[Show abstract][Hide abstract] ABSTRACT: Chronic obstructive pulmonary disease (COPD) is a major cause of death worldwide. No therapy stopping progress of the disease is available.
To investigate the role of the soluble guanylate cyclase (sGC)-cGMP axis in development of lung emphysema and pulmonary hypertension (PH) and to test whether the sGC-cGMP axis is a treatment target for these conditions.
Investigations were performed in human lung tissue from COPD patients, healthy donors, mice, and guinea pigs. Mice were exposed to cigarette smoke (CS) for 6 hours/day, 5 days/week for up to 6 months and treated with BAY 63-2521. Guinea pigs were exposed to CS from 6 cigarettes/day for 3 months, 5 days/week and treated with BAY 41-2272. Both BAY compounds are sGC stimulators. Gene and protein expression analysis were performed by quantitative real-time PCR and western blotting. Lung compliance, hemodynamics, right ventricular heart mass alterations, alveolar and vascular morphometry were performed, as well as inflammatory cell infiltrate assessment. In vitro assays of cell adhesion, proliferation and apoptosis have been done.
The functionally essential sGC β1-subunit was downregulated in COPD patients and in CS-exposed mice. sGC stimulators prevented the development of PH and emphysema in the two different CS-exposed animal models. sGC stimulation prevented peroxynitrite-induced apoptosis of alveolar and endothelial cells, reduced CS-induced inflammatory cell infiltrate in lung parenchyma and inhibited adhesion of CS-stimulated neutrophils.
The sGC-cGMP axis is perturbed by chronic exposure to CS. Treatment of COPD animal models with sGC stimulators can prevent CS-induced PH and emphysema.
American Journal of Respiratory and Critical Care Medicine 04/2014; · 11.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Chronic obstructive pulmonary disease (COPD) is one of the most common causes of death worldwide. We report in an emphysema model of mice chronically exposed to tobacco smoke that pulmonary vascular dysfunction, vascular remodeling, and pulmonary hypertension (PH) precede development of alveolar destruction. We provide evidence for a causative role of inducible nitric oxide synthase (iNOS) and peroxynitrite in this context. Mice lacking iNOS were protected against emphysema and PH. Treatment of wild-type mice with the iNOS inhibitor N(6)-(1-iminoethyl)-L-lysine (L-NIL) prevented structural and functional alterations of both the lung vasculature and alveoli and also reversed established disease. In chimeric mice lacking iNOS in bone marrow (BM)-derived cells, PH was dependent on iNOS from BM-derived cells, whereas emphysema development was dependent on iNOS from non-BM-derived cells. Similar regulatory and structural alterations as seen in mouse lungs were found in lung tissue from humans with end-stage COPD.
[Show abstract][Hide abstract] ABSTRACT: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Cigarette smoking has been identified as one of the major risk factors and several predisposing genetic factors have been implicated in the pathogenesis of COPD, including a single nucleotide polymorphism (SNP) in the latent transforming growth factor (TGF)-beta binding protein 4 (Ltbp4)-encoding gene. Consistent with this finding, mice with a null mutation of the short splice variant of Ltbp4 (Ltbp4S) develop pulmonary emphysema that is reminiscent of COPD. Here, we report that the mutational inactivation of the antioxidant protein sestrin 2 (sesn2) partially rescues the emphysema phenotype of Ltbp4S mice and is associated with activation of the TGF-beta and mammalian target of rapamycin (mTOR) signal transduction pathways. The results suggest that sesn2 could be clinically relevant to patients with COPD who might benefit from antagonists of sestrin function.
Disease Models and Mechanisms 01/2010; 3(3-4):246-53. · 4.96 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Hypoxic pulmonary vasoconstriction (HPV) is an important mechanism by which pulmonary gas exchange is optimized by the adaptation of blood flow to alveolar ventilation. In chronic hypoxia, in addition to HPV a vascular remodeling process leads to pulmonary hypertension. A complex of heme oxygenase-2 (HO-2) and the BK channel has been suggested as a universal oxygen sensor system.
We investigated whether this complex serves as an oxygen sensor for the vascular effects of alveolar hypoxia in the lung.
The investigations were performed in chronically hypoxic mice, in isolated perfused and ventilated lungs, and on the cellular level, including HO-2- and BK-channel deficient mice.
Immunohistochemical analysis of mouse lungs identified HO-2 mainly in pulmonary arteries, the bronchial epithelium, and alveolar epithelial cells. BK channel alpha-subunit (BKalpha) immunoreactivity was found primarily in the bronchial and vascular smooth muscle layer. Immunofluorescence staining and coimmunoprecipitation suggested only a weak complexation of HO-2 and BKalpha in pulmonary arterial smooth muscle cells. The strength of acute and sustained HPV, determined in isolated perfused and ventilated lungs, was not different among wild-type, HO-2-deficient, and BKalpha-deficient mice. Exposure of mice to 3 weeks of chronic hypoxia resulted in a slight down-regulation of HO-2 and no alteration in BKalpha expression. The degree of pulmonary hypertension that developed, quantified on the basis of right ventricular pressure, right-heart hypertrophy, and the degree of muscularization of precapillary pulmonary arteries, was not different among wild-type, HO-2-deficient, and BKalpha-deficient mice.
