ADAM8 signaling drives neutrophil migration and ARDS severity

Acute respiratory distress syndrome (ARDS) results in catastrophic lung failure and has an urgent, unmet need for improved early recognition and therapeutic development. Neutrophil influx is a hallmark of ARDS and is associated with the release of tissue-destructive immune effectors, such as matrix metalloproteinases (MMPs) and membrane-anchored metalloproteinase disintegrins (ADAMs). Here, we observed using intravital microscopy that Adam8–/– mice had impaired neutrophil transmigration. In mouse pneumonia models, both genetic deletion and pharmacologic inhibition of ADAM8 attenuated neutrophil infiltration and lung injury while improving bacterial containment. Unexpectedly, the alterations of neutrophil function were not attributable to impaired proteolysis but resulted from reduced intracellular interactions of ADAM8 with the actin-based motor molecule Myosin1f that suppressed neutrophil motility. In 2 ARDS cohorts, we analyzed lung fluid proteolytic signatures and identified that ADAM8 activity was positively correlated with disease severity. We propose that in acute inflammatory lung diseases such as pneumonia and ARDS, ADAM8 inhibition might allow fine-tuning of neutrophil responses for therapeutic gain

Degradation of 4-fluorophenol by Arthrobacter sp. strain IF1

A Gram-positive bacterial strain capable of aerobic biodegradation of 4-fluorophenol (4-FP) as the sole source of carbon and energy was isolated by selective enrichment from soil samples collected near an industrial site. The organism, designated strain IF1, was identified as a member of the genus Arthrobacter on the basis of 16S ribosomal RNA gene sequence analysis. Arthrobacter strain IF1 was able to mineralize 4-FP up to concentrations of 5 mM in batch culture. Stoichiometric release of fluoride ions was observed, suggesting that there is no formation of halogenated dead-end products during 4-FP metabolism. The degradative pathway of 4-FP was investigated using enzyme assays and identification of intermediates by gas chromatography (GC), GC–mass spectrometry (MS), high-performance liquid chromatography, and liquid chromatography–MS. Cell-free extracts of 4-FP-grown cells contained no activity for catechol 1,2-dioxygenase or catechol 2,3-dioxygenase, which indicates that the pathway does not proceed through a catechol intermediate. Cells grown on 4-FP oxidized 4-FP, hydroquinone, and hydroxyquinol but not 4-fluorocatechol. During 4-FP metabolism, hydroquinone accumulated as a product. Hydroquinone could be converted to hydroxyquinol, which was further transformed into maleylacetic acid and β-ketoadipic acid. These results indicate that the biodegradation of 4-FP starts with a 4-FP monooxygenase reaction that yields benzoquinone, which is reduced to hydroquinone and further metabolized via the β-ketoadipic acid pathway

Deficiency of the Metalloproteinase-Disintegrin ADAM8 Is Associated with Thymic Hyper-Cellularity

Thymopoiesis requires thymocyte-stroma interactions and proteases that promote cell migration by degrading extracellular matrix and releasing essential cytokines and chemokines. A role for several members of the A Disintegrin and Metalloprotease (ADAM) family in T cell development has been reported in the past

Role of ADAM and ADAMTS metalloproteinases in airway diseases

Lungs are exposed to the outside environment and therefore to toxic and infectious agents or allergens. This may lead to permanent activation of innate immune response elements. A Disintegrin And Metalloproteinases (ADAMs) and ADAMs with Thrombospondin motifs (ADAMTS) are proteinases closely related to Matrix Metalloproteinases (MMPs). These multifaceted molecules bear metalloproteinase and disintegrin domains endowing them with features of both proteinases and adhesion molecules. Proteinases of the ADAM family are associated to various physiological and pathological processes and display a wide spectrum of biological effects encompassing cell fusion, cell adhesion, "shedding process", cleavage of various substrates from the extracellular matrix, growth factors or cytokines... This review will focus on the putative roles of ADAM/ADAMTS proteinases in airway diseases such as asthma and COPD

ADAM8/MS2/CD156a: a metalloprotease-disintegrin involved in immune responses

From all ADAM family members known, interesting features of some members of this the family are is their distinct expression patterns. ADAM8 is such an example, as it was identified originally in monocytes and is expressed in many specialised cell types, among them macrophages, B-cells, granulocytes, follicle cells, glandular epithelial cells, osteoclasts, oligodendrocytes, microglia, neurons and astrocytes. ADAM8 is activated by autocatalytic prodomain removal and the substrates like the Close Homologue of L1 (CHL1) and CD23 identified so far are either involved in cell adhesion or immune responses. In turn, ADAM8 expression in some cell types such as macrophages, astrocytes and microglia is regulated by inflammatory mediators including tumor necrosis factor-α, lipopolysaccharides (LPS) and prostaglandins. Whereas embryonal development in ADAM8 deficient mice appears normal, its upregulation under inflammatory conditions like that seen in chronic neurodegeneration, after administration of LPS and in allergic asthma, seems to reflect a specific function of ADAM8 in cytokine response. From recent experiments it can be concluded that the ADAM8 induction by inflammatory cytokines serves protective functions, e.g. by shedding of receptors mediating inflammatory responses or by degrading immune mediators directly

Sustainable reference methodology for energy end-use efficiency data in the EU

One of the most important goals of the European energy policy involves the implementation of energy-efficiency measures in large scale so as to promote sustainable development in the European Union (EU) level. The multidimensional character of energy end-use efficiency (EEE) necessitates the collection of a number of related data, apart from the performance and system parameters data, such as socio-economic (e.g., employment, turnover) and Research and Development (R&D) expenditures. Moreover, improved co-ordination of EEE programmes and policies of the community and the member states so as a unified acceptable system to be developed for the monitoring of the EEE data with respect to the existing targets is of significant importance. Even though data-gathering efforts have been implemented, a lot of fragmented data and deduced findings are currently available, which sometimes lack consistency and verification. In this context, the main aim of the paper is to present a sustainable reference methodology for validating EEE data in EU, through the review of existing approaches and methods, defining of most relevant inconsistencies and gaps and provision of recommendations for improvements in EEE data aggregation and statistical interpretation, taking into consideration the related analysis of statisticians, energy technology experts and energy socio-economists