RESUMEN
Tissue fibrosis affects multiple organs and involves a master-regulatory role of macrophages which respond to an initial inflammatory insult common in all forms of fibrosis. The recently unravelled multi-organ heterogeneity of macrophages in healthy and fibrotic human disease suggests that macrophages expressing osteopontin (SPP1) associate with lung and liver fibrosis. However, the conservation of this SPP1+ macrophage population across different tissues and its specificity to fibrotic diseases with different etiologies remain unclear. Integrating 15 single-cell RNA-sequencing datasets to profile 235,930 tissue macrophages from healthy and fibrotic heart, lung, liver, kidney, skin, and endometrium, we extended the association of SPP1+ macrophages with fibrosis to all these tissues. We also identified a subpopulation expressing matrisome-associated genes (e.g., matrix metalloproteinases and their tissue inhibitors), functionally enriched for ECM remodelling and cell metabolism, representative of a matrisome-associated macrophage (MAM) polarisation state within SPP1+ macrophages. Importantly, the MAM polarisation state follows a differentiation trajectory from SPP1+ macrophages and is associated with a core set of regulon activity. SPP1+ macrophages without the MAM polarisation state (SPP1+MAM-) show a positive association with ageing lung in mice and humans. These results suggest an advanced and conserved polarisation state of SPP1+ macrophages in fibrotic tissues resulting from prolonged inflammatory cues within each tissue microenvironment.
Asunto(s)
Pulmón , Macrófagos , Femenino , Humanos , Animales , Ratones , Macrófagos/metabolismo , Fibrosis , Pulmón/metabolismo , Matriz Extracelular , Diferenciación CelularRESUMEN
Angiogenesis, formation of new microvessels providing oxygen and nutrient supply, is essential for tumor growth. It is dependent on the production of angiogenic growth factors by tumor cells. Angiopoietin 1 (Ang-1) and 2 (Ang-2) and their common receptor, Tie2, are thought to be critical regulators of tumor angiogenesis. We examined expression of Ang-1, Ang-2, and their common receptor Tie2 mRNAs and proteins in gastric cancers using in situ hybridization and immunohistochemistry. We also investigated the relationship between their expression and differentiation of cancer cells, lymph node metastasis, tumor size, depth of cancer cell invasion, TNM staging and microvessel density (MVD). The expression of Ang-1, Ang-2, and Tie2 mRNA in cancer cells significantly correlated with the MVD (p<0.001, <0.001 and =0.019, respectively). Ang-1 and Tie2 positivity correlated with advanced gastric cancers (p<0.05) and larger cancers had higher positive rates of Ang-1, Ang-2, and Tie2 mRNA expression (p<0.001, =0.010 and =0.039, respectively). Significant positive correlations were also found between mRNA expression of Tie2 and those of Ang-1 and Ang-2 (p<0.01 and <0.001, respectively). These findings indicate that the expression of Ang-1 and Ang-2 is important for tumor angiogenesis, and suggest a possible role of autocrine/paracrine function of angiopoietin/Tie2 system in gastric cancer progression.
Asunto(s)
Angiopoyetina 1/genética , Angiopoyetina 1/metabolismo , Angiopoyetina 2/genética , Angiopoyetina 2/metabolismo , Receptor TIE-2/genética , Receptor TIE-2/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Adenocarcinoma/irrigación sanguínea , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Adulto , Anciano , Carcinoma de Células en Anillo de Sello/irrigación sanguínea , Carcinoma de Células en Anillo de Sello/genética , Carcinoma de Células en Anillo de Sello/metabolismo , Carcinoma de Células en Anillo de Sello/patología , Femenino , Expresión Génica , Humanos , Inmunohistoquímica , Hibridación in Situ , Masculino , Persona de Mediana Edad , Neovascularización Patológica , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Neoplásico/genética , ARN Neoplásico/metabolismo , Neoplasias Gástricas/irrigación sanguínea , Neoplasias Gástricas/patologíaRESUMEN
Nonsteroidal anti-inflammatory drugs (NSAIDs) induce gastroduodenal mucosal injury and ulceration, and delay ulcer healing. In contrast, the effects of low dose ethanol in induction of gastroduodenal mucosal injury, and the subsequent wound repair remains unclear. The aim of this study was to determine, using an in-vitro duodenal epithelial wound model, whether low clinically relevant doses of ethanol or indomethacin interfere with the wound re-epithelialization of duodenal epithelial monolayers. The possible potentiating effect of ethanol on indomethacin modulation of duodenal re-epithelialization was also examined. In-vitro epithelial wounds were created in confluent IEC-6 duodenal epithelial monolayers by a razor blade scrape. Ethanol at low concentrations (0.25, 0.5, 0.75%) did not have significant effect on duodenal wound re-epithelialization. Similarly, low doses of indomethacin (.01,.05, 0.1 mM) also did not have a significant effect on wound re-epithelialization. However, the combination of ethanol (0.5 or 0.75%) and indomethacin (0.1mM) produced a marked inhibition of IEC-6 re-epithelialization. At the low doses used, ethanol and indomethacin (individually or in combination) did not have direct cytotoxic effect on IEC-6 cells. Ethanol or indomethacin (at the studied concentrations) had only minimal effect on the actin stress fibers in the cells at the migration front. However, in combination, they almost completely abolished the actin stress fibers at the migration front. These findings demonstrate that while low clinically relevant doses of ethanol and indomethacin individually do not affect re-epithelialization of wounded duodenal epithelial monolayers, in combination they produce a significant inhibition.
