Amelioration of elastase‐induced lung emphysema and reversal of pulmonary hypertension by pharmacological iNOS inhibition in mice

Abstract

Background and Purpose: Chronic obstructive pulmonary disease, encompassing chronic airway obstruction and lung emphysema, is a major worldwide health problem and a severe socio-economic burden. Evidence previously provided by our group has shown that inhibition of inducible NOS (iNOS) prevents development of mild emphysema in a mouse model of chronic tobacco smoke exposure and can even trigger lung regeneration. Moreover, we could demonstrate that pulmonary hypertension is not only abolished in cigarette smoke-exposed iNOS −/− mice but also precedes emphysema development. Possible regenerative effects of pharmacological iNOS inhibition in more severe models of emphysema not dependent on tobacco smoke, however, are hitherto unknown. Experimental Approach:We have established a mouse model using a single dose of porcine pancreatic elastase or saline, intratracheally instilled in C57BL/6J mice.Emphysema, as well as pulmonary hypertension development was determined by both structural and functional measurements.Key Results: Our data revealed that (i) emphysema is fully established after 21 days, with the same degree of emphysema after 21 and 28 days post instillation, (ii) emphysema is stable for at least 12 weeks and (iii) pulmonary hypertension is evident, in contrast to smoke models, only after emphysema development. Oral treatment with the iNOS inhibitor N(6)-(1-iminoethyl)-L-lysine (L-NIL) was started after Abbreviations: COPD, chronic obstructive pulmonary disease; GOLD, global initiative for chronic obstructive lung disease; iNOS, inducible NOS; L-NIL, N(6)-(1-iminoethyl)-L-lysine; LV, left ventricle; MLI, mean linear intercept; ONOO-, peroxynitrite; PBGD, porphobilinogen deaminase; PH, pulmonary hypertension; PPE, porcine pancreatic elastase; RV, right ventricle; RVSP, right ventricular systolic pressure; S, Septum. Athanasios Fysikopoulos, Michael Seimetz, Norbert Weissmann and Simone Kraut have equal contribution.Br J Pharmacol. 2020;1-20.wileyonlinelibrary.com/journal/bph 1 emphysema establishment and continued for 12 weeks. This resulted in significant lung regeneration, evident in the improvement of emphysema and reversal of pulmonary hypertension. Conclusion and Implications:Our data indicate that iNOS is a potential new therapeutic target to treat severe emphysema and associated pulmonary hypertension.

The effect of long-term doxycycline treatment in a mouse model of cigarette smoke-induced emphysema and pulmonary hypertension

“…cessation of smoke exposure in a follow-up period of 3 mo (4, 5). Intriguingly, a 3-mo treatment with an iNOS inhibitor or a guanylate cyclase activator could fully or partially reverse such changes, respectively (4,5,49), proving that curative treatment in this model can be achieved. We here took advantage of this model of established CS-induced emphysema and PH to investigate the effects of a subsequent doxycycline treatment on the lung and heart function.…”

“…Thus, when emphysema is already developed, our results suggest that doxycycline-mediated MMPs inhibition is not sufficient for lung regeneration. Nevertheless, in therapeutic approaches, MMP activity and expression might be an indicator/biomarker for emphysema and PH reversal (4,5,49).…”

Nitric Oxide System and Bronchial Epithelium: More Than a Barrier

“…There are disparate results seen for the treatment of emphysema and asthma patients with iNOS inhibitors. In a mouse model with emphysema, after the inhibition of iNOS was observed a significant regeneration of the lung ( Fysikopoulos et al, 2020 ), but these results contrast with those obtained by the group of Boyer et al (2011) in which inhibition of iNOS activity reduced protein nitration and protein oxidation without effect on inflammation, proliferation, and development of emphysema. These discrepant results are probably due to the degree of damage provoked by the elastase treatment applied to induce emphysema and the time of treatment with the iNOS inhibitor.…”

“…In addition, iNOS expression is related to the degree of airflow limitation in the airways ( Ghosh et al, 2006 ; Jiang et al, 2015 ; Ricciardolo et al, 2015 ; Bartesaghi and Radi, 2018 ). The group of Fysikopoulos et al (2020) established a mouse model of emphysema by treatment with elastase, and after pharmacological inhibition of iNOS, it demonstrated a partial regeneration of the parenchyma, so there is a relationship between increased expression of the enzyme and the appearance of emphysema, although it would not be the only cause.…”

Pulmonary hypertension with 2020 vision

“…Gassmann et al (2020) have looked at studies of high‐altitude pulmonary hypertension for insights in the regulation of the pulmonary circulation, in particular, at experiments of nature for clues to key regulatory pathways. Gredic et al (2020) delve into the association of pulmonary hypertension with chronic obstructive airway disease and Fysikopoulos et al (2020) have investigated inducible nitric oxide synthase (iNOS) as a potential new therapeutic target to treat severe emphysema and associated pulmonary hypertension. Rajagopal et al (2020) consider pulmonary hypertension in the setting of idiopathic pulmonary fibrosis, and Fu et al (2020) report on the potential of immune checkpoint inhibitor therapy as a viable therapeutic option.…”