Bronchitis symptoms, considered a defining characteristic of chronic obstructive pulmonary disease (COPD), are not fully reversible with available treatments. COPD also encompasses lung emphysema, another condition currently considered to be progressive.1

Results of recent preclinical trials published in Annals of the American Thoracic Society suggest that the use of inducible nitric oxide synthase (iNOS) and soluble guanylate cyclase (sGC) inhibitors may reverse both pulmonary hypertension (PH) and lung airspace enlargement in mice exposed to tobacco smoke.1 These results suggest that COPD caused by tobacco exposure could someday be cured.

COPD Mechanisms and Vascular Remodeling

COPD has historically been viewed primarily as an airway disease that occurs due to inhalation of smoke or other irritants. Systemic effects, such as cardiopulmonary disease and muscle wasting, have also been observed. These effects have often been viewed merely as secondary factors resulting from lung damage.

However, recent research has suggested that many of these systemic effects could also result from tobacco exposure. Chemicals present in tobacco smoke may pass into the circulatory system via lung alveoli. In a recent article, Norbert Weissmann, PhD, from the Excellence Cluster Cardio-Pulmonary System at the Universities of Giessen and Marburg Lung Center in  Giessen, Germany, noted that “vascular dysfunction can be a feature of COPD,”1 rather than a distant secondary effect. Smoke inhalation may directly affect the lung vasculature, causing significant structural changes.

In a previous study, lungs from human smokers who were not diagnosed with COPD revealed “severe pulmonary vascular remodeling, with prominent narrowing of the pulmonary vascular lumen.”2 The results gathered through human lung examinations were consistent with the pulmonary vascular remodeling observed in individuals with PH. Similar results were also observed in rodent models.

The Relationship Between PH and COPD

The exact occurrence of PH in individuals with COPD is debatable. Severe PH remains rare, affecting only 1% to 4% of individuals with COPD.3 However, mild to moderate PH occurs far more frequently.

Dr Weissmann emphasized that the current definitions for PH may obscure its prevalence: “If the definition of PH were to be expanded to a mean pulmonary artery pressure greater than 20 mm Hg, the prevalence would be approximately 91%” in individuals with COPD.1,3

Dr Weissmann’s group studied whether structural and molecular changes in pulmonary vascular cells may play a causative role in COPD. They focused on C57BL/6 mice exposed to tobacco smoke. Trials with these mice indicated that “pulmonary vascular remodeling and PH clearly preceded the development of airspace enlargement.”1

Long term-exposure to tobacco smoke was linked to airspace enlargement in the mice, detectable after 6 months. However, PH was present after just 3 months of smoke exposure. Dr Weissmann’s group noted that observed phenotypes during these trials were similar to previous mouse models of hypoxia-induced PH.

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The Link Between iNOS and Emphysema

Dr Weissmann further remarked that “oxidative and nitrosative stress have been implicated in the development of lung emphysema.”1 However, previous studies in rodents often neglected to expose mice to hypoxia, leading to incomplete results. During these trials, Dr Wiessmann’s group further examined the link between systemic effects COPD and gas exchange within the body.

The group “focused on the regulation of endothelial nitric oxide synthase (eNOS; NOS3) and [iNOS] as possible underlying mechanisms”1 in COPD. During their trials, they determined that that “upregulation of iNOS was restricted to the pulmonary vasculature.”1

iNOS upregulation may have a significant effect on COPD outcomes; iNOS-knockout mice were protected from PH and the development of airspace enlargement after smoke exposure. However, these results were not observed in eNOS-knockout mice. Dr Weissmann’s group concluded that iNOS might trigger emphysema even if vascular remodeling has not occurred. These trials provide further evidence for the notion that lung vascular molecular alterations may encourage the development of emphysema.