Roden, Anja C.

Context.— Pulmonary hypertension (PHT) is a complication of pulmonary Langerhans cell histiocytosis (PLCH); however, the pathogenesis remains largely unknown. Few studies have evaluated histopathologic changes in pulmonary arteries (PAs) of patients with PLCH; systematic quantification of arterial remodeling has yet to be undertaken. Objective.— To quantify the extent of arterial remodeling among patients with PLCH through morphometry and to correlate these results with pertinent clinical parameters. Design.— Patients with PLCH were identified from institutional files (1995–2015) along with age-, sex-, and smoking status–matched controls. Morphometric analysis of intimal and medial thickness of small to medium PAs was performed in patients with PLCH (within PLCH lesions [lesional] and away from PLCH lesions [nonlesional]) and controls. Paired measures were compared with Wilcoxon signed rank tests. Results.— Twenty-five patients with PLCH (14 men: median age, 46 years; interquartile range, 37–55 years) and 25 controls were included. The lesional arteries of patients with PLCH demonstrated thicker PA intima and media than controls (P < .001 and P < .001, respectively), as did PLCH nonlesional arteries compared to controls (P < .001 and P < .001, respectively). The PA intima and media were thicker within the PLCH lesions than nonlesional arteries (P = .02 and P = .002, respectively). Patients with PLCH-related PHT had a worse prognosis than those without PHT (P = .04; hazard ratio, 4.5 [1.1, 22.2]). Echocardiography parameters including right atrial size (P = .007), estimated right atrial pressure (P = .01), and right ventricular systolic pressure (P = .01) were inversely associated with survival. Conclusions.— Our findings suggest that factors other than direct vascular obstruction or inflammatory cell infiltration contribute, at least in part, to the vascular remodeling in PLCH.

ABSTRACT Myofibroblasts play key roles in wound healing and pathological fibrosis. Here, we used an RNAi screen to characterize myofibroblast regulatory genes, using a high-content imaging approach to quantify α-smooth muscle actin stress fibers in cultured human fibroblasts. Screen hits were validated on physiological compliance hydrogels, and selected hits tested in primary fibroblasts from patients with idiopathic pulmonary fibrosis. Our RNAi screen led to the identification of STAT3 as an essential mediator of myofibroblast activation and function. Strikingly, we found that STAT3 phosphorylation, while responsive to exogenous ligands on both soft and stiff matrices, is innately active on a stiff matrix in a ligand/receptor-independent, but ROCK- and JAK2-dependent fashion. These results demonstrate how a cytokine-inducible signal can become persistently activated by pathological matrix stiffening. Consistent with a pivotal role for this pathway in driving persistent fibrosis, a STAT3 inhibitor attenuated murine pulmonary fibrosis when administered in a therapeutic fashion after bleomycin injury. Our results identify novel genes essential for the myofibroblast phenotype, and point to STAT3 as an important target in pulmonary fibrosis and other fibrotic diseases.

Distinguishing reactive mesothelial proliferation from malignant mesothelioma (MM) can be difficult, particularly on small biopsies. In this scenario, a diagnosis of atypical mesothelial proliferation might be rendered. However, the distinction between a reactive process and MM is important for prognosis and treatment. Recently, loss of BRCA1-associated protein 1 (BAP1) expression and/or homozygous deletion of CDKN2A were identified in some MM, but not in reactive mesothelial proliferations. We studied 34 cases of atypical mesothelial proliferation from our institutional files (1993 to 2016) for BAP1 expression, deletion of CDKN2A, and clinical outcome. Fifteen of 34 patients (44%) were subsequently diagnosed with MM. BAP1 expression was lost in 6 of these 15 (40%) patients. Ten of 15 (67%) patients died of disease within a median time of 18.2 months. BAP1 expression was also lost in 1 case of probable MM. In this case atypical mesothelial proliferation was identified in the pleura during a lobectomy procedure for lung adenocarcinoma. Follow-up of 57.0 months was remarkable for visceral and parietal pleural thickening with continued unilateral effusion identified on imaging studies but no subsequent definitive diagnosis of MM. CDKN2A studies by fluorescence in situ hybridization (performed in 31 cases) found no homozygous deletion of that gene in any case. In conclusion, loss of BAP1 expression in atypical mesothelial proliferation helps to predict MM and is a useful adjunct test in these cases. Homozygous deletion of CDKN2A in mesothelial cell proliferations did not prove to be useful to predict MM in cases of atypical mesothelial proliferation.

Context.— The diagnosis and grading of acute cellular and antibody-mediated rejection (AMR) in lung allograft biopsies is important because rejection can lead to acute graft dysfunction and/or failure and may contribute to chronic graft failure. While acute cellular rejection is well defined histologically, no reproducible specific features of AMR are currently identified. Therefore, a combination of clinical features, serology, histopathology, and immunologic findings is suggested for the diagnosis of AMR. Objective.— To describe the perspective of members of the Pulmonary Pathology Society (PPS) on the workup of lung allograft transbronchial biopsy and the diagnosis of acute cellular rejection and AMR in lung transplant. Data Sources.— Reports by the International Society for Heart and Lung Transplantation (ISHLT), experience of members of PPS who routinely review lung allograft biopsies, and search of literature database (PubMed). Conclusions.— Acute cellular rejection should be assessed and graded according to the 2007 working formulation of the ISHLT. As currently no specific features are known for AMR in lung allografts, the triple test (clinical allograft dysfunction, donor-specific antibodies, pathologic findings) should be used for its diagnosis. C4d staining might be performed when morphologic, clinical, and/or serologic features suggestive of AMR are identified.

