Asthma is a chronic inflammatory disease of the airways that is typically accompanied by increased airway hyper-responsiveness to various stimuli, including allergens, pollutants and viruses, resulting in airway obstruction that leads to recurrent episodes of wheezing and coughing. The accumulation of inflammatory cells into the airway wall is a hallmark feature of asthma and is one of the key factors driving inflammation in this disease. We have found that these cells are embedded in an extensive hyaluronan-rich extracellular matrix produced by smooth muscle cells surrounding airway vasculature and bronchi. This hyaluronan (HA) matrix is abnormal in the sense that it is decorated with heavy chains (HCs) derived from a component found in blood. This HC-HA modification is important because it creates an HA ligand that is """"""""sticky"""""""" for inflammatory cells which bind to HC-HA via an unidentified receptor(s). The decoration of HA matrices with HCs is accomplished by the enzyme """"""""tumor-necrosis-factor-stimulated-gene-6"""""""" (TSG-6). As its name implies, synthesis of this protein is induced by tumor-necrosis-factor-alpha (TNF?), a well-known mediator of inflammation in asthma. Furthermore, TSG-6 is known to play a role in a variety of inflammatory diseases. Over the course of our investigations, we discovered that TSG-6 not only possesses the enzymatic ability to decorate HA with HCs but that it significantly stimulates HA synthesis by airway smooth muscle cells (ASMCs). Interestingly, this induction did not occur when TSG-6 was applied alone, but rather, only in combination with double-stranded RNA (dsRNA) that provides a stimulus mimicking a viral infection. For decades, the connection between viral infections and the exacerbation of asthmatic symptoms has been well known, but the mechanism whereby viruses trigger this pathology remains a medical mystery. Our observation that TSG-6 is a potent amplifier of the HA stress response by airway smooth muscle cells when challenged by a viral mimetic implies that the dual functionality of TSG-6 may be an important part of the mechanism whereby viral infections trigger asthma pathology. Our long-term goal is to understand how HC-HA directs inflammatory events and to apply this knowledge to design novel therapeutic approaches to restore these matrices to their normal state and improve clinical outcomes in patients with chronic inflammatory diseases. Our hypothesis is that TSG-6 amplifies HA synthesis by ASMCs via engagement of its enzymatic product (i.e. HC-HA) with a cell surface receptor that is induced during inflammation. We also hypothesize that HC-HA influences the behavior and activation of leukocytes embedded within the HC-HA matrix. We will test this hypothesis in the following specific aims: (i) identify the signaling pathways, receptors and ligands whereby TSG-6 stimulates HA synthesis, (ii) determine the effect HC-HA has on monocyte/macrophage activation, and (iii) evaluate the ability of TSG-6 to amplify HA synthesis in cooperation with a """"""""live"""""""" respiratory virus.
The mechanism whereby viruses trigger asthma pathology is unknown. We have found that the inflammatory protein TSG-6 amplifies the viral-mediated synthesis of a pathological hyaluronan extracellular matrix by airway smooth muscle cells that are important in asthma physiology. This implies that TSG-6 may be an important part of the mechanism by which viral infections trigger asthma.
|Ghatak, Shibnath; Markwald, Roger R; Hascall, Vincent C et al. (2017) Transforming growth factor ?1 (TGF?1) regulates CD44V6 expression and activity through extracellular signal-regulated kinase (ERK)-induced EGR1 in pulmonary fibrogenic fibroblasts. J Biol Chem 292:10465-10489|
|Ghatak, Shibnath; Hascall, Vincent C; Markwald, Roger R et al. (2017) Transforming growth factor ?1 (TGF?1)-induced CD44V6-NOX4 signaling in pathogenesis of idiopathic pulmonary fibrosis. J Biol Chem 292:10490-10519|
|Matuska, Brittany; Comhair, Suzy; Farver, Carol et al. (2016) Pathological Hyaluronan Matrices in Cystic Fibrosis Airways and Secretions. Am J Respir Cell Mol Biol 55:576-585|
|Vinukonda, Govindaiah; Dohare, Preeti; Arshad, Arslan et al. (2016) Hyaluronidase and Hyaluronan Oligosaccharides Promote Neurological Recovery after Intraventricular Hemorrhage. J Neurosci 36:872-89|
|Abbadi, Amina; Lauer, Mark; Swaidani, Shadi et al. (2016) Hyaluronan Rafts on Airway Epithelial Cells. J Biol Chem 291:1448-55|
|Lauer, Mark E; Majors, Alana K; Comhair, Suzy et al. (2015) Hyaluronan and Its Heavy Chain Modification in Asthma Severity and Experimental Asthma Exacerbation. J Biol Chem 290:23124-34|
|Lauer, Mark E; Dweik, Raed A; Garantziotis, Stavros et al. (2015) The Rise and Fall of Hyaluronan in Respiratory Diseases. Int J Cell Biol 2015:712507|
|Lauer, Mark E; Loftis, Jacqueline; de la Motte, Carol et al. (2015) Analysis of the heavy-chain modification and TSG-6 activity in pathological hyaluronan matrices. Methods Mol Biol 1229:543-8|
|Lamkin, Elliott; Cheng, Georgiana; Calabro, Anthony et al. (2015) Heavy chain transfer by tumor necrosis factor-stimulated gene 6 to the bikunin proteoglycan. J Biol Chem 290:5156-66|
|Lauer, Mark E; Hascall, Vincent C; Green, Dixy E et al. (2014) Irreversible heavy chain transfer to chondroitin. J Biol Chem 289:29171-9|