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Sotatercept acts as a type IIA-Fc activin receptor, thereby scavenging free activin from its physiological membrane receptor. Through this type of action, sotaterpect leads to a rebalancing of the proliferation and antiproliferation pathways of pulmonary smooth muscle cells in response to bone morphogenic protein (BMP). Although sotatercept has been approved as the fourth pillar of therapy for group 1 pulmonary arterial hypertension (PAH) in the United States and Europe, several studies are ongoing to broaden the application of the drug to non-Group 1 PAH. We provide an overview of the clinical and preclinical evidence of targeting the activation pathway by sotatercept in the treatment of PAH. We also discuss other potential applications of sotatercept in the context of pulmonary hypertension other than PAH group 1. [ABSTRACT FROM AUTHOR]

The viral infectious disease pandemic caused by SARS-CoV-2 has affected over 500 million people and killed over 6 million. This is the official data provided by the WHO as of the end of May 2022. Among people who have recovered from COVID-19, post-COVID syndrome is quite common. Scattered epidemiological studies on post-COVID syndrome, however, indicate its high relevance. One of the manifestations of post-COVID syndrome is the development of pulmonary fibrosis (PF). This article is devoted to the analysis of literature data on epidemiology, immunomorphology, as well as X-ray morphological and functional characteristics of PF in patients with post-COVID syndrome. Attention is drawn to the various phenotypes of the post-COVID syndrome and the incidence of PF, which, as clinical practice shows, is most common in people who have had severe COVID-19. This article discusses in detail the molecular biological and immunological mechanisms of PF development. The fibrotic process of the lung parenchyma is not an early manifestation of the disease; as a rule, radiomorphological signs of this pathological process develop after four weeks from the onset of acute manifestations of a viral infection. The characteristic signs of PF include those that indicate the process of remodulation of the lung tissue: volumetric decrease in the lungs, cellular degeneration of the lung parenchyma, bronchiectasis and traction bronchiolectasis. The process of remodulating the lung tissue, in the process of fibrosis, is accompanied by a violation of the lung function; a particularly sensitive test of functional disorders is a decrease in the diffusion capacity of the lung tissue. Therefore, in the process of monitoring patients with post-COVID syndrome, a dynamic study of the ventilation function of the lungs is recommended. The main clinical manifestation of PF is dyspnea that occurs with minimal exertion. Shortness of breath also reflects another important aspect of fibrous remodulation of the lung parenchyma oxygen dissociation is disturbed, which reflects a violation of the gas exchange function of the lungs. There are no generally accepted treatments for PF in post-COVID syndrome. The literature considers such approaches as the possibility of prescribing antifibrotic therapy, hyaluronidase, and medical gases: thermal helium, nitric oxide, and atomic hydrogen. The article draws attention to the unresolved issues of post-covid PF in people who have had COVID-19.

Abstract MicroRNA-21 (miR-21), probably one of the most studied miRNAs to date, is found pleiotropic in various biological events. Its emerging role in pulmonary remodeling has attracted extensive attention. This review summarizes the genomic information of its primary transcript and various transcriptional regulations on its promoter. In addition, the role of miR-21 in pulmonary remodeling related signaling such as transforming growth factor β (TGF-β), bone morphogenetic protein (BMP), epidermal growth factor receptor (EGFR) and Notch signaling is discussed. Various validated miR-21 target genes participate in controlling of the overactive cell accumulation, smooth muscle contraction, inflammatory stress (trigger for lung epithelium damage), extracellular matrix deposition and hypoxia-induced disorders. Moreover, we focus on its particular implication in events including inflammatory stress-driven epithelium damage, epithelial-to-mesenchymal transition (EMT), transdifferentiation of fibroblasts into myofibroblasts, hypoxia stimuli and ROS response, as well as some other pulmonary remodeling related events such as overactive fibroblast (myofibroblast) accumulation, extracellular matrix deposition, and angiogenesis. Here, we summarize the strong potential of miR-21 in pulmonary remodeling and provide novel clues for further research in this area.

