist Protein / Q000172:deficiency* / Q000235:genetics / Q000494:pharmacology; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism*; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D007958:Leukocyte Count; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D011014:Pneumonia / Q000097:blood / Q000276:immunology* / Q000378:metabolism; D053573:Receptors, Interleukin-1 Type I / Q000172:deficiency / Q000235:genetics
chemical_list: D019743:Chemokines, CXC; C098680:Il17a protein, mouse; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D020381:Interleukin-17; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D053573:Receptors, Interleukin-1 Type I; D016179:Granulocyte Colony-Stimulating Factor