AimsThe International Collaboration on Cancer Reporting (ICCR) is a not‐for‐profit organization formed by the Royal Colleges of Pathologists of Australasia and the United Kingdom, the College of American Pathologists, the Canadian Association of Pathologists–Association Canadienne des Pathologists in association with the Canadian Partnership Against Cancer, and the European Society of Pathology. Its goal is to produce standardized, internationally agreed, evidence‐based datasets for use throughout the world.Methods and resultsThis article describes the development of a cancer dataset by the multidisciplinary ICCR expert panel for the reporting of thymic epithelial tumours. The dataset includes ‘required’ (mandatory) and ‘recommended’ (non‐mandatory) elements, which are validated by a review of current evidence and supported by explanatory text. Seven required elements and 12 recommended elements were agreed by the international dataset authoring committee to represent the essential information for the reporting of thymic epithelial tumours.ConclusionsThe use of an internationally agreed, structured pathology dataset for reporting thymic tumours provides all of the necessary information for optimal patient management, facilitates consistent and accurate data collection, and provides valuable data for research and international benchmarking. The dataset also provides a valuable resource for those countries and institutions that are not in a position to develop their own datasets.

ABSTRACT TGF‐β plays a central role in the pathogenesis of fibroproliferative disorders. Defining the exact underlying molecular basis is therefore critical for the development of viable therapeutic strategies. Here, we show that expression of the facilitative glucose transporter 1 (GLUT1) is induced by TGF‐β in fibroblast lines and primary cells and is required for the profibrotic effects of TGF‐β. In addition, enhanced GLUT1 expression is observed in fibrotic areas of lungs of both patients with idiopathic pulmonary fibrosis and mice that are subjected to a fibrosis‐inducing bleomycin treatment. By using pharmacologic and genetic approaches, we demonstrate that up‐regulation of GLUT1 occurs via the canonical Smad2/3 pathway and requires autocrine activation of the receptor tyrosine kinases, platelet‐derived and epidermal growth factor receptors. Engagement of the common downstream effector PI3K subsequently triggers activation of the MEK and mammalian target of rapamycin complex 2, which cooperate in regulating GLUT1 expression. Of note, inhibition of GLUT1 activity and/or expression is shown to impair TGFβ–driven fibrogenic processes, including cell proliferation and production of profibrotic mediators. These findings provide new perspectives on the interrelation of metabolism and profibrotic TGF‐β signaling and present opportunities for potential therapeutic intervention.—Andrianifahanana, M., Hernandez, D. M., Yin, X., Kang, J.‐H., Jung, M.‐Y., Wang, Y., Yi, E. S., Roden, A. C., Limper, A. H., Leof, E. B. Profibrotic up‐regulation of glucose transporter 1 by TGF‐β involves activation of MEK and mammalian target of rapamycin complex 2 pathways. FASEB J. 30, 3733–3744 (2016) www.fasebj.org

Previous work investigating respiratory system mechanics in mice has reported an aging-related increase in compliance and mean linear intercept ( Lm). However, these changes were assessed using only a young (2-mo-old) and old (20- and 26-mo-old) group yet were interpreted to reflect a linear evolution across the life span. Therefore, to investigate respiratory system mechanics and lung morphometry across a more complete spectrum of ages, we utilized 2 (100% survival, n = 6)-, 6 (100% survival, n = 12)-, 18 (90% survival, n = 12)-, 24 (75% survival, n = 12)-, and 30 (25% survival, n = 12)-mo-old C57BL/6 mice. We found a nonlinear aging-related decrease in respiratory system resistance and increase in dynamic compliance and hysteresis between 2- and 24-mo-old mice. However, in 30-mo-old mice, respiratory system resistance increased, and dynamic compliance and hysteresis decreased relative to 24-mo-old mice. Respiratory system impedance spectra were measured between 1–20.5 Hz at positive end-expiratory pressures (PEEP) of 1, 3, 5, and 7 cmH2O. Respiratory system resistance and reactance at each level of PEEP were increased and decreased, respectively, only in 2-mo-old animals. No differences in the respiratory system impedance spectra were observed in 6-, 18-, 24-, and 30-mo-old mice. Additionally, lungs were fixed following tracheal instillation of 4% paraformaldehyde at 25 cmH2O and processed for Lm and airway collagen deposition. There was an aging-related increase in Lm consistent with emphysematous-like changes and no evidence of increased airway collagen deposition. Accordingly, we demonstrate nonlinear aging-related changes in lung mechanics and morphometry in C57BL/6 mice.