Transformation of primary human hepatocytes in hepatocellular carcinoma.

The present study investigated primary human hepatocyte cultures obtained from liver specimens of patients affected by cirrhosis and HCC, their proliferation and transformation. The degree of invasiveness of cells acquiring neoplastic characteristics was studied with a transwell migration assay. With the present study, we are the first to have identified and describe the existence of human hepatocytes near the cancerous lesion that can transform in HCC in vitro

Nuclear factor-kappa B- and glucocorticoid receptor alpha-mediated mechanisms in the regulation of systemic and pulmonary inflammation during sepsis and acute respiratory distress syndrome - Evidence for inflammation-induced target tissue resistance to glucocorticoids

To test the hypothesis that the interaction between nuclear factor-kappa B (NF-kappa B) and glucocorticoid receptor alpha (GR alpha) is a key pathogenetic mechanism regulating the progression of systemic and pulmonary inflammation in sepsis and acute respiratory distress syndrome (ARDS), we used an ex vivo model of systemic inflammation. Naive peripheral blood leukocytes (PBL) were exposed to longitudinal (days 1-10) plasma samples from ARDS patients divided into three groups based on physiological improvement and clinical outcome by days 7-10: improvers, nonimprovers-survivors, and nonimprovers-nonsurvivors. In a separate group of nonimprovers-survivors, we correlated the severity of lung histopathology with the intensity of NF-kappa B and GR alpha nuclear staining in immunohistochemistry analysis of lung tissue obtained by open lung biopsy. We found that exposure of naive cells to longitudinal plasma samples led to divergent directions in NF-kappa B and GR alpha activation that reflected the severity of systemic inflammation. Plasma samples from improvers with declining cytokine levels over time elicited a progressive increase in all measured aspects of glucocorticoid (GC)-induced GR alpha-mediated activity (p = 0.0001) and a correspondent reduction in NF-kappa B nuclear binding (p = 0.0001) and transcription of TNF-alpha and IL-1 (regulated, GR alpha-driven response). In contrast, plasma samples from nonimprovers with sustained elevation in cytokine levels over time elicited only a modest longitudinal increase in GC-GR alpha-mediated activity (p = 0.04) and a progressive increase in NF-kappa B nuclear binding over time (p = 0.0001) that was most striking in nonsurvivors (dysregulated, NF-kappa B-driven response). By days 3-5, no overlap was observed between groups for NF-kappa B and GC-GR alpha nuclear binding. In immunohistochemistry analyses, lung tissues of patients with severe versus mild ARDS had a higher intensity of NF-kappa B nuclear staining (13 +/- 1.3 vs. 7 +/- 2.9; p = 0.01) and a lower ratio of GR alpha:NF-kappa B in nuclear staining (0.5 +/- 0.2 vs. 1.5 +/- 0.2; p = 0.007). In conclusion, we demonstrated that the ability of GC-GR alpha to downregulate NF-kappa B activation is critical for the resolution of systemic and pulmonary inflammation in ARDS. The findings provide a rationale for the use of prolonged GC treatment in early ARDS. Copyright (C) 2005 S. Karger AG, Basel

Nuclear factor-κB- and glucocorticoid receptor α-mediated mechanisms in the regulation of systemic and pulmonary inflammation during sepsis and acute respiratory distress syndrome: Evidence for inflammation-induced target tissue resistance to glucocorticoids

To test the hypothesis that the interaction between nuclear factor-κB (NF-κB) and glucocorticoid receptor α (GRα) is a key pathogenetic mechanism regulating the progression of systemic and pulmonary inflammation in sepsis and acute respiratory distress syndrome (ARDS), we used an ex vivo model of systemic inflammation. Naïve peripheral blood leukocytes (PBL) were exposed to longitudinal (days 1-10) plasma samples from ARDS patients divided into three groups based on physiological improvement and clinical outcome by days 7-10: improvers, nonimprovers-survivors, and nonimprovers-nonsurvivors. In a separate group of nonimprovers-survivors, we correlated the severity of lung histopathology with the intensity of NF-κB and GRα nuclear staining in immunohistochemistry analysis of lung tissue obtained by open lung biopsy. We found that exposure of naïve cells to longitudinal plasma samples led to divergent directions in NF-κB and GRα activation that reflected the severity of systemic inflammation. Plasma samples from improvers with declining cytokine levels over time elicited a progressive increase in all measured aspects of glucocorticoid (GC)-induced GRα-mediated activity (p = 0.0001) and a correspondent reduction in NF-κB nuclear binding (p = 0.0001) and transcription of TNF-α and IL-1β (regulated, GRα-driven response). In contrast, plasma samples from nonimprovers with sustained elevation in cytokine levels over time elicited only a modest longitudinal increase in GC-GRα-mediated activity (p = 0.04) and a progressive increase in NF-κB nuclear binding over time (p = 0.0001) that was most striking in nonsurvivors (dysregulated, NF-κB-driven response). By days 3-5, no overlap was observed between groups for NF-κB and GC-GRα nuclear binding. In immunohistochemistry analyses, lung tissues of patients with severe versus mild ARDS had a higher intensity of NF-κB nuclear staining (13 ± 1.3 vs. 7 ± 2.9; p = 0.01) and a lower ratio of GRα:NF-κB in nuclear staining (0.5 ± 0.2 vs. 1.5 ± 0.2; p = 0.007). In conclusion, we demonstrated that the ability of GC-GRα to downregulate NF-κB activation is critical for the resolution of systemic and pulmonary inflammation in ARDS. The findings provide a rationale for the use of prolonged GC treatment in early ARD

Clinico- pathologic presentation of hypersensitivity pneumonitis in Egyptian patients: a multidisciplinary study

Abstract Background Hypersensitivity pneumonitis (HP) is a common diffuse parenchymal lung disease in Egypt which can be difficult to recognize due to the dynamic symptoms & associated environmental factors. Methods Forty-three Egyptian patients were enrolled in this study, presenting with dyspnea and cough, predominant ground-glass opacity (GGO) in high-resolution computed tomography (HRCT) where lung biopsy was needed to establish the diagnosis. Results The age range was 15 to 60 years. Females represented 90.7% (39 patients) while 9.3% (4 patients) of our patients were males. History of contact with birds was detected in 9 (20.9%) patients. Most of our patients (60.5%) didn’t have exposure history, and only 8 patients (18.6%) were living in geographic areas in Egypt that are known for the exposure to environmental etiologic factors (cane sugar exhaust fumes). The most common HRCT pattern was GGO with mosaic parenchyma in 18 patients (41.86%), followed by GGO with centrilobular nodules in 9 patients (20.93%), then isolated diffuse GGO in 5 patients (11.62%), GGO with traction bronchiectasis in 4 patients (9.3%), GGO with consolidation in 3 patients (6.97%), GGO with reticulations in 2 patients (4.65%), and GGO with cysts in 2 patients (4.65%). The most common histologic finding was isolated multinucleated giant cells in 38 patients (88.3%) commonly found in airspaces (24 patients) and less commonly in the interstitium (14 patients), followed by interstitial pneumonia and cellular bronchiolitis in 36 patients (83.7% each), interstitial ill-formed non-necrotizing granulomas in 12 patients (27.9%), fibrosis in 10 patients (23.2%), and organizing pneumonia pattern in 4 patients (9.3%). Conclusion The diagnosis of HP presenting with predominant GGO pattern in HRCT requires a close interaction among clinicians, radiologists, and pathologists. Some environmental and household factors may be underestimated as etiologic factors. Further environmental and genetic studies are needed especially in patients with negative exposure history