title: Evidence for early fibrosis and increased airway resistance in bone marrow transplant recipient mice deficient in MMP12.
abstract: Idiopathic pneumonia syndrome (IPS) is a significant cause of morbidity and mortality post-bone marrow transplantation (BMT) in humans. In our established murine IPS model in which lethally conditioned recipients are given allogeneic bone marrow and splenocytes, recruitment of host monocytes occurs early post-BMT, followed by donor T cells concomitant with development of severe lung dysfunction. Because matrix metalloproteinase 12 (MMP12) is important for macrophage infiltration and injury in other mouse models of lung disease such as emphysema, lethally conditioned MMP12(-/-) mice were used as allogeneic recipients to determine whether MMP12 plays a similar role in potentiating lung injury in IPS. Surprisingly, MMP12(-/-) mice developed IPS and exhibited an accelerated allogeneic T cell-dependent decrease in compliance compared with wild-type (WT) recipients. MMP12(-/-), but not WT, mice also had allogeneic T cell-dependent elevated lung resistance post-BMT. Recruitment of monocytes and T cells into the lungs was not altered on day 7 post-BMT, but the lungs of MMP12(-/-) recipients had increased collagen deposition, a feature normally not seen in our IPS model. MMP12(-/-) mice had a compensatory increase in MMP2 in the lungs post-BMT, as well as increased β6-integrin compared with WT recipients, and only in the presence of allogeneic T cells. Levels of total transforming growth factor (TGF)-β1 protein in the lungs were elevated compared with WT recipients, consistent with the profibrotic function of β6-integrin as an activator of TGF-β. These data indicate that host-derived MMP12 may be important in limiting development of IPS by allowing proper remodeling of extracellular matrix and effective repair of BMT-related injury.
authors.affiliation: Department of Pediatrics, Heme/Onc/BMT Division, University of Minnesota Cancer Center, USA.
authors.forename: Kristen A
authors.initials: KA
authors.lastname: England
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Price
authors.forename: Kevin V
authors.initials: KV
authors.lastname: Tram
authors.forename: Steven D
authors.initials: SD
authors.lastname: Shapiro
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.forename: Angela
authors.initials: A
authors.lastname: Panoskaltsis-Mortari
mesh_terms: D056151:Airway Remodeling; D000403:Airway Resistance; D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects*; D003094:Collagen / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005355:Fibrosis / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D039641:Integrin beta Chains / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D053508:Matrix Metalloproteinase 12 / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D012129:Respiratory Function Tests; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D014184:Transplantation, Homologous; D015854:Up-Regulation; D014916:Whole-Body Irradiation
chemical_list: D039641:Integrin beta Chains; D016212:Transforming Growth Factor beta; C072170:integrin beta6; D003094:Collagen; D053508:Matrix Metalloproteinase 12