BackgroundSerine proteases promote inflammation and tissue remodeling by activating proteinase-activated receptors, urokinase, metalloproteinases and angiotensin. In the present study, 4-(2-Aminoethyl) benzenesulfonyl fluoride (AEBSF) a serine protease inhibitor was evaluated for prophylactic and therapeutic treatment in mouse model of airway allergy.MethodsBALB/c mice were sensitized by i.p route and challenged with ovalbumin. They were treated i.n. with 2, 10 and 50 µg of AEBSF, one hour before or after challenge and euthanized to collect BALF (bronchoalveolar lavage fluid), blood and lungs. Proteolytic activity, total cell/eosinophil/neutrophil count eosinophil peroxidase activity (EPO), IL-4, IL-5, IL-10, IL-13, cysteinyl leukotrienes and 8-isoprostane were determined in BALF and immunoglobulins were measured in serum. H&E and PAS stained lung sections were examined for cellular infiltration and airway inflammation.ResultsMice exposed to ovalbumin and treated with PBS showed increased cellular infiltration in lungs and higher serum IgE, IgG1 and IgG2a levels as compared to sham mice. Treatment with AEBSF reduced total cells/eosinophil/neutrophil infiltration. Both prophylactic and therapeutic AEBSF treatment of 10 or 50 µg reduced serum IgE and IgG1 significantly (p<0.05) than control. AEBSF treatment reduced the proteolytic activity in BALF. IL-4 IL-5 and IL-13 levels decreased significantly (p<0.05) after AEBSF treatment while IL-10 levels increased significantly (p<0.05) in BALF. Airway inflammation and goblet cell hyperplasia reduced as demonstrated by lung histopathology, EPO activity and cysteinyl leukotrienes in BALF after treatment. AEBSF treatment also suppressed oxidative stress in terms of 8-isoprostane in BALF. Among the treatment doses, 10 or 50 µg of AEBSF were most effective in reducing the inflammatory parameters.ConclusionsProphylactic and therapeutic treatment with serine protease inhibitor attenuates the airway inflammation in mouse model of airway allergy and have potential for adjunct therapy.

Hematopoietic stem cells (HSCs) self-renew or differentiate into blood cell lineages following extrinsic cues propagated in specialized niches. Support cells and soluble factors in the niche respond to stress and enable progenitor activity. Metalloproteases (MMPs, ADAMs, ADAMTSs) and their inhibitors (TIMPs) control certain physical and biochemical features of the niche by altering protease-dependent bioavailability of local niche factors (e.g., CXCL12, SCF, TGFb, VEGF), matrix turnover, and cellular interactions. With over 40 examples of diverse metalloprotease substrates known to trigger fate-changing decisions, the spatially confined activity of this multi-member protease family is ideally positioned to constitute a higher order control over hematopoiesis. Comprehension of regulated proteolysis in the bone marrow may fuel innovative strategies to harness HSC fate and function. Metalloproteases Can Orchestrate Physical and Biochemical Cues for Mammalian HematopoiesisHSCs are the only cells able to reconstitute all blood cell lineages. HSCs reside in a niche that provides instructions for self-renewal or the signals to develop into specific progenitors. The niche serves as a physical address (perivascular bone marrow for most adult HSC) and comprises various entities, including support cells (macrophages, megakaryocytes, osteoblasts, endothelial, perivascular, and specialized reticular cells), the extracellular matrix (ECM; comprising structural collagens, fibronectin, and laminin), local growth factors and cytokines, shear forces of circulation, oxygen tension, and sympathetic innervation [1-3]. These features create a discrete environment for the quiescence and maintenance of the HSC pool or proliferation and differentiation into progenitors, which give rise to all effector blood cells during homeostasis and following stress (e.g., pregnancy, anemia, infection, and irradiation). In both mice and humans, the initial location of hematopoietic cells is the early embryonic yolk sac and aorta-gonad-mesonephros; they subsequently reside in the embryonic liver before taking up residence in the bone marrow (BM) [4]. The spleen and liver provide additional poststress sites of hematopoiesis for mobilized HSCs in the adult. Most HSCs are perivascular in the BM, with other cellular players providing support through cell-cell contact or delivery of soluble factors (detailed elsewhere) [1,2].Along with structural and physical properties of the ECM shaping the niche, the ECM is a growth factor-rich scaffold that mediates many of the extracellular interactions. Multiple aspects of the niche entities are subject to regulation by metalloproteases and their natural inhibitors. Metalloproteases are the largest of the five groups of proteases in the human genome (Box 1), where metzincins have a zinc at the active site and include enzymes such as matrix metalloproteases (MMPs), a disintegrin and metalloproteases (ADAMs), and ADAM with thrombospondin motifs (ADAMTSs); these are inhibited by tissue inhibitors of metalloproteases (TIM...