Widespread pulmonary destruction and fibrosis can be seen in end-stage pulmonary diseases. This situation causes vascular remodeling of the pulmonary circulation and pulmonary hypertension. Lung transplantation is an alternative treatment for end-stage pulmonary diseases. The purpose of this study is to research pathological vascular alterations retrospectively in explanted lungs with or without pulmonary hypertension. 57 explanted lungs were evaluated for occlusive intimal fibroelastosis, smooth muscle proliferation, medial hypertrophy, intimal cellular or fibrous thickening, hemosiderosis, plexiform lesion, angiomatoid lesion, arteriosclerosis, venopathy, capillary duplication and arteriovenous malformation. Both systolic and mean pulmonary artery pressures were defined. The relationship between vascular patterns and pulmonary hypertension was investigated. Pathological vascular alterations in explanted lungs with or without pulmonary hypertension included medial hypertrophy (80.71%), intimal cellular or fibrous thickening (80.7%), arteriosclerosis (77.19%), smooth muscle proliferation (55.3%) and arteriovenous malformation (50.3%). Hemosiderosis (12.5%), plexiform lesion (14%) and venopathy (21%) were less frequent pathological vascular alterations. Capillary duplication was common in secondary pulmonary hypertension and was statistically meaningful. Although medial hypertrophy and intimal thickness were seen in pulmonary hypertension, they can also be observed in end-stage pulmonary diseases without pulmonary hypertension. Interstitial capillary duplication was an important histopathological finding in end-stage lung diseases with pulmonary arterial hypertension. [ABSTRACT FROM AUTHOR]

Transforming growth factor (TGF)-β-induced myofibroblast transformation and alterations in mesenchymal-epithelial interactions contribute to chronic lung diseases such as chronic obstructive pulmonary disease (COPD), asthma and pulmonary fibrosis. Rho-associated coiled-coil-forming protein kinase (ROCK) consists as two isoforms, ROCK1 and ROCK2, and both are playing critical roles in many cellular responses to injury. In this study, we aimed to elucidate the differential role of ROCK isoforms on TGF-β signaling in lung fibrosis and repair. For this purpose, we tested the effect of a non-selective ROCK 1 and 2 inhibitor (compound 31) and a selective ROCK2 inhibitor (compound A11) in inhibiting TGF-β-induced remodeling in lung fibroblasts and slices; and dysfunctional epithelial-progenitor interactions in lung organoids. Here, we demonstrated that the inhibition of ROCK1/2 with compound 31 represses TGF-β-driven actin remodeling as well as extracellular matrix deposition in lung fibroblasts and PCLS, whereas selective ROCK2 inhibition with compound A11 did not. Furthermore, the TGF-β induced inhibition of organoid formation was functionally restored in a concentration-dependent manner by both dual ROCK 1 and 2 inhibition and selective ROCK2 inhibition. We conclude that dual pharmacological inhibition of ROCK 1 and 2 counteracts TGF-β induced effects on remodeling and alveolar epithelial progenitor function, suggesting this to be a promising therapeutic approach for respiratory diseases associated with fibrosis and defective lung repair.

Rationale: Lymphangioleiomyomatosis (LAM) is a metastatic neoplasm of reproductive-age women associated with mutations in tuberous sclerosis complex genes. LAM causes cystic remodeling of the lung and progressive respiratory failure. The sources and cellular characteristics of LAM cells underlying disease pathogenesis remain elusive.Objectives: Identification and characterization of LAM cells in human lung and uterus using a single-cell approach.Methods: Single-cell and single-nuclei RNA sequencing on LAM (n = 4) and control (n = 7) lungs, immunofluorescence confocal microscopy, ELISA, and aptamer proteomics were used to identify and validate LAMCORE cells and secreted biomarkers, predict cellular origins, and define molecular and cellular networks in LAM.Measurements and Main Results: A unique cell type termed LAMCORE was identified, which was distinct from, but closely related to, lung mesenchymal cells. LAMCORE cells expressing signature genes included known LAM markers such as PMEL, FIGF, CTSK, and MLANA and novel biomarkers validated by aptamer screening, ELISA, and immunofluorescence microscopy. LAM cells in lung and uterus are morphologically indistinguishable and share similar gene expression profiles and biallelic TSC2 mutations, supporting a potential uterine origin for the LAMCORE cell. Effects of LAM on resident pulmonary cell types indicated recruitment and activation of lymphatic endothelial cells.Conclusions: A unique population of LAMCORE cells was identified in lung and uterus of patients with LAM, sharing close transcriptomic identity. LAM cell selective markers, secreted biomarkers, and the predicted cellular molecular features provide new insights into the signaling and transcriptional programs that may serve as diagnostic markers and therapeutic targets to influence the pathogenesis of LAM. [ABSTRACT FROM AUTHOR]

