Inducible NOS inhibition reverses tobacco-smoke-induced emphysema and pulmonary hypertension in mice.

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.

Palliative care of older glioblastoma patients in neurosurgery.

PURPOSE: The care of older neurosurgical patients at the end life is a particularly demanding challenge. Especially, the specific needs of very old patients with glioblastoma at the end of life are at risk of being deprived of adequate care. METHODS: Based on a narrative literature review, this article aims to explore key issues of the thematic intersection of geriatric glioblastoma patients, palliative care and neurosurgery. RESULTS AND DISCUSSION: Four key issues were identified: patient-centeredness (need orientation and decision making), early palliative care, advance care planning, and multi-professionalism. Possible benefits and barriers are highlighted with regard to integrating these concepts into neurosurgery. CONCLUSIONS: Palliative care complements neurosurgical care of geriatric glioblastoma multiforme patients to optimise care for this highly vulnerable category of patients.

Outpatient palliative care during the COVID-19 pandemic: a retrospective single centre analysis in Germany.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has challenged health care systems worldwide. In Germany, patients in a palliative care setting have the opportunity to receive treatment by a specialised mobile outpatient palliative care team (OPC). The given retrospective single centre analysis describes the use of OPC structures for terminally ill COVID-19 patients during the height of the pandemic in Germany and aims to characterise this exceptional OPC patient collective. METHODS: First, death certificates were analysed in order to collect data about the place of death of all deceased COVID-19 patients (n = 471) within our local governance district. Second, we investigated whether advance care planning structures were established in local nursing homes (n = 30) during the height of the COVID-19 pandemic in 2020. Third, we examined patient characteristics of COVID-19 negative (n = 1579) and COVID-19 positive (n = 28) patients treated by our tertiary care centre guided OPC service. RESULTS: The analysis of death certificates in our local district revealed that only 2.1% of all deceased COVID-19 patients had succumbed at their home address (n = 10/471). In contrast, 34.0% of COVID-19 patients died in nursing homes (n = 160/471), whereas 63.5% died in an inpatient hospital setting (n = 299/471). A large proportion of these hospitalised patients died on non-intensive care unit wards (38.8%). Approximately 33.0% of surveyed nursing homes had a palliative care council service and 40.0% of them offered advance care planning (ACP) structures for their nursing home residents. In our two OPC collectives we observed significant differences concerning clinical characteristics such as the Index of Eastern Cooperative Oncology Group [ECOG] (p = 0.014), oncologic comorbidity (p = 0.004), as well as referrer and primary patient location (p = 0.001, p = 0.033). CONCLUSIONS: Most COVID-19 patients in our governance district died in an inpatient setting. However, the highest number of COVID-19 patients in our governance district who died in an outpatient setting passed away in nursing homes where palliative care structures should be further expanded. COVID-19 patients who died under the care of our OPC service had considerably fewer oncologic comorbidities. Finally, to relieve conventional health care structures, we propose the expansion of established OPC structures for treating terminally ill COVID-19 patients.

Poor sleep quality is associated with exercise limitation in precapillary pulmonary hypertension.

BACKGROUND: Patients with precapillary pulmonary hypertension (PH) have been reported to suffer from poor sleep quality, however, if this is related to physical exercise performance has not yet been thoroughly investigated. METHODS: Clinically stable out-patients with idiopathic pulmonary arterial hypertension (IPAH, n = 52) and chronic thromboembolic PH (CTEPH, n = 64) in NYHA classes II and III were prospectively enrolled. 54 healthy volunteers matched for anthropometric variables served as a control group. The Pittsburgh Sleep Quality Index (PSQI) was used to rate subjective sleep quality. In the PH patients, six-minute walk tests (6MWT) were performed to assess exercise capacity. RESULTS: Poor sleep quality (i.e. a PSQI score > 5) occurred more frequently in PH (IPAH: n = 25 [48.1%], CTEPH: n = 39 [60.9%], controls: n = 10 [18.5%]; p < 0.01 when compared to controls). In addition, poor vs. good sleepers had significantly higher average NYHA class (IPAH: 2.6 ± 0.1 vs. 2.3 ± 0.1, CTEPH: 2.8 ± 0.1 vs. 2.3 ± 0.2; p < 0.01) and shorter 6MWT distances (IPAH: 338 ± 23 vs. 441 ± 29 m, CTEPH: 355 ± 15 vs. 413 ± 26 m; p < 0.05). CONCLUSIONS: Self-reported poor sleep quality is more common in PH than in healthy controls. Furthermore, it is related to reduced physical exercise capacity.

