Abstract-The mechanisms by which persistent proteinuria induces interstitial inflammation and fibrosis are not well known, although nuclear factor-B (NF-B), which regulates the transcription of many genes involved in renal injury, could be implicated. In rats with intense proteinuria, we studied the renal activation of NF-B as well as the potential involvement of the vasoactive hormones angiotensin II (Ang II) and endothelin-1 (ET-1). Uninephrectomized Wistar-Kyoto rats receiving 1 g/d of BSA had proteinuria but no renal morphological lesions at day 1. By contrast, tubular atrophy and/or dilation and mononuclear cell infiltration were observed after 8 or 28 days of BSA administration, coinciding with maximal proteinuria. In relation to control uninephrectomized rats, the renal cortex of nephritic rats showed an increment in the activation of NF-B at all time periods studied. By in situ Southwestern histochemistry, NF-B activity was mainly localized in proximal tubules, interstitial mononuclear cells, and, to a lesser extent, the glomeruli. The administration of the ACE inhibitor quinapril plus the ET A /ET B receptor antagonist bosentan during 28 days to BSA-overloaded animals diminished proteinuria, renal lesions, and NF-B activity more markedly than single drugs. Cultured tubular epithelial cells exposed to BSA revealed an intense NF-B activation in a time-and dose-dependent manner. Incubation of cells with receptor antagonists of Ang II (AT 1 : losartan and AT 2 : PD-123,319) or ET-1 (ET A : BQ123 and ET B : IRL1038) inhibited significantly the BSA-induced NF-B activity (90%, 75%, 90%, and 60% of inhibition versus basal, respectively). Our results show that overload proteinuria causes NF-B activation in tubular epithelial cells both in vivo and in vitro. The vasoactive peptides Ang II and ET-1 appear to be implicated in this effect. The results reveal a novel mechanism of perpetuation of renal damage induced by persistent proteinuria.

A deficit in bone formation is a major factor in diabetes-related osteopenia. We examined here whether diabetes-associated changes in osteoblast phenotype might in part result from a decrease in PTH-related protein (PTHrP). We used a bone marrow ablation model in diabetic mice by multiple streptozotocin injections. PTHrP (1-36) (100 microg/kg, every other day) or vehicle was administered to mice for 13 d starting 1 wk before marrow ablation. Diabetic mice showed bone loss in both the intact femur and the regenerating tibia on d 6 after ablation; in the latter, this was related to decreased bone-forming cells, osteoid surface, and blood vessels, and increased marrow adiposity. Moreover, a decrease in matrix mineralization occurred in ex vivo bone marrow cultures from the unablated tibia from diabetic mice. These skeletal alterations were associated with decreased gene expression (by real-time PCR) of Runx2, osterix, osteocalcin, PTHrP, the PTH type 1 receptor, vascular endothelial growth factor and its receptors, and osteoprotegerin to receptor activator of nuclear factor-kappaB ligand mRNA ratio, and increased peroxisome proliferator-activated receptor-gamma2 mRNA levels. Similar changes were induced by hyperosmotic (high glucose or mannitol) medium in osteoblastic MC3T3-E1 cells, which were mimicked by adding a neutralizing anti-PTHrP antibody or PTH type 1 receptor antagonists to these cells in normal glucose medium. PTHrP (1-36) administration reversed these changes in both intact and regenerating bones from diabetic mice in vivo, and in MC3T3-E1 cells exposed to high glucose. These findings strongly suggest that PTHrP has an important role in the altered osteoblastic function related to diabetes.

Sixty cases of uterine adenomatoid tumors (ATs) are reported. All except four were incidental findings in hysterectomy specimens, three of these being discovered preoperatively as large multicystic tumors. ATs were classified into two distinctive macroscopic patterns: small, solid tumors and large, cystic ones. The 56 small, solid ATs ranged from 0.2 to 3.5 cm, (average 2.1 cm); 48 were nodular and 8 diffuse. The four large, cystic tumors ranged from 7 to 10 cm. Inflammation occurred in 65% of the tumors, and a smooth muscle reaction, identified by an increased Ki-67 index, was present in most cases. Both types were histologically similar except for the presence of short papillae in cystic tumors, which also showed serosal involvement. Both were immunoreactive for cytokeratins, calretinin, HMBE-1, and vimentin. Estrogen and progesterone nuclear receptors and EMA were negative. These tumors represent a spectrum ranging from small and solid to large and cystic ATs in the female genital tract, whereas outside the genital tract they are morphologically similar to multicystic mesothelioma. Although a reactive origin for ATs often seems plausible, especially when inflammation is present, their neoplastic nature should not be ignored.