Tissue matrix remodeling and fibrosis leading to loss of pulmonary arterial and right ventricular compliance are important features of both experimental and clinical pulmonary hypertension (PH). We have previously reported that transglutaminase 2 (TG2) is involved in PH development while others have shown it to be a cross-linking enzyme that participates in remodeling of extracellular matrix in fibrotic diseases in general. In the present studies, we used a mouse model of experimental PH (Sugen 5416 and hypoxia; SuHypoxia) and cultured primary human cardiac and pulmonary artery adventitial fibroblasts to evaluate the relationship of TG2 to the processes of fibrosis, protein cross-linking, extracellular matrix collagen accumulation, and fibroblast-to-myofibroblast transformation. We report here that TG2 expression and activity as measured by serotonylated fibronectin and protein cross-linking activity along with fibrogenic markers are significantly elevated in lungs and right ventricles of SuHypoxic mice with PH. Similarly, TG2 expression and activity, protein cross-linking activity, and fibrogenic markers are significantly increased in cultured cardiac and pulmonary artery adventitial fibroblasts in response to hypoxia exposure. Pharmacological inhibition of TG2 activity with ERW1041E significantly reduced hypoxia-induced cross-linking activity and synthesis of collagen 1 and α-smooth muscle actin in both the in vivo and in vitro studies. TG2 short interfering RNA had a similar effect in vitro. Our results suggest that TG2 plays an important role in hypoxia-induced pulmonary and right ventricular tissue matrix remodeling in the development of PH. [ABSTRACT FROM AUTHOR]

Pulmonary vascular remodeling is the key structural alteration in pulmonary hypertension and involves changes in the intima, media and adventitia, often with the interplay of inflammatory cells. This review examines the pathology of these changes and highlights some of the pathogenetic mechanisms that underlie the remodeling process. [ABSTRACT FROM AUTHOR]

The angiotensin-(1–7) [ANG-(1–7)]/Mas receptor pathway is currently recognized as a counterbalancing mechanism of the renin-angiotensin system in different pathophysiological conditions. We have previously described that treatment with ANG-(1–7) attenuates lung inflammation and remodeling in an experimental model of asthma. In the present study, we investigated whether lack of the Mas receptor could alter the inflammatory response in a model of chronic allergic lung inflammation induced by ovalbumin (OVA). Mas receptor wild-type (MasWT) and knockout (MasKO) mice were subjected to four doses of OVA (20 μg/mice ip) with a 14-day interval. At the 21st day, nebulization with OVA (1%) was started, three times per week until the 46th day. Control groups received saline (0.9% ip) and were nebulized with saline (0.9%). MasWT-OVA developed a modest inflammatory response and minor pulmonary remodeling to OVA challenge. Strikingly, MasKO-OVA presented a significant increase in inflammatory cell infiltrate, increase in extracellular matrix deposition, increase in thickening of the alveolar parenchyma, increase in thickening of the smooth muscle layer of the pulmonary arterioles, increase in proinflammatory cytokine and chemokine levels in the lungs, characteristic of chronic asthma. Additionally, MasKO-OVA presented an increase in ERK1/2 phosphorylation compared with MasWT-OVA. Furthermore, MasKO-OVA showed a worse performance in a test of maximum physical exercise compared with MasWT-OVA. Our study shows that effects triggered by the Mas receptor are important to attenuate the inflammatory and remodeling processes in a model of allergic lung inflammation in mice. Our data indicate that impairment of the ANG-(1–7)/Mas receptor pathway may lead to worsening of the pathophysiological changes of asthma. [ABSTRACT FROM AUTHOR]

Peroxisome proliferator-activated receptor (PPAR)-γ is reduced in pulmonary arteries (PAs) of patients with PA hypertension (PAH), and we reported that deletion of PPAR-y in smooth muscle cells (SMCs) of transgenic mice results in PAH. However, the sequelae of loss of PPAR-γ in PA endothelial cells (ECs) are unknown. Therefore, we bred Tie2-Cre mice with PPARγflox/flox mice to induce EC loss of PPARγ (Tie2 PPAR-γ-/-), and we assessed PAH by right ventricular systolic pressure (RVSP), RV hypertrophy (RVH), and muscularized distal PAs in room air (RA), after chronic hypoxia (CH), and after 4 wk of recovery in RA (Rec-RA). The Tie2 PPARγ-/- mice developed spontaneous PAH in RA with increased RVSP, RVH, and muscularized PAs vs. wild type (WT); both genotypes exhibited a similar degree of PAH following chronic hypoxia, but Tie2 PPARγ-/- mice had more residual PAH compared with WT mice after Rec-RA. The Tie2 PPARγ-/- vs. WT mice in RA had increased platelet-derived growth factor receptor-β (PDGF-Rβ) expression and signaling, despite an elevation in the PPARγ target apolipoprotein E, an inhibitor of PDGF signaling. Inhibition of PDGF-Rγ signaling with imatinib, however, was sufficient to reverse the PAH observed in the Tie2 PPARγ-/- mice. Thus the disruption of PPARγ signaling in EC is sufficient to cause mild PAH and to impair recovery from CH-induced PAH. Inhibition of heightened PDGF-Rβ signaling is sufficient to reverse PAH in this genetic model. [ABSTRACT FROM AUTHOR]

