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Idiopathic pulmonary fibrosis (IPF) is a progressive, often fatal, fibrosing lung disease for which treatment remains suboptimal. Fibrogenic cytokines, including transforming growth factor-β (TGF-β), are central to its pathogenesis. Protein tyrosine phosphatase-α (PTPα) has emerged as a key regulator of fibrogenic signaling in fibroblasts. We have reported that mice globally deficient in PTPα ( Ptpra -/- ) were protected from experimental pulmonary fibrosis, in part via alterations in TGF-β signaling. The goal of this study was to determine the lung cell types and mechanisms by which PTPα controls fibrogenic pathways and whether these pathways are relevant to human disease. Immunohistochemical analysis of lungs from patients with IPF revealed that PTPα was highly expressed by mesenchymal cells in fibroblastic foci and by airway and alveolar epithelial cells. To determine whether PTPα promotes profibrotic signaling pathways in lung fibroblasts and/or epithelial cells, we generated mice with conditional (floxed) Ptpra alleles ( Ptpra f/f ). These mice were crossed with Dermo1 -Cre or with Sftpc -CreER T2 mice to delete Ptpra in mesenchymal cells and alveolar type II cells, respectively. Dermo1 -Cre/ Ptpra f/f mice were protected from bleomycin-induced pulmonary fibrosis, whereas Sftpc- CreER T2 /Ptpra f/f mice developed pulmonary fibrosis equivalent to controls. Both canonical and noncanonical TGF-β signaling and downstream TGF-β-induced fibrogenic responses were attenuated in isolated Ptpra -/- compared with wild-type fibroblasts. Furthermore, TGF-β-induced tyrosine phosphorylation of TGF-β type II receptor and of PTPα were attenuated in Ptpra -/- compared with wild-type fibroblasts. The phenotype of cells genetically deficient in PTPα was recapitulated with the use of a Src inhibitor. These findings suggest that PTPα amplifies profibrotic TGF-β-dependent pathway signaling in lung fibroblasts.

Autologous C-kit + cells robustly prolong cardiac allografts. As C-kit + cells can transdifferentiate to hematopoietic cells as well as non-hematopoietic cells, we aimed to clarify the class(es) of C-kit-derived cell(s) required for cardiac allograft prolongation. Autologous C-kit + cells were administered post-cardiac transplantation and allografts were evaluated for C-kit + inoculum-derived cells. Results suggested that alloimmunity was a major signal for trafficking of C-kit-derived cells to the allograft and demonstrated that C-kit + inoculum-derived cells expressed CD11b early after transfer. Allograft survival studies with CD11b-DTR C-kit + cells demonstrated a requirement for C-kit + -derived CD11b + cells. Co-therapy studies demonstrated near complete abrogation of acute rejection with concomitant CTLA4-Ig therapy and no loss of prolongation in combination with Cyclosporine A. These results strongly implicate a C-kit-derived myeloid population as critical for allograft preservation and demonstrate the potential therapeutic application of autologous C-kit + progenitor cells as calcineurin inhibitor-sparing agents and possibly as co-therapeutics for durable graft survival., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Activity-based costing and the theory of constraints have been applied successfully in many manufacturing organizations. Recently, those concepts have been applied in service organizations. This article describes the application of activity-based costing and the theory of constraints in a managed care mental health and substance abuse organization. One of the unique aspects of this particular application was the integration of activity-based costing and the theory of constraints to guide process improvement efforts. This article describes the activity-based costing model and the application of the theory of constraint's focusing steps with an emphasis on unused capacities of activities in the organization.