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.

Figure 1

Overview of hyaluronan in respiratory disease: the lung is continuously exposed to external stimuli which can then impact HA synthesis and turnover. Factors such as type of stimuli, genetics, and the lung environment itself determine if resolution or persistent inflammation and HA changes persist.

Figure 2

Mechanistic role of HA in the response to lung injury: lung injury leads to the synthesis of HA that accumulates in the peribronchial and perivascular spaces. The ongoing inflammation leads to the generation of heavy-chain-HA (HC-HA) complexes mediated via TSG-6 which is a bottleneck in the pathological transformation of HA matrices. These HC-HA complexes can be degraded into smaller LMW fragments which engage cell receptors such as CD44, TLR4, and TLR2 and create downstream biological effects like fibrosis, AHR, and inflammation.