Case Report: Durable therapy response to Osimertinib in rare EGFR Exon 18 mutated NSCLC.

Up to 20% of all non-small cell lung cancer patients harbor tumor specific driver mutations that are effectively treated with tyrosine kinase inhibitors. However, for the rare EGFR deletion-insertion mutation of exon 18, there is very little evidence regarding the effectiveness of tyrosine kinase inhibitors. A particular challenge for clinicians in applying tyrosine kinase inhibitors is not only diagnosing a mutation but also interpreting rare mutations with unclear therapeutic significance. Thus, we present the case of a 65-year-old Caucasian male lung adenocarcinoma patient with an EGFR Exon 18 p.Glu709_Thr710delinsAsp mutation of uncertain therapeutic relevance. This patient initially received two cycles of standard platinum-based chemotherapy without any therapeutic response. After administration of Osimertinib as second line therapy, the patient showed a lasting partial remission for 12 months. Therapy related toxicities were limited to mild thrombocytopenia, which ceased after dose reduction of Osimertinib. To our knowledge, this is the first report of effective treatment of this particular mutation with Osimertinib. Hence, we would like to discuss Osimertinib as a viable treatment option in EGFR Exon 18 p.Glu709_Thr710delinsAsp mutated lung adenocarcinoma.

Sleep-disordered breathing in deep vein thrombosis and acute pulmonary embolism.

Sleep-disordered breathing (SDB) may trigger thromboembolic events by enhancing intravascular clot formation. The primary objective of the present nested case-control study was to investigate whether the prevalence of SDB is increased in patients with deep vein thrombosis (DVT) and/or acute pulmonary embolism (PE). 82 consecutive patients with DVT and/or PE (cases) were prospectively enrolled irrespective of SDB-related symptoms and formed matched pairs with patients without DVT and/or PE (controls) according to sex and pre-defined categories of age and body mass index. The prevalence of SDB (respiratory disturbance index assessed by polygraphy ≥ 15 events·h(-1)) was significantly greater in the cases with DVT and/or PE than in controls (40 versus 26%, p=0.046) and was predominantly obstructive in nature. Multiple regression analysis revealed that SDB was significantly associated with DVT and/or PE (OR 2.28, 95% CI 1.08-4.85; p=0.032) independent of established risk factors for thrombosis. In the sex-specific analyses this association was significant in females (OR 4.14, 95% CI 1.05-16.36; p=0.042), but not in males (OR 1.55, 95% CI 0.57-4.21; p=0.391). SDB occurs more frequently in females with DVT and/or PE than in controls matched for anthropometric variables, and is independently associated with the occurrence of these thromboembolic events.

Activation of the WNT/ß-catenin pathway attenuates experimental emphysema.

