July 19, 2019
Pulmonology Advisor Contributing Writer
https://www.pulmonologyadvisor.com/home/topics/copd/chronic-obstructive-pulmonary-disease-with-vascular-dysfunction-as-primary-feature/
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.
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.
Dr Weissmann’s group further suggested that “iNOS and subsequent nitric oxide upregulation exert their effect via peroxynitrite formation that occurs in the presence of superoxide.”1 Peroxynitrite appeared to increase cell death in both alveolar epithelial type II cells and endothelial cells. Peroxynitrite formation also appeared to decrease the generation of type II cells. The group noted that this theory would explain the loss of alveoli and small vessels that is characteristic of individuals with emphysema.
However, using iNOS inhibitors in mice exposed to tobacco smoke prevented the development of both lung airspace enlargement and PH. This treatment also reversed existing lung emphysema and PH when initiated after the disease had been present for 3 months without additional smoke exposure. Tests performed by Dr Weissmann’s group revealed complete alveolar restoration.
Promising Results Observed With sGC Inhibitors
Dr Weissmann’s trials also assessed other therapies for PH treatment in mice exposed to smoke. As a possible preventive measure, some smoke-exposed mice received an sGC inhibitor drug known as riociguat. Meanwhile, smoke-exposed guinea pigs received BAY 41-2272, a different sGC inhibitor.
In mice, this treatment prevented the development of PH and lung airspace enlargement. Results were less dramatic in guinea pigs, but vascular remodeling was improved and lung airspace enlargement prevented.
Results also indicated that sGC stimulation might increase cyclic guanosine monophosphate (cGMP) production. Dr Weissmann concluded that the sGC-cGMP system “has been shown to be essential for vascular homeostasis and the regulation of vascular tone.”1 As tobacco smoke interferes with this process, it may trigger systematic vascular problems.
Treatment With the iNOS Inhibitors
Further tests with iNOS from bone marrow-derived cells triggered PH, but iNOS from non-bone marrow-derived cells was also determined to cause lung airspace enlargement. However, treatment with iNOS inhibitor N6-(1-iminoethyl)-L-lysine dihydrochloride fully reversed both PH and airspace enlargement.
“With regard to iNOS-NO-peroxynitrite,” Dr Weissmann remarked, “studies by my group showed that there are large similarities in terms of structural and molecular alterations. Even smokers without COPD showed pulmonary vascular remodeling, upregulation of iNOS, and increased levels of an end product of peroxynitrite formation, nitrotyrosine. Similar to mice, the [sGC] subunit-β1 was downregulated in human smokers with and without PH.”1
Although some results of treatment with iNOS and sGC inhibitors and may not be fully transferrable to humans, the similarity between structural alterations in human lungs and mouse lungs after exposure to tobacco smoke is intriguing. “If these results are transferable to the human situation,” Dr Weissmann observed, “treatment of lung vascular molecular alterations may allow the development of new treatment concepts for lung emphysema.”1
Dr Weissmann conceded that some cases of spontaneous lung regeneration have been found in mice not exposed to tobacco smoke. However, no spontaneous regeneration was observed in mice exposed to long-term smoke exposure resulting in airspace enlargements. He suggested that these preclinical trials may hold the key to discovering new mechanisms for lung regeneration in adult humans.
Summary and Clinical Applicability
The results of these trials reinforce the idea that pulmonary vascular molecular alterations caused by tobacco smoke are a possible factor in the development of lung emphysema, which indicates several possibilities for new COPD treatment strategies.
Historically, COPD treatments have focused solely on treating symptoms. However, new rodent trials suggest that the damage linked to COPD could someday be reversed. iNOS inhabitation offers a promising treatment strategy. However, long-term studies are needed to better evaluate structural changes in lung cells in COPD accompanied and unaccompanied by PH.
References
1. Weissmann N. Chronic obstructive pulmonary disease and pulmonary vascular disease. A comorbidity? Ann Am Thorac Soc. 2018;15(Suppl 4):S278-S281.
2. Santos S, Peinado VI, Ramírez J, et al. Characterization of pulmonary vascular remodeling in smokers and patients with mild COPD. Eur Respir J. 2002;19(4):632-638.3.
3. Scharf SM, Iqbal M, Keller C, Criner G, Lee S, Fessler HE; on behalf of the National Emphysema Treatment Trial (NETT) Group. Hemodynamic characterization of patients with severe emphysema. Am J Respir Crit Care Med. 2002;166(3):314-322.