It is demonstrated that neither deletion of HO-2 nor BK channels affect acute, sustained, and chronic vascular responses to alveolar hypoxia in the lung.
American Journal of Respiratory and Critical Care Medicine 07/2009; 180(4):353-64. · 11.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Chronic obstructive pulmonary disease is a major cause of high morbidity and mortality with a high socioeconomic burden worldwide. The contribution of vascular alterations to the pathogenesis of the disease remains controversial and there is still ongoing debate about the possible development of pulmonary hypertension in COPD. Against this background, the current thesis aimed to decipher the time course for the development of lung emphysema as well as vascular alterations to the pulmonary circulation by use of a mouse model of tobacco smokeinduced COPD. For this purpose, WT mice were exposed for up to eight months to tobacco smoke (6 h/day, 5 days/week). It was demonstrated that both vascular structural and functional alterations occurred, including loss of pulmonary vessels, narrowing of vascular lumen, an increased degree of muscularization, pulmonary hypertension as well as endothelial dysfunction. Against the background, it was hypothesized that oxidative as well nitrosative stress plays a major role to the development of COPD by the regulation of inducible as well as the endothelial NO synthases. An upregulation of the inducible nitric oxide synthase (iNOS) was found in the pulmonary vasculature concomitant with increased nitrotyrosine levels. Comparing the development of vascular alteration and emphysema in WT, iNOS/, and eNOS/ mice, this study found that iNOS/ were completely protected from these structural and functional changes. Moreover, the same effect was observed by the treatment of wild-type mice with the iNOS inhibitor L-NIL. Similar regulatory processes and structural alterations as for tobacco smoke exposed mice were found in GOLD stage IV for explanted COPD patient lungs. Thus, iNOS inhibition may be a strategy for prevention of COPD in the future. COPD ist weltweit eine der wichtigsten Ursachen für hohe Morbidität und Mortalität mit hoher sozioökonomischer Bedeutung. Der Beitrag von vaskulären Veränderungen zur Pathogenese der COPD ist derzeit umstritten und es besteht eine laufende Debatte über die mögliche Entwicklung und Bedeutung der pulmonalen Hypertonie in der COPD. Vor diesem Hintergrund, war das Ziel der vorliegenden Arbeit, den zeitlichen Verlauf der Emphysementwicklung und der vaskulären Veränderungen anhand des Mausmodells der Tabakrauch induzierten COPD zu entschlüsseln. Für diesen Zweck wurden Wildtyp-Mäuse für acht Monate Tabak-Rauch für 6 Stunden/Tag und 5 Tage/Woche ausgesetzt. Es konnte gezeigt werden, dass sowohl strukturelle als auch funktionelle Gefäßveränderungen stattfinden, einschließlich des Verlusts der Lungengefäße, der Verengung des Gefäßlumens, des erhöhten Muskularisierungsgrades von Gefäßen, pulmonaler Hypertonie und endothelialer Dysfunktion. Basierend auf diesen Beobachtungen, wurde die Hypothese aufgestellt, dass oxidativer so wie nitrosativer Stress eine wichtige Rolle bei der Entwicklung von COPD spielen, indem es zu einer Regulation von induzierbaren und endothelialen NO-Synthasen kommt. Tatsächlich konnte in der vorliegenden Arbeit im pulmonalen Gefäßsystem eine Hochregulierung der induzierbaren NO Synthase (iNOS) nachgewiesen werden, einhergehend mit erhöhtem Vorkommen von Nitrotyrosin. Durch den Vergleich der Entwicklung von Gefäßveränderungen und der Emphysementwicklung in Wildtyp-, iNOS-/-- und eNOS-/-- Mäusen, konnte diese Studie zeigen, dass iNOS/ -Mäuse vor den genannten strukturellen und funktionellen Änderungen komplett geschützt waren. Darüber hinaus, konnte der gleiche Effekt nach Behandlung von Wildtyp-Mäusen mit dem iNOS Inhibitor L-NIL beobachtet werden. Ähnliche regulatorische Prozesse und strukturelle Veränderungen wie in den Wildtyp-Mauslungen nach Rauchexposition wurden in Resektaten von Lungen von Patienten mit COPD(GOLD stage IV) nachgewiesen. Demnach könnte die Inhibierung von iNOS in Zukunft eine Strategie zur COPD Prävention darstellen.