Activated MCTC mast cells infiltrate diseased lung areas in cystic fibrosis and idiopathic pulmonary fibrosis

<p>Abstract</p> <p>Background</p> <p>Although mast cells are regarded as important regulators of inflammation and tissue remodelling, their role in cystic fibrosis (CF) and idiopathic pulmonary fibrosis (IPF) has remained less studied. This study investigates the densities and phenotypes of mast cell populations in multiple lung compartments from patients with CF, IPF and never smoking controls.</p> <p>Methods</p> <p>Small airways, pulmonary vessels, and lung parenchyma were subjected to detailed immunohistochemical analyses using lungs from patients with CF (20 lung regions; 5 patients), IPF (21 regions; 7 patients) and controls (16 regions; 8 subjects). In each compartment the densities and distribution of MC_Tand MC_TCmast cell populations were studied as well as the mast cell expression of IL-6 and TGF-β.</p> <p>Results</p> <p>In the alveolar parenchyma in lungs from patients with CF, MC_TCnumbers increased in areas showing cellular inflammation or fibrosis compared to controls. Apart from an altered balance between MC_TCand MC_Tcells, mast cell in CF lungs showed elevated expression of IL-6. In CF, a decrease in total mast cell numbers was observed in small airways and pulmonary vessels. In patients with IPF, a significantly elevated MC_TCdensity was present in fibrotic areas of the alveolar parenchyma with increased mast cell expression of TGF-β. The total mast cell density was unchanged in small airways and decreased in pulmonary vessels in IPF. Both the density, as well as the percentage, of MC_TCcorrelated positively with the degree of fibrosis. The increased density of MC_TC, as well as MC_TCexpression of TGF-β, correlated negatively with patient lung function.</p> <p>Conclusions</p> <p>The present study reveals that altered mast cell populations, with increased numbers of MC_TCin diseased alveolar parenchyma, represents a significant component of the histopathology in CF and IPF. The mast cell alterations correlated to the degree of tissue remodelling and to lung function parameters. Further investigations of mast cells in these diseases may open for new therapeutic strategies.</p

Amplified Genes May Be Overexpressed, Unchanged, or Downregulated in Cervical Cancer Cell Lines

Several copy number-altered regions (CNAs) have been identified in the genome of cervical cancer, notably, amplifications of 3q and 5p. However, the contribution of copy-number alterations to cervical carcinogenesis is unresolved because genome-wide there exists a lack of correlation between copy-number alterations and gene expression. In this study, we investigated whether CNAs in the cell lines CaLo, CaSki, HeLa, and SiHa were associated with changes in gene expression. On average, 19.2% of the cell-line genomes had CNAs. However, only 2.4% comprised minimal recurrent regions (MRRs) common to all the cell lines. Whereas 3q had limited common gains (13%), 5p was entirely duplicated recurrently. Genome-wide, only 15.6% of genes located in CNAs changed gene expression; in contrast, the rate in MRRs was up to 3 times this. Chr 5p was confirmed entirely amplified by FISH; however, maximum 33.5% of the explored genes in 5p were deregulated. In 3q, this rate was 13.4%. Even in 3q26, which had 5 MRRs and 38.7% recurrently gained SNPs, the rate was only 15.1%. Interestingly, up to 19% of deregulated genes in 5p and 73% in 3q26 were downregulated, suggesting additional factors were involved in gene repression. The deregulated genes in 3q and 5p occurred in clusters, suggesting local chromatin factors may also influence gene expression. In regions amplified discontinuously, downregulated genes increased steadily as the number of amplified SNPs increased (p<0.01, Spearman's correlation). Therefore, partial gene amplification may function in silencing gene expression. Additional genes in 1q, 3q and 5p could be involved in cervical carcinogenesis, specifically in apoptosis. These include PARP1 in 1q, TNFSF10 and ECT2 in 3q and CLPTM1L, AHRR, PDCD6, and DAP in 5p. Overall, gene expression and copy-number profiles reveal factors other than gene dosage, like epigenetic or chromatin domains, may influence gene expression within the entirely amplified genome segments

Natural infection by Trypanosoma cruzi in triatomines of central and northern Mexico [Infección natural por Trypanosoma cruzi en triatominos del Centro y Norte de México]

