Amelioration of elastase-induced lung emphysema and reversal of pulmonary hypertension by pharmacological iNOS inhibition in mice.
Chronic obstructive pulmonary disease (COPD), 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 nitric oxide synthase (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 (PH) 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.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 PH-development was determined by structural and functional measurements.Our data revealed that 1) emphysema is fully established after 21 days, with the same degree of emphysema after 21 and 28 days post instillation, 2) emphysema is stable for at least 12 weeks and 3) PH 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), started after emphysema establishment – and continued for 12 weeks – resulted in significant lung regeneration, evident from improvement of emphysema and reversal of PH.Our data indicate that iNOS is a potential new therapeutic target to treat severe emphysema and associated PH.