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Nitric Oxide Stimulates the Production of Leukocyte-Binding Hyaluronan by Airway Smooth Muscle Cells

Understanding the role of nitric oxide and hyaluronan in asthma


Nitric oxide (NO) is a biomarker of airway inflammation in asthma and an indicator of progressing disease. Studies have shown that asthmatics with high levels of exhaled NO have greater airway inflammation and airway reactivity. However, very little is known about the potential role of NO in driving airway inflammation.


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In their latest study published in the July 2018 issue of PLOS One, Mark A. Aronica, MD, from Cleveland Clinic’s Department of Allergy and Clinical Immunology, and his team of collaborators investigated the association between NO-modulated hyaluronan (HA) production and inflammation in asthma.

“Hyaluronan is a linear glycosaminoglycan found in pulmonary secretions and the airway extracellular matrix of patients with asthma,” says Dr. Aronica. “It was first described in the secretions of asthmatics in the 1970s, but subsequent to that very little work was done on understanding its role in asthma, until more recently.

“Our study was prompted by an earlier observation that airway smooth muscle cells (SMCs) produce HA cables. We wanted to investigate whether NO, which is prevalent in asthma, might have an impact on its production.”

NO stimulates the production of hyaluronan

Dr. Aronica and his team utilized airway SMCs isolated from wild type and hyaluronan synthase knockout mice to test their hypothesis. They chose to do their experiments on SMCs because of their established clinical relevance in asthma.

“SMCs have been known to play an important role in asthma,” he says. “The airway in humans is surrounded by smooth muscle, and smooth muscle was the primary therapeutic target in asthma back in the 1950s with the use of bronchodilators. In addition, SMCs are easily accessible for research purposes.”

Treatment of SMCs isolated from wild type mice with the NO donor (500 mM NOC-18) resulted in the deposition of long, cable-like structures of HA. When these stimulated SMC cultures were incubated with fluorescently labeled leukocytes, leukocyte binding occurred. The binding was reversible upon treatment with hyaluronidase, indicating that HA-containing structures facilitate leukocyte adhesion after stimulation with NO.

Putting together the puzzle pieces

Dr. Aronica explains that these findings bring us a step closer to understanding the mechanism behind chronic airway inflammation in asthma and point to non-immune cells as potential drivers of inflammation. However, further research is warranted.

“Our study is a piece of the bigger puzzle that aims to understand the role of NO and HA in asthma,” he says. “These early findings open up a myriad of additional questions that still need to be answered: Is HA harmful or beneficial? Are there ways we can impact HA production and what impact does it have in the pathogenesis of asthma? Does HA have an impact on airway remodeling?”


In an effort to tackle some of these questions, Dr. Aronica plans to continue his studies in knockout mice lacking the gene that encodes HA synthase — the enzyme responsible for HA synthesis.

“One of the findings of our study was that HAS2 knockout mice do not produce HA cables,” he says. “The HAS2 knockout mice are embryonic lethal, so we are now continuing our work on conditional HAS2 knockout mice to better understand how the lack of HA synthase, or the lack of HA production in the lung, might impact the overall disease.”


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