RATIONALE: Chronic obstructive pulmonary disease (COPD) is a devastating disease, for which no causal therapy is available. OBJECTIVES: To characterize WNT/ß-catenin signaling in COPD in humans and elucidate its potential role as a preventive and therapeutic target in experimental emphysema in mice. METHODS: The expression, localization, and activity of WNT/ß-catenin signaling was assessed in 12 COPD and 12 transplant donor samples using quantitative reverse transcriptase polymerase chain reaction, immunohistochemistry, and Western blotting. The role of WNT/ß-catenin signaling was assessed in elastase- and cigarette smoke-induced emphysema and therapeutic modulation thereof in elastase-induced emphysema in TOPGAL reporter and wild-type mice in vivo. MEASUREMENTS AND MAIN RESULTS: No differences in the mRNA expression profile of the main WNT/ß-catenin signaling components were observed comparing COPD and donor lung homogenates. Immunohistochemical analysis revealed reduced numbers of nuclear ß-catenin-positive alveolar epithelial cells in COPD. Similarly, WNT/ß-catenin signaling was down-regulated in both experimental emphysema models. Preventive and therapeutic, WNT/ß-catenin activation by lithium chloride attenuated experimental emphysema, as assessed by decreased airspace enlargement, improved lung function, reduced collagen content, and elevated expression of alveolar epithelial cell markers. CONCLUSIONS: Decreased WNT/ß-catenin signaling is involved in parenchymal tissue destruction and impaired repair capacity in emphysema. These data indicate a crucial role of WNT/ß-catenin signaling in lung repair mechanisms in vivo, and highlight WNT/ß-catenin activation as a future therapeutic approach for emphysema.

Role of epidermal growth factor inhibition in experimental pulmonary hypertension.

RATIONALE: Epidermal growth factor (EGF) and its receptors play a role in cell proliferation and survival and are implicated in the pathobiology of pulmonary arterial hypertension (PAH). OBJECTIVES: To study the role of EGF inhibition on experimental pulmonary hypertension. METHODS: We investigated (1) the effects of three clinically approved EGF receptor (EGFR) antagonists in vitro on rat pulmonary arterial smooth muscle cell proliferation and in vivo on experimental pulmonary hypertension (PH) induced by monocrotaline injection in rats and by chronic hypoxia in mice, and (2) the expression of EGFR in the lung tissues from experimental and clinical PH. MEASUREMENTS AND MAIN RESULTS: The EGFR inhibitors gefitinib, erlotinib, and lapatinib inhibited the EGF-induced proliferation of pulmonary arterial smooth muscle cells. In rats with established PH, gefitinib and erlotinib significantly reduced right ventricular systolic pressure and right ventricular hypertrophy. In addition, the medial wall thickness and muscularization of pulmonary arteries were improved. In contrast, lapatinib did not provide therapeutic benefit. These EGFR antagonists at their highest tolerable dose did not yield significant improvement in right ventricular systolic pressure, right ventricular hypertrophy, and pulmonary vascular remodeling in mice with chronic hypoxic PH. Moreover, no significant alteration in the EGFR expression was detected in the lung tissues from patients with idiopathic PAH. CONCLUSIONS: The partial therapeutic efficacy of the EGFR antagonists in animal models of pulmonary hypertension and the absence of significant alteration in EGFR expression in the lungs from patients with idiopathic PAH suggest that EGFRs do not represent a promising target for the treatment of pulmonary hypertension.

Increased expression of 5-hydroxytryptamine2A/B receptors in idiopathic pulmonary fibrosis: a rationale for therapeutic intervention.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) has a poor prognosis and limited responsiveness to available treatments. It is characterised by epithelial cell injury, fibroblast activation and proliferation and extracellular matrix deposition. Serotonin (5-hydroxytryptamine; 5-HT) induces fibroblast proliferation via the 5-HTR(2A) and 5-HTR(2B) receptors, but its pathophysiological role in IPF remains unclear. A study was undertaken to determine the expression of 5-HT receptors in IPF and experimental lung fibrosis and to investigate the effects of therapeutic inhibition of 5-HTR(2A/B) signalling on lung fibrosis in vivo and in vitro. METHODS AND RESULTS: Quantitative RT-PCR showed that the expression of 5-HTR(1A/B) and 5-HTR(2B) was significantly increased in the lungs of patients with IPF (n=12) and in those with non-specific interstitial pneumonia (NSIP, n=6) compared with transplant donors (n=12). The expression of 5-HTR(2A) was increased specifically in IPF lungs but not in NSIP lungs. While 5-HTR(2A) protein largely localised to fibroblasts, 5-HTR(2B) localised to the epithelium. To assess the effects of 5HTR(2A/B) inhibition on fibrogenesis in vivo, mice were subjected to bleomycin-induced lung fibrosis and treated with the 5-HTR(2A/B) antagonist terguride (or vehicle) in a therapeutic approach (days 14-28 after bleomycin). Terguride-treated mice had significantly improved lung function and histology and decreased collagen content compared with vehicle-treated mice. Functional in vitro studies showed that terguride is a potent inhibitor of transforming growth factor ß(1)- or WNT3a-induced collagen production. CONCLUSION: The studies revealed an increased expression of 5-HTR(2A) specifically in IPF. Blockade of 5-HTR(2A/B) signalling by terguride reversed lung fibrosis and is thus a promising therapeutic approach for IPF.

