Airway Fibrinogenolysis and the Initiation of Allergic Inflammation

Abstract

The past 15 years of allergic disease research have produced extraordinary improvements in our understanding of the pathogenesis of airway allergic diseases such as asthma. Whereas it was previously viewed as largely an immunoglobulin E-mediated process, the gradual recognition that T cells, especially Type 2 T helper (Th2) cells and Th17 cells, play a major role in asthma and related afflictions has inspired clinical trials targeting cytokine-based inflammatory pathways that show great promise. What has yet to be clarified about the pathogenesis of allergic inflammatory disorders, however, are the fundamental initiating factors, both exogenous and endogenous, that drive and sustain B-and T-cell responses that underlie the expression of chronic disease. Here we review how proteinases derived from diverse sources drive allergic responses. A central discovery supporting the proteinase hypothesis of allergic disease pathophysiology is the role played by airway fibrinogen, which in part appears to serve as a sensor of unregulated proteinase activity and which, when cleaved, both participates in a novel allergic signaling pathway through Toll-like receptor 4 and forms fibrin clots that contribute to airway obstruction. Unresolved at present is the ultimate source of airway allergenic proteinases. From among many potential candidates, perhaps the most intriguing is the possibility such enzymes derive from airway fungi. Together, these new findings expand both our knowledge of allergic disease pathophysiology and options for therapeutic intervention.

Plasma metabolite profiles in children with current asthma

“…43 Fibrinogen cleavage products act as TLR4 ligands, enhancing innate immune response. 44 For instance, fibrinogen cleavage products can bind Toll like receptor 4 (TLR4), priming innate immune and airway epithelial cell response to IL-13, with downstream triggering of airway inflammation. 45 Two of the metabolites with altered levels in current asthmatics, taurocholate and biliverdin, are bile constituents.…”

Reincarnation of ancient links between coagulation and complement

“…This is speculated to impact on development and progression of diabetes‐related vasculopathy. It is likely that dissolution of fibrin clots in other thrombotic or inflammatory disease states, such as asthma or colitis , might be modulated by integration of complement components into the clots and that targeting this step may be of value therapeutically.…”

Proteome analysis of bronchoalveolar lavage fluids reveals host and fungal proteins highly expressed during invasive pulmonary aspergillosis in mice and humans

“…Previous studies have shown the expression of fibrinogen-binding proteins on the surface of conidia of A. fumigatus which promote binding to fibrinogen and host tissue [40,47]. The release of fungal proteases during infection has been reported to result in fibrinogen cleaving and activation of the TLR4 signaling pathway through binding of fibrinogen cleavage products [48][49][50]. The airway protease activity promoted by A. fumigatus initiates both allergic airway disease and antifungal immunity [48,49].…”

“…The release of fungal proteases during infection has been reported to result in fibrinogen cleaving and activation of the TLR4 signaling pathway through binding of fibrinogen cleavage products [ 48 – 50 ]. The airway protease activity promoted by A. fumigatus initiates both allergic airway disease and antifungal immunity [ 48 , 49 ].…”