Recent evidence suggests that asthma leads to inflammation and remodeling not only in the airways but also in pulmonary vessels and parenchyma. In addition, some studies demonstrated that aerobic training decreases chronic allergic inflammation in the airways; however, its effects on the pulmonary vessels and parenchyma have not been previously evaluated. Our objective was to test the hypothesis that aerobic conditioning reduces inflammation and remodeling in pulmonary vessels and parenchyma in a model of chronic allergic lung inflammation. Balb/c mice were sensitized at days 0, 14, 28, and 42 and challenged with ovalbumin (OVA) from day 21 to day 50. Aerobic training started on day 21 and continued until day 50. Pulmonary vessel and parenchyma inflammation and remodeling were evaluated by quantitative analysis of eosinophils and mononuclear cells and by collagen and elastin contents and smooth muscle thickness. Immunohistochemistry was performed to quantify the density of positive cells to interleukin (IL)-2, IL-4, IL-5, interferon-γ, IL-10, monocyte chemotatic protein (MCP)-1, nuclear factor (NF)-κB p65, and insulin-like growth factor (IGF)-1. OVA exposure induced pulmonary blood vessels and parenchyma inflammation as well as increased expression of IL-4, IL-5, MCP-1, NF-κB p65, and IGF-I by inflammatory cells were reduced by aerobic conditioning. OVA exposure also induced an increase in smooth muscle thickness and elastic and collagen contents in pulmonary vessels, which were reduced by aerobic conditioning. Aerobic conditioning increased the expression of IL-10 in sensitized mice. We conclude that aerobic conditioning decreases pulmonary vascular and parenchymal inflammation and remodeling in this experimental model of chronic allergic lung inflammation in mice. [ABSTRACT FROM AUTHOR]

Exercise training increases circulating and tissue levels of angiotensin-(1-7) [Ang-(1-7)], which was shown to attenuate inflammation and fibrosis in different diseases. Here, we evaluated whether Ang-(1-7)/Mas receptor is involved in the beneficial effects of aerobic training in a chronic model of asthma. BALB/c mice were subjected to a protocol of asthma induced by ovalbumin sensitization (OVA; 4 i.p. injections) and OVA challenge (3 times/week for 4 weeks). Simultaneously to the challenge period, part of the animals was continuously treated with Mas receptor antagonist (A779, 1 μg/h; for 28 days) and trained in a treadmill (TRE; 60% of the maximal capacity, 1 h/day, 5 days/week during 4 weeks). PGC1-α mRNA expression (qRT-PCR), plasma IgE and lung cytokines (ELISA), inflammatory cells infiltration (enzymatic activity assay) and airway remodeling (by histology) were evaluated. Blocking the Mas receptor with A779 increased IgE and IL-13 levels and prevented the reduction in extracellular matrix deposition in airways in OVA-TRE mice. Mas receptor blockade prevented the reduction of myeloperoxidase activity, as well as, prevented exercise-induced IL-10 increase. These data show that activation of Ang-(1-7)/Mas receptor pathway is involved in the anti-inflammatory and anti-fibrotic effects of aerobic training in an experimental model of chronic asthma. Our results support exercise training as a non-pharmacological tool to defeat lung remodeling induced by chronic pulmonary inflammation. Further, our result also supports development of new therapy based on Ang-(1-7) or Mas agonists as important tool for asthma treatment in those patients that cannot perform aerobic training. [ABSTRACT FROM AUTHOR]