Epidemiological studies have demonstrated that there is a correlation between oral lichen planus and chronic hepatitis C virus (HCV) infection. HCV RNA has been recently detected in epithelial cells from oral lichen planus lesions by reverse-transcription polymerase chain reaction (RT-PCR). However, this technique does not discriminate which types of cells are infected by the virus or if the viralThe hepatitis C virus (HCV) is the etiological agent of most cases of posttransfusional hepatitis. 1 The viral genome consists of a 9.4-kb-long single-stranded RNA molecule of positive polarity. 2 HCV is thought to replicate in the liver through an RNA intermediate of negative polarity. 3 HCV causes acute and chronic hepatitis in humans. 4 Chronic HCV infection is characterized by a wide spectrum of liver damage ranging from mild chronic hepatitis to cirrhosis, and even hepatocellular carcinoma. 5 On the other hand, several dermatological diseases such as cutaneous necrotizing vasculitis, mixed cryoglobulinemia, porphiria cutanea tarda, and lichen planus have been associated with HCV infection. 6 Lichen planus is a mucocutaneous disease characterized by a band-inflammatory infiltrate enriched in CD4-positive cells, vacuolating degeneration of the basal epithelial layer, and the presence of acidophilic bodies that may represent apoptotic keratinocytes. 7 Its etiology is unknown and may be caused by a cell-mediated immunological response to induced antigenic changes in the skin and mucosa epithelium. 8 The association between HCV infection and lichen planus comes from epidemiological studies that have shown that the prevalence of antibodies against HCV antigens (anti-HCV) is higher in patients with lichen planus than in the general population. [9][10][11] Recently, the presence of positive and negative HCV-RNA strands (which is evidence of viral replication) has been demonstrated by reverse-transcription polymerase chain reaction (RT-PCR) in mucosa biopsies from anti-HCV-positive patients with oral lichen planus. 12 However, because of the high sensitivity of the RT-PCR technique, these PCR products may come from blood that contaminates the biopsies. Furthermore, the presence of HCV RNA in epithelial oral cells has not been demonstrated by in situ hybridization. To establish a role for HCV in the pathology of lichen planus, morphological evidence of HCV replication in the cells of the lesion is needed.For this reason, in this report, we have analyzed the presence of positive and negative HCV-RNA strands by in situ hybridization in paraffin-embedded mucosa biopsies from patients diagnosed as having oral lichen planus and from patients with a chronic HCV infection, but without evidence of suffering oral lichen planus. PATIENTS AND METHODSPatients. Paraffin-embedded oral mucosa biopsies from 23 patients clinically diagnosed as having oral lichen planus were analyzed in this study. Oral mucosa biopsies from the jugal mucosa were obtained to confirm the clinical diagnosis. After the histological examination, the remaining tiss...

Chronic hepatitis C virus (HCV) infection has been associated with several extrahepatic manifestations, among these, to diseases with oral manifestations such as Sjögren's syndrome or sialadenitis. HCV-RNA has been detected in saliva and in salivary glands from patients with sialadenitis by polymerase chain reaction. However, morphological evidence of HCV replication in salivary gland cells is needed to support a role for HCV in causing sialadenitis or Sjögren's syndrome. We have used in situ hybridization and immunohistochemistry to analyze the presence of HCV-RNA of sense and antisense polarity and HCV core antigen, respectively, in salivary gland biopsies from 19 patients with chronic sialadenitis or Sjögren's syndrome (eight anti-HCV-positive; 11 anti-HCV-negative). HCV-RNA of both positive and negative polarity as well as HCV core antigen were detected in the epithelial cells of the salivary gland biopsies from all of the anti-HCV-positive patients but in none of the anti-HCV-negative cases. The percentage of HCV-infected cells ranged from 25 to 48.8% in the patients studied. In conclusion, we have shown that HCV infects and replicates in the epithelial cells from salivary glands of patients with Sjögren's syndrome or chronic sialadenitis. However, its implication in the pathogenesis of these diseases deserves future research.

We previously demonstrated that treatment of acute asthmatic rats with gene therapy using plasmid-encoding Galectin-3 (Gal-3) resulted in an improvement of cellular and functional respiratory parameters. The next question that we wanted to clarify was if in a chronic situation where the treated animal continues to inhale the Ag, does this procedure prevent the chronicity and the remodeling? Chronic inflammation was induced by intranasal administration of OVA over a period of 12 wk. In the treated group, the Gal-3 gene was introduced by intranasal instillation in 50 mul of plasmid-encoding Gal-3. Noninvasive airway responsiveness to methacholine was tested at different times. Cells were obtained by bronchoalveolar lavage and used for RNA extraction and cytometric studies. Eosinophils were counted in blood and bronchoalveolar lavage fluid. Real-time PCR was used to measure Gal-3 and cytokine mRNA expression in lung. Lungs were paraffined and histologic analyses were performed (H&E, periodic acid-Schiff, and Masson Trichrome stain). Our results showed that 12 wk after the first intranasal Ag instillation in chronically asthmatic mice, treatment with the Gal-3 gene led to an improvement in the eosinophil count and the normalization of hyperresponsiveness to methacholine. Concomitantly, this treatment resulted in an improvement in mucus secretion and subepithelial fibrosis in the chronically asthmatic mice, with a quantitatively measured reduction in lung collagen, a prominent feature of airway remodeling. Plasmid-encoding Gal-3 acts as a novel treatment for chronic asthma in mice producing nearly complete blockade of Ag responses with respect to eosinophil airway accumulation, airway hyperresponsiveness, and remodeling.

Decreased renal function has been observed in diseases with intravascular haemolysis, including paroxysmal nocturnal haemoglobinuria (PNH). However, the mechanisms via which haemoglobin enhances renal damage in this pathology are not fully known. We report a case of acute renal failure associated to PNH and extensive haemosiderin deposits in tubular cells. Renal biopsy also revealed a strong immunostaining of CD163 (a haemoglobin scavenger receptor expressed in macrophages) and oxidative stress markers (NADPH-p22 phox and haeme oxigenase-1) in areas with deposits of iron. This fact provides evidence for a pathogenic role for free haemoglobin in tubulointerstitial renal injury in human PNH disease.

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