title: Src homology 2 domain-containing inositol 5-phosphatase 1 deficiency leads to a spontaneous allergic inflammation in the murine lung.
abstract: BACKGROUND
  Src homology 2 domain-containing inositol 5-phosphatase 1 (SHIP-1) controls the intracellular level of the phosphoinositide 3-kinase product phosphotidylinositol-3,4,5-trisphosphate and functions as a negative regulator of cytokine and immune receptor signaling. Emerging evidence suggests that the phosphoinositide 3-kinase pathway might be involved in allergic inflammation in the lung. However, the functional relevance of SHIP-1 in the T(H)2 activation pathway has not been established. SHIP-1(-/-) mice have spontaneous myeloproliferative inflammation in the lung, the nature of which has not been elucidated. We hypothesized that SHIP-1 plays an important role as a regulator in pulmonary allergic inflammation and in maintaining lung homeostasis.
  
  
  OBJECTIVE
  To test our hypothesis, we characterized the pulmonary phenotype of SHIP-1(-/-) mice.
  
  
  RESULTS
  Analyses of lung histopathology and bronchoalveolar lavage cellularity revealed that the majority of SHIP-1(-/-) mice had progressive and severe pulmonary inflammation of macrophages, lymphocytes, neutrophils, and eosinophils; mucous hyperplasia; airway epithelial hypertrophy; and subepithelial fibrosis. These pathologic changes were accompanied by exaggerated production of T(H)2 cytokines and chemokines, including IL-4, IL-13, eotaxin, and monocyte chemoattractant protein 1, in the lung. Furthermore, the number of mast cells significantly increased, and many of these cells were undergoing degranulation, which was correlated with increased content and spontaneous release of histamine in the lung tissue of SHIP-1(-/-) mice.
  
  
  CONCLUSIONS
  These findings provide strong evidence that mice lacking SHIP-1 have an allergic inflammation in the lung, suggesting that SHIP-1 plays an important role in regulating the T(H)2 signaling pathway and in maintaining lung homeostasis.
  
  
  CONCLUSIONS
  SHIP-1 as a regulator might be a potential therapeutic target for controlling allergic inflammation in diseases such as asthma.
authors.affiliation: Division of Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA.
authors.forename: Sun-Young
authors.initials: SY
authors.lastname: Oh
authors.forename: Tao
authors.initials: T
authors.lastname: Zheng
authors.forename: Monica L
authors.initials: ML
authors.lastname: Bailey
authors.forename: Dwayne L
authors.initials: DL
authors.lastname: Barber
authors.forename: John T
authors.initials: JT
authors.lastname: Schroeder
authors.forename: Yoon-Keun
authors.initials: YK
authors.lastname: Kim
authors.forename: Zhou
authors.initials: Z
authors.lastname: Zhu
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002688:Chitinases / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D006632:Histamine / Q000378:metabolism; D007073:Immunoglobulin E / Q000032:analysis; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism; D000072181:Inositol Polyphosphate 5-Phosphatases; D007958:Leukocyte Count; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D055271:Mucin 5AC; D009077:Mucins / Q000235:genetics; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000172:deficiency*; D012333:RNA, Messenger / Q000096:biosynthesis; D012130:Respiratory Hypersensitivity / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology; D015854:Up-Regulation
chemical_list: D016207:Cytokines; C524679:Muc5ac protein, mouse; D055271:Mucin 5AC; D009077:Mucins; D012333:RNA, Messenger; D007073:Immunoglobulin E; D006632:Histamine; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; C000606433:Inpp5d protein, mouse; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D002688:Chitinases