Effects of phosphodiesterase 4 inhibition on bleomycin-induced pulmonary fibrosis in mice.

BACKGROUND: Pulmonary fibrosis (PF) is a group of devastating and largely irreversible diseases. Phosphodiesterase (PDE) 4 is involved in the processes of remodeling and inflammation, which play key role in tissue fibrosis. The aim of the study was, therefore, to investigate the effect of PDE4 inhibition in experimental model of PF. METHODS: PF was induced in C57BL/6N mice by instillation of bleomycin. Pharmacological inhibition of PDE4 was achieved by using cilomilast, a selective PDE4 inhibitor. Changes in either lung inflammation or remodeling were evaluated at different stages of experimental PF. Lung inflammation was assessed by bronchoalveolar lavage fluid (BALF) differential cell count and reverse transcription quantitative polymerase chain reaction (RT-qPCR) for inflammatory cytokines. Changes in tissue remodeling were evaluated by pulmonary compliance measurement, quantified pathological examination, measurement of collagen deposition and RT-qPCR for late remodeling markers. Survival in all groups was analyzed as well. RESULTS: PDE4 inhibition significantly reduced the total number of alveolar inflammatory cells in BALF of mice with bleomycin-induced PF at early fibrosis stage (days 4 and 7). Number of macrophages and lymphocytes, but not neutrophils, was significantly reduced as well. Treatment decreased lung tumor necrosis factor (TNF)-alpha mRNA level and increased mRNA level of interleukin (IL)-6 but did not influence IL-1 beta. At later stage (days 14 and 24) cilomilast improved lung function, which was shown by increase in lung compliance. It also lowered fibrosis degree, as was shown by quantified pathological examination of Hematoxilin-Eosin stained lung sections. Cilomilast had no significant effect on the expression of late remodeling markers such as transforming growth factor (TGF)-beta1 and collagen type Ia1 (COL(I)alpha1). However, it tended to restore the level of lung collagen, assessed by SIRCOL assay and Masson's trichrome staining, and to improve the overall survival. CONCLUSIONS: Selective PDE4 inhibition suppresses early inflammatory stage and attenuates the late stage of experimental pulmonary fibrosis.

Changes in Pain Medication Profile among Patients Admitted to Specialized Home Palliative Care in Relation to Referral Source: An Exploratory Study.

Pain is a common symptom leading to referrals to specialized home palliative care (SHPC) services and is known to affect patients' quality of life. To date, little is known about the impact of referral source on its management. To assess changes to pain medication profile in the course of SHPC and to identify potential differences in relation to referral source. This exploratory study is a retrospective analysis of 501 electronic medical records of a SHPC team in Germany. This included the assessment of baseline pain medication profiles according to the WHO analgesic ladder and changes to analgesic treatment in the course of SHPC with respect to referral source. At the time of admission, 77.4% of patients referred by a hospital and 78.8% of patients referred by the outpatient sector received a fixed analgesic regimen. In all, 61.9% of the inpatient group versus 62.9% of the outpatient group were treated with opioids, and 79.0% received modifications to pain medication at one point in time following admission. Thereby, patients referred by the outpatient sector received significantly earlier modifications and more supplementations of pain medication. Our study suggests positive development in the prescription of opioid analgesics compared to earlier studies in Germany. On the one hand, it highlights the relevance of thorough assessment and responsive evaluation of pain in SHPC, and on the other hand it reveals possible training needs of referring physicians, particularly those working in the outpatient sector. Our results inspired further research examining more closely the links between referral source and pain management.

