Could Vascular Dysfunction Be a Primary vs Secondary Feature of COPD?

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.