Human endotoxin tolerance is associated with enrichment of the CD14+ CD16+ monocyte subset.

Prior exposure to lipopolysaccharides (LPS) induces a state of cell resistance to subsequent LPS restimulation, known as endotoxin tolerance, mainly by repressing the expression of pro-inflammatory cytokines. We established an endotoxin tolerance model in human monocytes Endotoxin-tolerant cells showed a decrease in IκBα degradation and diminished expression of Tumor necrosis factor (TNF) (both messenger RNA [mRNA] and protein content). The myeloid differentiation factor 88 (MyD88)/MyD88 splice variant (MyD88s) ratio, an indirect way to test the Toll-like receptor 4 (TLR4) MyD88-dependent signaling cascade, did not change in endotoxin-tolerant cells when compared to LPS-stimulated or -unstimulated ones. Remarkably, cell population analysis indicated a significant increase of the CD14+ CD16+ subset only under the endotoxin-tolerant condition. Furthermore, endotoxin-tolerant cells produced higher amounts of C-X-C motif chemokine 10 (CXCL10), a typical MyD88-independent cytokine.

Aspirin-intolerant asthma: a comprehensive review of biomarkers and pathophysiology.

Aspirin-exacerbated respiratory disease is a tetrad of nasal polyps, chronic hypertrophic eosinophilic sinusitis, asthma, and sensitivity to aspirin. Unawareness of this clinical condition by patients and physicians may have grave consequences because of its association with near-fatal asthma. The pathogenesis of aspirin-intolerant asthma is not related with an immunoglobin E mechanism, but with an abnormal metabolism of the lipoxygenase (LO) and cyclooxygenase (COX) pathways. At present, a diagnosis of aspirin sensitivity can be established only by provocative aspirin challenge, which represents a health risk for the patient. This circumstance has encouraged the search for aspirin intolerance-specific biomarkers. Major attempts have focused on mediators related with inflammation and eicosanoid regulation. The use of modern laboratory techniques including high-throughput methods has facilitated the detection of dozens of biological metabolites associated with aspirin-intolerant asthma disease. Not surprisingly, the majority of these is implicated in the LO and COX pathways. However, substantial amounts of data reveal the participation of many genes deriving from different ontologies. Biomarkers may represent a powerful, noninvasive tool in the diagnosis of aspirin sensitivity; moreover, they could provide a new way to classify asthma phenotypes.

The role of macrophages and mast cells in lymphangiogenesis and angiogenesis in cervical carcinogenesis.

During carcinogenesis it is known that growth factors and cytokines from stromal and inflammatory cells from the microenvironment promote angiogenesis and lymphangiogenesis. However, the participation of macrophages and mast cells in these processes is not well understood. The aim of this study was to evaluate the relationship between mast cell and macrophage density with blood and lymphatic vessels in various stages of carcinoma of the uterine cervix. Tissue sections from archival paraffin-embedded samples from cases with cervical intraepithelial neoplasias (CIN) 1, 2, 3, carcinoma in situ, and invasive carcinoma were used. Immunohistochemical staining was done using the following antibodies: anti-LYVE-1; anti-CD31; anti-CD68, and anti-tryptase. Our results showed a significant increase in the number of macrophages in carcinoma in situ, a correlation between lymphatic vessels and macrophages in premalignant lesions CIN 2, and a correlation between mast cells and blood vessels in both CIN 2 and carcinoma in situ. In conclusion, our data underscore the importance of the recruitment of macrophages and mast cells in the development of tumor-associated blood and lymphatic capillaries.

Chemokine (C-X-C motif) ligand 12/stromal cell-derived factor-1 is associated with leukocyte recruitment in asthma.

BACKGROUND: Asthma is characterized by allergic airway inflammatory response involving extensive leukocyte infiltration. The stromal cell-derived factor (SDF)-1 or chemokine (C-X-C motif) ligand 12 (CXCL12) attracts a number of cells, including resting T lymphocytes, monocytes, CD34(+) stem cells, basophils, and mature eosinophils. To date, however, the potential role of CXCL12/SDF-1 in relation to leukocyte recruitment in asthma has not been previously examined, to our knowledge. METHODS: Levels of CXCL12/SDF-1 in the BAL fluid (BALF) of 15 subjects with asthma and 13 healthy subjects were measured by enzyme-linked immunosorbent assay. Immunohistochemistry was performed to identify the cellular source of this chemokine. RESULTS: CXCL12/SDF-1 concentrations were significantly elevated in BALF from subjects with asthma compared with normal subjects (median 845 pg/mL, range, 296-1,700 pg/mL vs median 55 pg/mL, range 25-97 pg/mL; P < .001). Concentrations of CXCL12/SDF-1 correlated with macrophages (r = 0.728, P < .01), lymphocytes (r = 0.651, P < .01), and eosinophils (r = 0.765, P < .01). By immunohistochemistry, CXCL12/SDF-1 was localized to the airway epithelium and to a lesser extent to mononuclear cells. CONCLUSION: CXCL12/SDF-1 is released in high concentration in BALF of patients with asthma. The finding that concentrations of this chemokine correlated with leukocyte numbers in BALF suggests that this chemokine may contribute to the cell recruitment in asthma.