The soluble guanylate cyclase activator HMR1766 reverses hypoxia-induced experimental pulmonary hypertension in mice.

Severe pulmonary hypertension (PH) is a disabling disease with high mortality, characterized by pulmonary vascular remodeling and right heart hypertrophy. In mice with PH induced by chronic hypoxia, we examined the acute and chronic effects of the soluble guanylate cyclase (sGC) activator HMR1766 on hemodynamics and pulmonary vascular remodeling. In isolated perfused mouse lungs from control animals, HMR1766 dose-dependently inhibited the pressor response of acute hypoxia. This dose-response curve was shifted leftward when the effects of HMR1766 were investigated in isolated lungs from chronic hypoxic animals for 21 days at 10% oxygen. Mice exposed for 21 or 35 days to chronic hypoxia developed PH, right heart hypertrophy, and pulmonary vascular remodeling. Treatment with HMR1766 (10 mg x kg(-1) x day(-1)), after full establishment of PH from day 21 to day 35, significantly reduced PH, as measured continuously by telemetry. In addition, right ventricular (RV) hypertrophy and structural remodeling of the lung vasculature were reduced. Pharmacological activation of oxidized sGC partially reverses hemodynamic and structural changes in chronic hypoxia-induced experimental PH.

Phosphodiesterase 1 upregulation in pulmonary arterial hypertension: target for reverse-remodeling therapy.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a life-threatening disease, characterized by vascular smooth muscle cell hyperproliferation. The calcium/calmodulin-dependent phosphodiesterase 1 (PDE1) may play a major role in vascular smooth muscle cell proliferation. METHODS AND RESULTS: We investigated the expression of PDE1 in explanted lungs from idiopathic PAH patients and animal models of PAH and undertook therapeutic intervention studies in the animal models. Strong upregulation of PDE1C in pulmonary arterial vessels in the idiopathic PAH lungs compared with healthy donor lungs was noted on the mRNA level by laser-assisted vessel microdissection and on the protein level by immunohistochemistry. In chronically hypoxic mouse lungs and lungs from monocrotaline-injected rats, PDE1A upregulation was detected in the structurally remodeled arterial muscular layer. Long-term infusion of the PDE1 inhibitor 8-methoxymethyl 3-isobutyl-1-methylxanthine in hypoxic mice and monocrotaline-injected rats with fully established pulmonary hypertension reversed the pulmonary artery pressure elevation, structural remodeling of the lung vasculature (nonmuscularized versus partially muscularized versus fully muscularized small pulmonary arteries), and right heart hypertrophy. CONCLUSIONS: Strong upregulation of the PDE1 family in pulmonary artery smooth muscle cells is noted in human idiopathic PAH lungs and lungs from animal models of PAH. Inhibition of PDE1 reverses structural lung vascular remodeling and right heart hypertrophy in 2 animal models. The PDE1 family may thus offer a new target for therapeutic intervention in pulmonary hypertension.

Effects of cell-penetrating peptides and pegylation on transfection efficiency of polyethylenimine in mouse lungs.