On this study are reported some collections of triatomines from the Mexican states of Chihuahua and Aguascalientes, where recent data about vector infection by Trypanosoma cruzi was not available. In the state of Chihuahua only adult specimens of Triatoma recurva and of Meccus phyllosomus longipennis were collected. Percentages of infection by T. cruzi were respectively 5.17% and 12.5%. In the state of Aguascalientes adult as well nymph specimens of M. p. longipennis were collected. Percentage of infection by T. cruzi reached 96.7%. Our results show a null colonization of human dwellings by triatomines in the study area of the state of Chihuahua, as well as low risk of infection by T. cruzi for the inhabitants of that area. On the other hand, in the study area in the state of Aguascalientes, the risk of infection by T. cruzi was high for inhabitants of the area. Complementary entomological studies are necessary to establish the proper risk of infection by vectorial transmission of T. cruzi to human and animal reservoir host in the two studied areas

Natural infection by Trypanosoma cruzi in triatomines of central and northern Mexico [Infección natural por Trypanosoma cruzi en triatominos del Centro y Norte de México]

On this study are reported some collections of triatomines from the Mexican states of Chihuahua and Aguascalientes, where recent data about vector infection by Trypanosoma cruzi was not available. In the state of Chihuahua only adult specimens of Triatoma recurva and of Meccus phyllosomus longipennis were collected. Percentages of infection by T. cruzi were respectively 5.17% and 12.5%. In the state of Aguascalientes adult as well nymph specimens of M. p. longipennis were collected. Percentage of infection by T. cruzi reached 96.7%. Our results show a null colonization of human dwellings by triatomines in the study area of the state of Chihuahua, as well as low risk of infection by T. cruzi for the inhabitants of that area. On the other hand, in the study area in the state of Aguascalientes, the risk of infection by T. cruzi was high for inhabitants of the area. Complementary entomological studies are necessary to establish the proper risk of infection by vectorial transmission of T. cruzi to human and animal reservoir host in the two studied areas

Role of nitric oxide and prostaglandins in the potentiating effects of calcitonin gene-related peptide on lipopolysaccharide-induced interleukin-6 release from mouse peritoneal macrophages

Previous data from our laboratory have shown that calcitonin gene-related peptide (CGRP) has a potentiating effect on lipopolysaccharide-(LPS) induced interleukin-6 (IL-6) release from mouse macrophages. However, the mechanism of this effect was not clear. Since the nitric oxide (NO) and prostaglandins (PGs) induced by LPS might modulate IL-6 release, we examined whether NO and PGs were also involved in the potentiating effect of rat CGRP (rCGRP) on LPS-induced IL-6 release from mouse macrophages. The IL-6 level in the medium was measured by enzyme-linked immunosorbent assay. Accumulation of NO was assessed by measuring the presence of nitrite by the Greiss reaction. PGI2 was assessed by measuring the formation of 6-keto-prostaglandin F1α (6-keto-PGF1α) by radioimmunoassay. The results showed that the potentiating effect of rCGRP (0·1 nm) on LPS-induced IL-6 release was significantly inhibited by either 100 μm NG-monomethyl-l-arginine acetate (l-NMMA; an inhibitor of NO synthase) or 10 μm indomethacin (an inhibitor of cyclo-oxygenase). The LPS-induced NO and PGI2 production from these cells was increased significantly by rCGRP at 0·01–10 nm in a concentration-dependent manner, which was blocked by l-NMMA and indomethacin. These results suggest that rCGRP enhances the NO production elicited by LPS and subsequently increases the PGs production which is involved in the potentiating effect of rCGRP on LPS-induced IL-6 release from the peritoneal macrophages in the mouse

The Vibrio cholerae cytolysin (VCC) promotes activation of mast cell (T helper 2) cytokine production

Many strains of Vibrio cholerae produce a cytolysin (VCC) that forms oligomeric transmembrane pores responsible for vacuolization of several cell types in culture. Here we suggest that VCC could contribute to the T helper 2 (Th2) response seen in the natural infection; acting through TLR2, VCC enhances mast cells secretion of IL-4, IL-6 and TNF-alpha by 330-, 290- and 550-fold respectively. Moreover, VCC-induced cytokine production is dependent on increased cytosolic Ca(2+) and on the presence of the Src family kinases Lyn and Fyn, known to be required for FcepsilonRI-dependent activation of mast cells. These findings strongly suggest that VCC has a pro-inflammatory activity promoting a Th2-type immune profil