Novel airway smooth muscle-mast cell interactions and a role for the TRPV4-ATP axis in non-atopic asthma.

Mast cell-airway smooth muscle (ASM) interactions play a major role in the immunoglobulin (Ig)E- dependent bronchoconstriction seen in asthma but less is known about IgE-independent mechanisms of mast cell activation. Transient receptor potential cation channel, subfamily V, member 4 (TRPV4) activation causes contraction of human ASM via the release of cysteinyl leukotrienes (cysLTs) but the mechanism is unknown. The objective of the present study was to investigate a role for IgE-independent, mast cell-ASM interaction in TRPV4-induced bronchospasm.Bronchoconstriction was measured in anaesthetised guinea pigs and contraction of human and guinea-pig airway tissue assessed using isometric tension measurements. Increases in intracellular [Ca2+] were imaged using the Ca2+-sensitive dye FURA2, and time-lapse ptychography was utilised as a surrogate for contraction of ASM cells.The TRPV4 agonist GSK1016790A caused contraction in vivo in the guinea pig, and in human and guinea-pig tracheal tissue, which was inhibited by the TRPV4 antagonist GSK2193874. GSK1016790A increased [Ca2+]i and released ATP in human ASM cells without causing contraction. TRPV4 and ATP evoked contraction in isolated tracheal tissue but co-culture experiments indicated a requirement for human lung mast cells. Expression profiling and pharmacological studies demonstrated that mast cell activation was dependent upon ATP activating the P2X4 receptor. Trypsin was shown to evoke contraction of tracheal tissue via activation of PAR-2-TRPV4-ATP-cysLT axis indicating the potential disease relevance of this signalling pathway.TRPV4 activation increases [Ca2+]i and releases ATP from ASM cells triggering P2X4-dependent release of cysLTs from mast cells resulting in ASM contraction. This study delineates a novel mast cell-ASM interaction and TRPV4 as a driver of IgE-independent mast cell-dependent bronchospasm.

Human airway trypsin-like protease exerts potent, antifibrotic action in pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is characterized by the deposition of excessive extracellular matrix and the destruction of lung parenchyma, resulting from an aberrant wound-healing response. Although IPF is often associated with an imbalance in protease activity, the mechanisms underlying the sustained repair mechanisms are not fully understood. Here, we addressed the role of the recently identified, membrane-anchored serine protease human airway trypsin-like protease (HAT). In the present study, we show that both HAT expression and activity were up-regulated in human IPF specimens. Next, adenoviral overexpression of HAT before bleomycin challenge attenuated lung injury as well as extracellular matrix deposition in the bleomycin-induced pulmonary fibrosis model. In vitro, HAT prevented specific fibrosis-associated responses in primary human pulmonary fibroblasts and induced the expression of mediators associated with the prostaglandin E2 pathway. Altogether, our findings suggested that HAT could have a protective role in IPF and other fibrotic lung disorders.-Menou, A., Flajolet, P., Duitmen, J., Justet, A., Moog, S., Jaillet, M., Tabèze, L., Solhonne, B., Garnier, M., Mal, H., Mordant, P., Castier, Y., Cazes, A., Sallenave, J.-M., Mailleux, A. A., Crestani, B. Human airway trypsin-like protease exerts potent, antifibrotic action in pulmonary fibrosis.

Human airway trypsin-like protease, a serine protease involved in respiratory diseases.

More than 2% of all human genes are coding for a complex system of more than 700 proteases and protease inhibitors. Among them, serine proteases play extraordinary, diverse functions in different physiological and pathological processes. The human airway trypsin-like protease (HAT), also referred to as TMPRSS11D and serine 11D, belongs to the emerging family of cell surface proteolytic enzymes, the type II transmembrane serine proteases (TTSPs). Through the cleavage of its four major identified substrates, HAT triggers specific responses, notably in epithelial cells, within the pericellular and extracellular environment, including notably inflammatory cytokine production, inflammatory cell recruitment, or anticoagulant processes. This review summarizes the potential role of this recently described protease in mediating cell surface proteolytic events, to highlight the structural features, proteolytic activity, and regulation, including the expression profile of HAT, and discuss its possible roles in respiratory physiology and disease.

ERS International Congress, Madrid, 2019: highlights from the Airway Diseases, Asthma and COPD Assembly.

The European Respiratory Society (ERS) International Congress 2019 in Madrid, Spain, was a platform for scientific discussion of the highest quality scientific research, cutting-edge techniques and innovative new therapies within the respiratory field. This article discusses some of the high-quality research studies presented at that Congress, with a focus on airway diseases, including asthma, COPD, small airways, bronchiectasis and cough, presented through the Airway Diseases, Asthma and COPD Assembly (Assembly 5) of the ERS. The authors establish the key take-home messages of these studies, compare their findings and place them into context of current understanding.