BACKGROUND: Cell-penetrating peptides (CPPs) could potentially be used as vectors for intracellular delivery of proteins, peptides and nucleic acids. The present study examined different CPPs, such as TAT-derived and arginine rich sequences, as well as model amphiphilic peptide, with respect to transfection efficiency of pegylated polyethylenimine (PEI) in A549, Calu-3 cells and in mice after intra-tracheal administration. METHODS: The conjugates were prepared by the coupling of CPPs to PEI via a heterobifunctional polyethylene glycol (PEG) linker, resulting in the bioconjugates CPP-PEG-PEI. Structures were successfully confirmed by (1)H-nuclear magnetic resonance and diffusion-ordered spectroscopy. Unmodified PEI 25 kDa was compared with pegylated PEI, and aggregation tendency in cell culture medium, interaction with mucin and stability against heparin was assayed. After evaluating transfection efficiency of the polymers in two different lung cell lines, luciferase reporter gene expression was determined in mouse lungs. RESULTS: All conjugates showed superior transfection efficiency compared to unmodified PEI 25 kDa. The conjugates sizes were generally < 300 nm, thus enabling them to penetrate through the mucus lining of the lung and reach the target cells. Coupling of CPPs to PEG-PEI, however, did not significantly improve transfection efficiency in A549 cells, calu-3 cells and in mouse lungs. CONCLUSIONS: We show that small and stable polyplex size achieved by pegylation is favourable for successful pulmonary gene delivery. Compared to PEI 25 kDa, pegylated PEI and CPP-PEG-PEI displayed enhanced transfection efficiency both in vitro and in vivo.

Dysregulated bone morphogenetic protein signaling in monocrotaline-induced pulmonary arterial hypertension.

BACKGROUND: Mutations in the bmpr2 gene, encoding the type II bone morphogenetic protein (BMP) receptor, have been identified in patients with pulmonary arterial hypertension (PAH), implicating BMP signaling in PAH. The aim of this study was to assess BMP signaling and its physiological effects in a monocrotaline (MCT) model of PAH. METHODS AND RESULTS: Expression of BMP receptors Ib and II, and Smads 4, 5, 6, and 8, was downregulated in lungs but not kidneys of MCT-treated rats. Smad1 phosphorylation and expression of BMP/Smad target genes id1 and id3 was also reduced, although ERK1/2 and p38(MAPK) phosphorylation remained unaffected. BMP receptor and Smad expression, Smad1 phosphorylation, and induction of the BMP/Smad-responsive element of the id1 promoter were reduced in pulmonary artery smooth muscle cells (PASMCs) from MCT-treated rats. As a consequence of impaired BMP/Smad signaling, PASMCs from MCT-treated rats were resistant to apoptosis induced by BMP-4 and BMP-7, and were also resistant to BMP-4 antagonism of proliferation induced by platelet-derived growth factor. CONCLUSION: BMP signaling and BMP-regulated physiological phenomena are perturbed in MCT-treated rats, lending solid support to the proposed roles for BMP signaling in the pathogenesis of human PAH.

Characterization of a murine model of monocrotaline pyrrole-induced acute lung injury.

BACKGROUND: New animal models of chronic pulmonary hypertension in mice are needed. The injection of monocrotaline is an established model of pulmonary hypertension in rats. The aim of this study was to establish a murine model of pulmonary hypertension by injection of the active metabolite, monocrotaline pyrrole. METHODS: Survival studies, computed tomographic scanning, histology, bronchoalveolar lavage were performed, and arterial blood gases and hemodynamics were measured in animals which received an intravenous injection of different doses of monocrotaline pyrrole. RESULTS: Monocrotaline pyrrole induced pulmonary hypertension in Sprague Dawley rats. When injected into mice, monocrotaline pyrrole induced dose-dependant mortality in C57Bl6/N and BALB/c mice (dose range 6-15 mg/kg bodyweight). At a dose of 10 mg/kg bodyweight, mice developed a typical early-phase acute lung injury, characterized by lung edema, neutrophil influx, hypoxemia and reduced lung compliance. In the late phase, monocrotaline pyrrole injection resulted in limited lung fibrosis and no obvious pulmonary hypertension. CONCLUSION: Monocrotaline and monocrotaline pyrrole pneumotoxicity substantially differs between the animal species.

Activation of soluble guanylate cyclase reverses experimental pulmonary hypertension and vascular remodeling.

