The Rise and Fall of Hyaluronan in Respiratory Diseases.

Mark E. Lauer,Raed A. Dweik,Stavros Garantziotis,Mark A. Aronica

doi:10.1155/2015/712507

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.

Highlights

Considerable progress has been made over the past few decades in our understanding of the role of hyaluronan (HA) in pulmonary health and disease
These studies indicate that (i) elevated levels of HA in bronchoalveolar lavage fluid (BAL) fluid are associated with a variety of environmental and occupational airway injuries. (ii) HA levels correspond to the extent of exposure and lung injury
Conclusions. (i) In normal tissues, HA matrices are primarily located within (a) the airway submucosa, (b) the walls of pulmonary vasculature, (c) and to a lesser extent, alveoli. (ii) During pulmonary injury and repair, there is increased synthesis of HA matrices in these regions that colocalizes with inflammatory cells and likely influences their activation. (iii) The HA that accumulates in these regions is often covalently modified with heavy chains from inter-ainhibitor which significantly promotes leukocyte adhesion to HA matrices [15,16,17, 72, 73] (Figure 2). (iv) Elevated HA BAL levels correspond with the extent of lung injury while HA serum levels do not always correlate with lung injury

Summary

Introduction

Considerable progress has been made over the past few decades in our understanding of the role of hyaluronan (HA) in pulmonary health and disease. Once thought to be an inert molecule of the extracellular matrix, a picture has emerged of HA as an important regulator of inflammation, airway hyperresponsiveness (AHR), edema, and fibrosis in the lung. This image has been made clearer by a significant number of investigations into a wide variety of different pulmonary diseases, environmental effects, and animal models of lung injury, which are summarized in this review (Figure 1). The present review provides a survey of HA-related data in the area of pulmonary pathobiology with an emphasis upon its expression, distribution, and turnover in a variety of respiratory disorders and conditions from both human subjects and animal models. The data was presented as an approximation (i.e., ∼10 μg/L)

Environmental and Occupational Exposure

Human Respiratory Diseases

Animal Models of Pulmonary Injury

Findings

Overall Summary and Conclusions