To explore the different consequences of acute and chronic exposure to chlorine gas (Cl 2) on the functional and histological parameters of health mice. Firstly, male BALB/c mice were acute exposed to 3.3 or 33.3 or 70.5 mg/m3 Cl 2. We analyzed the lung function, the inflammatory cells in the bronchoalveolar lavage, cell influx in the peribrochoalveolar space and mucus production. In a second phase, mice were chronic exposed to 70.5 mg/m3 Cl 2. Besides the first phase analyses, we also evaluated the epithelial cells thickness, collagen deposition in the airways, immunohistochemistry stain for IL-1β, iNOS, IL-17 and ROCK-2 and the levels of IL-5, IL-13, IL-17, IL-1β and TNF-α in lung homogenate. Acute exposure to chlorine impaired the lung function, increased the number of inflammatory cells in the BALF and in the airways, also increased the mucus production. Furthermore, when chlorine was exposed chronically, increased the airway remodeling with collagen deposition and epithelial cells thickness, positive cells for IL-1β, iNOS, IL-17 in the airways and in the alveolar walls and ROCK-2 in the alveolar walls, lung inflammation with increased levels of IL-5, IL-13, IL-1β and TNF-α in the lung homogenate, and also, induced the acid mucus production by the nasal epithelium. Acute and chronic exposure to low dose of chlorine gas worsens lung function, induces oxidative stress activation and mucus production and contributes to augmenting inflammation in health mice. Unlabelled Image [ABSTRACT FROM AUTHOR]

Transforming growth factor (TGF)-β-induced myofibroblast transformation and alterations in mesenchymal-epithelial interactions contribute to chronic lung diseases such as chronic obstructive pulmonary disease (COPD), asthma and pulmonary fibrosis. Rho-associated coiled-coil-forming protein kinase (ROCK) consists as two isoforms, ROCK1 and ROCK2, and both are playing critical roles in many cellular responses to injury. In this study, we aimed to elucidate the differential role of ROCK isoforms on TGF-β signaling in lung fibrosis and repair. For this purpose, we tested the effect of a non-selective ROCK 1 and 2 inhibitor (compound 31) and a selective ROCK2 inhibitor (compound A11) in inhibiting TGF-β-induced remodeling in lung fibroblasts and slices; and dysfunctional epithelial-progenitor interactions in lung organoids. Here, we demonstrated that the inhibition of ROCK1/2 with compound 31 represses TGF-β-driven actin remodeling as well as extracellular matrix deposition in lung fibroblasts and PCLS, whereas selective ROCK2 inhibition with compound A11 did not. Furthermore, the TGF-β induced inhibition of organoid formation was functionally restored in a concentration-dependent manner by both dual ROCK 1 and 2 inhibition and selective ROCK2 inhibition. We conclude that dual pharmacological inhibition of ROCK 1 and 2 counteracts TGF-β induced effects on remodeling and alveolar epithelial progenitor function, suggesting this to be a promising therapeutic approach for respiratory diseases associated with fibrosis and defective lung repair. [ABSTRACT FROM AUTHOR]

Angiotensin-(1-7) [Ang-(1-7)], a peptide of the renin-angiotensin system, has anti-inflammatory, anti-fibrotic and antiproliferative effects in acute or chronic inflammatory disease of respiratory system. In this study, we evaluated the effect of treatment with Ang-(1-7) on pulmonary tissue damage and behavior of mice submitted to experimental model of elastase-induced pulmonary emphysema (PE). Initially, male C57BL/6 mice were randomly assigned into two main groups: control (CTRL) and PE. In the PE group, the animals received three intratracheal instillations of pancreatic porcine elastase (PPE) at 1-week intervals (0.2 IU in 50 μL of saline). The CTRL group received the same volume of saline solution (50 μL). Twenty-four hours after the last instillation, animals of the PE group were randomly divided into two groups: PE and PE + Ang-(1-7). The PE + Ang-(1-7) group was treated with 60 μg/kg of Ang-(1-7) and 92 μg kg of HPβCD in gavage distilled water, 100 μl. The CTRL and PE groups were treated with vehicle (HPβCD- 92 μg/kg in distilled water per gavage, 100 μl), orally daily for 3 weeks. On the 19th day of treatment, all groups were tested in relation to locomotor activity and exploratory behavior. After 48 h, the animals were euthanized and lungs were collected. The animals of PE group presented rupture of alveolar walls and consequently reduction of alveolar tissue area. Treatment with Ang-(1-7) partially restored the alveolar tissue area. The PE reduced the locomotor activity and the exploratory behavior of the mice in relation to the control group. Treatment with Ang-(1-7) attenuated this change. In addition, it was observed that Ang-(1-7) reduced lung levels of IL-1β and increased levels of IL-10. These results show an anti-inflammatory effect of Ang-(1-7), inducing the return of pulmonary homeostasis and attenuation of the behavioral changes in experimental model of PE by elastase. [ABSTRACT FROM AUTHOR]