BACKGROUND: Severe pulmonary hypertension is a disabling disease with high mortality, characterized by pulmonary vascular remodeling and right heart hypertrophy. Using wild-type and homozygous endothelial nitric oxide synthase (NOS3(-/-)) knockout mice with pulmonary hypertension induced by chronic hypoxia and rats with monocrotaline-induced pulmonary hypertension, we examined whether the soluble guanylate cyclase (sGC) stimulator Bay41-2272 or the sGC activator Bay58-2667 could reverse pulmonary vascular remodeling. METHODS AND RESULTS: Both Bay41-2272 and Bay58-2667 dose-dependently inhibited the pressor response of acute hypoxia in the isolated perfused lung system. When wild-type (NOS3(+/+)) or NOS3(-/-) mice were housed under 10% oxygen conditions for 21 or 35 days, both strains developed pulmonary hypertension, right heart hypertrophy, and pulmonary vascular remodeling, demonstrated by an increase in fully muscularized peripheral pulmonary arteries. Treatment of wild-type mice with the activator of sGC, Bay58-2667 (10 mg/kg per day), or the stimulator of sGC, Bay41-2272 (10 mg/kg per day), after full establishment of pulmonary hypertension from day 21 to day 35 significantly reduced pulmonary hypertension, right ventricular hypertrophy, and structural remodeling of the lung vasculature. In contrast, only minor efficacy of chronic sGC activator therapies was noted in NOS3(-/-) mice. In monocrotaline-injected rats with established severe pulmonary hypertension, both compounds significantly reversed hemodynamic and structural changes. CONCLUSIONS: Activation of sGC reverses hemodynamic and structural changes associated with monocrotaline- and chronic hypoxia-induced experimental pulmonary hypertension. This effect is partially dependent on endogenous nitric oxide generated by NOS3.

Arterial hypertension in a murine model of sleep apnea: role of NADPH oxidase 2.

OBJECTIVES: To investigate whether NADPH oxidase 2 (NOX2), a major source of reactive oxygen species (ROS), contributes to the emergence of arterial hypertension in a murine model of sleep apnea. BACKGROUND: Obstructive sleep apnea (OSA) is a risk factor for arterial hypertension and it is linked to oxidative stress. METHODS: C57BL/6J mice were exposed to chronic intermittent hypoxia (CIH) for 6 weeks (5 days/week, 8 h/day, alternating cycles of hypoxia and normoxia, each lasting 120 s, nadir FiO2: 7%). Blood pressure was monitored by telemetric catheters implanted into the abdominal aorta. Pharmacological inhibition of NOX by apocynin and NOX2-deficient mice were used to assess the role of NOX in CIH-induced arterial hypertension. NOX2 gene expression was measured by real-time PCR in different cardiovascular tissues. RESULTS: When compared with room air conditions, wild-type mice showed significant blood pressure elevations after exposure to CIH. This response was attenuated after treating animals with apocynin and in NOX2 (=gp91) knockout mice, whereas NOX2 was not upregulated in the heart, aorta, and femoral/carotid arteries of CIH mice. CONCLUSION: We suggest that the CIH-induced arterial hypertension is mediated by ROS derived from an activation of NOX2 within cells located outside the cardiovascular system.

Obstructive sleep apnea, oxidative stress and cardiovascular disease: lessons from animal studies.

Obstructive sleep apnea (OSA) is an independent risk factor for cardiovascular (CV) diseases such as arterial hypertension, heart failure, and stroke. Based on human research, sympathetic activation, inflammation, and oxidative stress are thought to play major roles in the pathophysiology of OSA-related CV diseases. Animal models of OSA have shown that endothelial dysfunction, vascular remodelling, and systemic and pulmonary arterial hypertension as well as heart failure can develop in response to chronic intermittent hypoxia (CIH). The available animal data are clearly in favour of oxidative stress playing a key role in the development of all of these CV manifestations of OSA. Presumably, the oxidative stress is due to an activation of NADPH oxidase and other free oxygen radicals producing enzymes within the CV system as evidenced by data from knockout mice and pharmacological interventions. It is hoped that animal models of OSA-related CV disease will continue to contribute to a deeper understanding of their underlying pathophysiology and will foster the way for the development of cardioprotective treatment options other than conventional CPAP therapy.