The Rise and Fall of Hyaluronan in Respiratory Diseases

Abstract

In normal airways, hyaluronan (HA) matrices are primarily located within the airway submucosa, pulmonary vasculature walls, and, to a lesser extent, the alveoli. Following pulmonary injury, elevated levels of HA matrices accumulate in these regions, and in respiratory secretions, correlating with the extent of injury. Animal models have provided important insight into the role of HA in the onset of pulmonary injury and repair, generally indicating that the induction of HA synthesis is an early event typically preceding fibrosis. The HA that accumulates in inflamed airways is of a high molecular weight (>1600 kDa) but can be broken down into smaller fragments (<150 kDa) by inflammatory and disease-related mechanisms that have profound effects on HA pathobiology. During inflammation in the airways, HA is often covalently modified with heavy chains from inter-alpha-inhibitor via the enzyme tumor-necrosis-factor-stimulated-gene-6 (TSG-6) and this modification promotes the interaction of leukocytes with HA matrices at sites of inflammation. The clearance of HA and its return to normal levels is essential for the proper resolution of inflammation. These data portray HA matrices as an important component of normal airway physiology and illustrate its integral roles during tissue injury and repair among a variety of respiratory diseases.

Provisional matrix: A role for versican and hyaluronan

“…This type of cross linking stabilizes the hyaluronan-enriched matrices and is prominent during provisional matrix formation. This is the only covalent modification known to occur on hyaluronan that facilitates changes in its organization and assembly critical to specific events in development and disease [29, 75, 76]. These interactions are critical to shaping both the microenvironment and the provisional matrix, and to a large extent may regulate the ability of hyaluronan to impact cell phenotype [29, 58, 59].…”

“…Such examples highlight the importance of provisional matrix components controlling events such as immunity and inflammation. Other diseases that involve hyaluronan and versican impacting immune and inflammatory cell invasion include lung disease [76, 171–176], inflammatory bowel disease (IBD) [32, 158], kidney disease [162, 177], and autoimmune diseases, such as T1D [178, 179]. In diseases of the lung, both versican and hyaluronan accumulate as part of provisional matrices in subepithelial regions and perivascular compartments of the lung, impacting the recruitment of inflammatory cells, such as neutrophils, eosinophils, and macrophages.…”

Thinking Outside the Cell: A Key Role for Hyaluronan in the Pathogenesis of Human Type 1 Diabetes

“…Increased accumulation of HA in tissues occurs during cellular stress responses or viral infection and in a variety of inflammatory diseases (23,82,83). Following tissue injury, intact HMW-HA (.1,000 kDa) breaks down into fragments of low-molecular-weight HA (LMW-HA) through enzymatic degradation by endogenous or microbial hyaluronidases and nonenzymatic processes such as mechanical forces and oxidative stress (26,77,84).…”

Low‐molecular‐mass hyaluronan induces pulmonary inflammation by up‐regulation of Mcl‐1 to inhibit neutrophil apoptosis via PI3K/Akt1 pathway

“…2 Low-molecular-mass HA (LMMHA), a product of rapid turnover and degradation of HA, can serve as an intracellular signalling molecule in inflammation and has been found to be pro-inflammatory. 3 LMMHA is dramatically increased in patients with idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, asthma and acute respiratory distress Abbreviations: BALF, bronchoalveolar lavage fluid; ECM, extracellular matrix; ERK 1/2, extracellular signal-regulated kinase 1/2; IFN-b, interferon-b; IL-1b, interleukin-1b; IRF-3, interferon regulatory factor 3; KC, keratinocyte cell-derived chemokine; LMMHA, low-molecular-mass hyaluronan; Mcl-1, myeloid leukaemia cell differentiation protein; MMP-9, matrix metalloproteinase-9; MPO, myeloperoxidase; PBS, phosphate-buffered saline; PI3K, phosphoinositide 3-kinase; TLR, Toll-like receptor; WT, wild-type ª 2018 John Wiley & Sons Ltd, Immunology, 155, 387-395 syndrome. [4][5][6][7] A previous study on the role of LMMHA in lung injury revealed that blocking the effect of LMMHA with specific peptides decreases neutrophil infiltration and fibrosis activity and alleviates lung tissue damage in a bleomycin-mediated LMMHA-induced mouse lung injury model.…”