Background: Idiopathic pulmonary fibrosis (IPF) is a chronic and ultimately fatal disease characterized by a progressive decline in lung function. Fibrotic diseases, such as IPF, are characterized by uncontrolled activation of fibroblasts. Since the microenvironment is known to affect cell behavior, activated fibroblasts can in turn activate healthy neighboring cells. Thus, we investigated IPF paracrine signaling in human lung fibroblasts (HLFs) derived from patients with IPF. Methods: Primary human fibroblast cultures from IPF (IPF-HLF) and control donor (N-HLF) lung tissues were established and their supernatants were collected. These supernatants were then added to N-HLFs for further culture. Protein and RNA were extracted from IPF/ N-HLFs at baseline. Interleukin-6 (IL-6) and TGF-β-related signaling factors (e.g. STAT3, Smad3) were evaluated by western blot and qPCR. IL-6 levels were measured by ELISA. IL-6 signaling was blocked by Tocilizumab (TCZ) (10 ng/ml). Results: IPF-HLFs were found to significantly overexpress IL-6 receptor (IL-6R), suppressor of cytokine signaling 3 (SOCS3), phospho-STAT3-Y705 and phospho-Smad3 in comparison to N-HLFs (p < 0.05). In addition, they were found to proliferate faster, secrete more IL-6 and express higher levels of the soluble IL-6R. IPF-HLF increased proliferation was inhibited by TCZ. Moreover, IPF-HLF derived supernatants induced both direct and indirect STAT3 activation that resulted in Smad3 phosphorylation and elevated Gremlin levels in N-HLFs. These effects were also successfully blocked by TCZ. Conclusions: IPF-HLF paracrine signaling leads to IL-6R overexpression, which in turn, affects N-HLF survival. The IL-6/STAT3/Smad3 axis facilitates cellular responses that could potentially promote fibrotic disease. This interplay was successfully blocked by TCZ.

Progressive multifocal leukoencephalopathy (PML) is a demyelinating infection caused by the JC virus. It is an emerging disease in transplant recipients; however, it remains poorly defined. Twenty-four cases of PML reported in the literature in transplant recipients were reviewed. Of the 24 cases, nine occurred in renal, six in bone marrow, four in liver, three in heart and two in lung transplant recipients. Median time to onset was 17 months; 71% occurred within 24 months of transplantation. PML tended to occur later in the kidney recipients (P=0.04). Seventy-five percent had subacute presentation; hemiparesis (50%), apathy (46%) and confusion (38%) were the most frequently presented features. Treatment included reduction of immunosuppression and chemotherapy, mainly cidofovir. Death occurred within 2.5 months of the onset of symptoms in 17 patients (71%). PML is a unique entity that should be considered in any transplant recipient with neurological symptoms. The outcome is usually fatal, although regression has been reported.

Levels of tumor markers in pleural effusions may help to establish the diagnosis of pleural malignancy, but the precise diagnostic value of each marker remains unclear. The aim of this study was to assess the diagnostic value of five common pleural fluid tumor markers, carcinoembryonic antigen (CEA), cytokeratin fragment (CYFRA) 21-1, cancer antigen (CA) 15-3, CA 19-9, and CA 125, and to review the literature from the past 15 years. Pleural fluid samples were collected prospectively from 116 patients and assayed for CEA, CYFRA 21-1, CA 15-3, CA 19-9, and CA 125 levels. A MEDLINE search of the English-language literature from the past 15 years was also done.Effusions were classified as benign or malignant on the basis of their definitive pathologic or cytologic diagnoses. The levels of all pleural tumor markers were statistically significantly higher in the malignant group than in the benign group. The marker with the highest accuracy was CEA (85.3%); CA 15-3, CYFRA 21-1, and CA 19-9 had similar accuracies (75.2%, 72.4%, and 71.5%, respectively), and CA 125 had the lowest accuracy (40.5%). On univariate analysis, tumor-marker combinations did not result in a greater accuracy than that of CEA alone. On multivariate logistic regression, CA 15-3 and CYFRA 21-1 were significant predictors of malignancy. Among the nine reports in the literature comparing 11 different tumor markers, CEA, CA 15-3, and CYFRA 21-1 yielded the best results. We conclude that pleural fluid analysis should include CEA for the diagnosis of malignancy. CA 15-3 and CYFRA 21-1 may serve as alternative options.