Pulmonology Advisor Contributing Writer
https://www.pulmonologyadvisor.com/home/topics/copd/chronic-obstructive-pulmonary-disease-with-vascular-dysfunction-as-primary-feature/
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.
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.
Dr Weissmann’s group further suggested that “iNOS and subsequent nitric oxide upregulation exert their effect via peroxynitrite formation that occurs in the presence of superoxide.”1 Peroxynitrite appeared to increase cell death in both alveolar epithelial type II cells and endothelial cells. Peroxynitrite formation also appeared to decrease the generation of type II cells. The group noted that this theory would explain the loss of alveoli and small vessels that is characteristic of individuals with emphysema.
However, using iNOS inhibitors in mice exposed to tobacco smoke prevented the development of both lung airspace enlargement and PH. This treatment also reversed existing lung emphysema and PH when initiated after the disease had been present for 3 months without additional smoke exposure. Tests performed by Dr Weissmann’s group revealed complete alveolar restoration.
Promising Results Observed With sGC Inhibitors
Dr Weissmann’s trials also assessed other therapies for PH treatment in mice exposed to smoke. As a possible preventive measure, some smoke-exposed mice received an sGC inhibitor drug known as riociguat. Meanwhile, smoke-exposed guinea pigs received BAY 41-2272, a different sGC inhibitor.
In mice, this treatment prevented the development of PH and lung airspace enlargement. Results were less dramatic in guinea pigs, but vascular remodeling was improved and lung airspace enlargement prevented.
Results also indicated that sGC stimulation might increase cyclic guanosine monophosphate (cGMP) production. Dr Weissmann concluded that the sGC-cGMP system “has been shown to be essential for vascular homeostasis and the regulation of vascular tone.”1 As tobacco smoke interferes with this process, it may trigger systematic vascular problems.
Treatment With the iNOS Inhibitors
Further tests with iNOS from bone marrow-derived cells triggered PH, but iNOS from non-bone marrow-derived cells was also determined to cause lung airspace enlargement. However, treatment with iNOS inhibitor N6-(1-iminoethyl)-L-lysine dihydrochloride fully reversed both PH and airspace enlargement.
“With regard to iNOS-NO-peroxynitrite,” Dr Weissmann remarked, “studies by my group showed that there are large similarities in terms of structural and molecular alterations. Even smokers without COPD showed pulmonary vascular remodeling, upregulation of iNOS, and increased levels of an end product of peroxynitrite formation, nitrotyrosine. Similar to mice, the [sGC] subunit-β1 was downregulated in human smokers with and without PH.”1
Although some results of treatment with iNOS and sGC inhibitors and may not be fully transferrable to humans, the similarity between structural alterations in human lungs and mouse lungs after exposure to tobacco smoke is intriguing. “If these results are transferable to the human situation,” Dr Weissmann observed, “treatment of lung vascular molecular alterations may allow the development of new treatment concepts for lung emphysema.”1
Dr Weissmann conceded that some cases of spontaneous lung regeneration have been found in mice not exposed to tobacco smoke. However, no spontaneous regeneration was observed in mice exposed to long-term smoke exposure resulting in airspace enlargements. He suggested that these preclinical trials may hold the key to discovering new mechanisms for lung regeneration in adult humans.
Summary and Clinical Applicability
The results of these trials reinforce the idea that pulmonary vascular molecular alterations caused by tobacco smoke are a possible factor in the development of lung emphysema, which indicates several possibilities for new COPD treatment strategies.
Historically, COPD treatments have focused solely on treating symptoms. However, new rodent trials suggest that the damage linked to COPD could someday be reversed. iNOS inhabitation offers a promising treatment strategy. However, long-term studies are needed to better evaluate structural changes in lung cells in COPD accompanied and unaccompanied by PH.
References
1. Weissmann N. Chronic obstructive pulmonary disease and pulmonary vascular disease. A comorbidity? Ann Am Thorac Soc. 2018;15(Suppl 4):S278-S281.
2. Santos S, Peinado VI, Ramírez J, et al. Characterization of pulmonary vascular remodeling in smokers and patients with mild COPD. Eur Respir J. 2002;19(4):632-638.3.
3. Scharf SM, Iqbal M, Keller C, Criner G, Lee S, Fessler HE; on behalf of the National Emphysema Treatment Trial (NETT) Group. Hemodynamic characterization of patients with severe emphysema. Am J Respir Crit Care Med. 2002;166(3):314-322.