Widespread pulmonary destruction and fibrosis can be seen in end-stage pulmonary diseases. This situation causes vascular remodeling of the pulmonary circulation and pulmonary hypertension. Lung transplantation is an alternative treatment for end-stage pulmonary diseases. The purpose of this study is to research pathological vascular alterations retrospectively in explanted lungs with or without pulmonary hypertension. 57 explanted lungs were evaluated for occlusive intimal fibroelastosis, smooth muscle proliferation, medial hypertrophy, intimal cellular or fibrous thickening, hemosiderosis, plexiform lesion, angiomatoid lesion, arteriosclerosis, venopathy, capillary duplication and arteriovenous malformation. Both systolic and mean pulmonary artery pressures were defined. The relationship between vascular patterns and pulmonary hypertension was investigated. Pathological vascular alterations in explanted lungs with or without pulmonary hyper- tension included medial hypertrophy (80.71%), intimal cellular or fibrous thickening (80.7%), arteriosclerosis (77.19%), smooth muscle proliferation (55.3%) and arteriovenous malformation (50.3%). Hemosiderosis (12.5%), plexiform lesion (14%) and venopathy (21%) were less frequent pathological vascular alterations. Capillary duplication was common in secondary pulmonary hypertension and was statistically meaningful. Although medial hypertrophy and intimal thickness were seen in pulmonary hypertension, they can also be observed in end-stage pulmonary diseases without pulmonary hypertension. Interstitial capillary duplication was an important histopathological finding in end-stage lung diseases with pulmonary arterial hypertension.

MicroRNA-21 (miR-21), probably one of the most studied miRNAs to date, is found pleiotropic in various biological events. Its emerging role in pulmonary remodeling has attracted extensive attention. This review summarizes the genomic information of its primary transcript and various transcriptional regulations on its promoter. In addition, the role of miR-21 in pulmonary remodeling related signaling such as transforming growth factor β (TGF-β), bone morphogenetic protein (BMP), epidermal growth factor receptor (EGFR) and Notch signaling is discussed. Various validated miR-21 target genes participate in controlling of the overactive cell accumulation, smooth muscle contraction, inflammatory stress (trigger for lung epithelium damage), extracellular matrix deposition and hypoxia-induced disorders. Moreover, we focus on its particular implication in events including inflammatory stress-driven epithelium damage, epithelial-to-mesenchymal transition (EMT), transdifferentiation of fibroblasts into myofibroblasts, hypoxia stimuli and ROS response, as well as some other pulmonary remodeling related events such as overactive fibroblast (myofibroblast) accumulation, extracellular matrix deposition, and angiogenesis. Here, we summarize the strong potential of miR-21 in pulmonary remodeling and provide novel clues for further research in this area. [ABSTRACT FROM AUTHOR]

Pulmonary hypertension (PH) is an incurable disease that often leads to right ventricular hypertrophy and right heart failure. This study investigated single versus combined therapy with sildenafil and erythropoietin on hypoxia-induced pulmonary hypertension in mice. Mice were randomized into 5 groups and exposed to either hypoxia (10% oxygen) or normoxia for a total of 5 weeks. Hypoxic mice were treated with saline solution, erythropoietin (500 IU/kg 3 times weekly), sildenafil (10 mg/kg daily), or a combination of the two drugs for the last 2 weeks of hypoxic exposure. We measured right ventricular pressures using right heart catheterization, and the ventilatory response to hypoxia was recorded via whole-body plethysmography. Histological analyses were performed to elucidate changes in pulmonary morphology and appearance of right heart hypertrophy. Plasma levels of cardiotrophin-1 and atrial natriuretic peptide were quantified. Treatment with either erythropoietin or sildenafil alone lowered the hypoxia-induced increase of pulmonary pressure and reduced pulmonary edema formation, pulmonary vascular remodeling, and right ventricular hypertrophy. Notably, the combination of the two drugs had the most prominent effect. Changes in cardiotrophin-1 and atrial natriuretic protein levels confirmed these observations. The combination treatment with erythropoietin and sildenafil demonstrated an attenuation of the development of hypoxia-induced PH in mice that was superior to that observed for either drug when given alone.