Pulmonary Remodeling Research Articles

The Isoquinoline-Sulfonamide Compound H-1337 Attenuates SU5416/Hypoxia-Induced Pulmonary Arterial Hypertension in Rats.

Pulmonary arterial hypertension (PAH) is characterized by elevated pulmonary arterial pressure and right heart failure. Selective pulmonary vasodilators have improved the prognosis of PAH; however, they are not able to reverse pulmonary vascular remodeling. Therefore, a search for new treatment agents is required. H-1337 is an isoquinoline-sulfonamide compound that inhibits multiple serine/threonine kinases, including Rho-associated protein kinase (ROCK) and mammalian target of rapamycin (mTOR). Here, we investigated the effects of H-1337 on pulmonary hypertension and remodeling in the pulmonary vasculature and right ventricle in experimental PAH induced by SU5416 and hypoxia exposure. H-1337 and H-1337M1 exerted inhibitory effects on ROCK and Akt. H-1337 inhibited the phosphorylation of myosin light chain and mTOR and suppressed the proliferation of smooth muscle cells in vitro. H-1337 treatment also suppressed the phosphorylation of myosin light chain and mTOR in the pulmonary vasculature and decreased right ventricular systolic pressure and the extent of occlusive pulmonary vascular lesions. Furthermore, H-1337 suppressed aggravation of right ventricle hypertrophy. In conclusion, our data demonstrated that inhibition of ROCK and mTOR pathways with H-1337 suppressed the progression of pulmonary vascular remodeling, pulmonary hypertension, and right ventricular remodeling.

Role of Store-Operated Ca2+ Entry in the Pulmonary Vascular Remodeling Occurring in Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a severe and multifactorial disease. PAH pathogenesis mostly involves pulmonary arterial endothelial and pulmonary arterial smooth muscle cell (PASMC) dysfunction, leading to alterations in pulmonary arterial tone and distal pulmonary vessel obstruction and remodeling. Unfortunately, current PAH therapies are not curative, and therapeutic approaches mostly target endothelial dysfunction, while PASMC dysfunction is under investigation. In PAH, modifications in intracellular Ca2+ homoeostasis could partly explain PASMC dysfunction. One of the most crucial actors regulating Ca2+ homeostasis is store-operated Ca2+ channels, which mediate store-operated Ca2+ entry (SOCE). This review focuses on the main actors of SOCE in human and experimental PASMC, their contribution to PAH pathogenesis, and their therapeutic potential in PAH.

The function role of ubiquitin proteasome pathway in the ER stress-induced AECII apoptosis during hyperoxia exposure

BackgroundBronchopulmonary dysplasia (BPD) is a major cause of mortality and morbidity in premature infants, characterized by alveolar dysplasia and pulmonary microvascular remodeling. In the present study, we have investigated the functional roles of ubiquitin proteasome pathway (UPP) in BPD, and its relationship with endoplasmic reticulum stress (ERS) mediated type II alveolar epithelial cell (AECII) apoptosis.MethodsA hyperoxia-induced BPD rat model was constructed and the pathologic changes of lung tissues were evaluated by hematoxylin–eosin staining. Cell apoptosis and protein expression were determined by TUNEL assay and Western blotting, respectively. Further reagent kit with specific fluorescent substrate was utilized to measure the activity of 20 s proteasome. Meanwhile, AECII were cultured in vitro and exposed to hyperoxia. AECII apoptosis were measured by flow cytometry. In contrast, MG132 treatment was induced to explore UPP during hyperoxia exposure on AECII apoptosis and ERS sensors expression.ResultsA significant increase in apoptosis and total ubiquitinated proteins expression were observed in BPD rats and AECII culture, and the change of UPP was associated with ERS. In order to confirm the role of UPP in AECII apoptosis of BPD, AECII cells were treated by MG132 with the concentration of 10 μmol/L under hyperoxia exposure. We found that the proteins expression of glucose-regulated protein 78 (GRP-78), PKR-like ER kinase (PERK), activating transcription factor 4 (ATF4), activating transcription factor 6 (ATF6) and C/EBP homologous protein (CHOP), as well as AECII apoptosis were increased following MG132 treatment. Furthermore, the relatively up-regulated in the levels of total ubiquitinated proteins expression and 20 s proteasome activity were correlated with increased ERS sensors expression.ConclusionsOur findings indicate that UPP may participate in the ERS-induced AECII apoptosis under hyperoxia condition.

Abstract 14101: CES1 Deficiency is Associated With Oxidative Stress and Endoplasmic Reticulum/Mitochondrial Injury in Pulmonary Endothelial Cells

Background: Pulmonary Arterial Hypertension (PAH) is a life-threatening disease characterized by loss of pulmonary microvessels and vascular remodeling. BMPR2 insufficiency in PAH is associated with oxidative stress and mitochondrial dysfunction but mechanism remain incompletely understood. We recently identified CES1 as a downstream target of BMPR2 and key mediator of EC survival. Carboxylesterase1 (CES1) is an endoplasmic reticulum(ER) enzyme responsible for lipid metabolism, cellular detoxification and redox balance. Here, we explore the consequences of CES1 deficiency and its link to EC dysfunction in PAH. Hypothesis: Loss of CES1 promotes EC dysfunction through oxidative stress and disruption of ER-mitochondrial homeostasis. Methods: PECs were transfected with siRNA/plasmid to knockdown/overexpress CES1. To induce oxidative stress, we used Luperox (100 μM). Chronic hypoxia (10% O 2 for 3 weeks) studies were carried out with male wild type and CRISPR-CES1 KO mice. Hemodynamic measurement and vessel morphometry was performed to assess right ventricular (RV) and vascular remodeling. Mitochondrial and ER structure and function was assessed by confocal microscopy and WB assays. Results: Both BMPR2 and CES1-deficient PECs have higher rates of apoptosis in the context of increased ROS production and mitochondrial fragmentation. Lipid staining with OilRedO demonstrated accumulation of lipid droplets in the cytoplasm of CES1-deficient PECs suggesting disruption in lipid metabolism. CES1-deficient PECs also showed an increase in ER stress markers (CHOP, BiP, IRE-1) compared to controls. Overexpression of CES1 was able to protect PECs against ROS accumulation and apoptosis while increasing tube formation in Matrigel assay. Compared to WT, CRISPR-CES1 KO mice demonstrated higher RV systolic pressures, RV and pulmonary microvessel remodeling in normoxia and with chronic hypoxia. Analysis of CES1-KO lung tissue demonstrates high lipid peroxidation, oxidative damage and reduced number of alveolar vessels. Conclusions: CES1 expression is crucial for PMVEC survival by preventing ROS and maintaining mitochondria/ER homeostasis. Therapeutic interventions to restore CES1 expression could serve as novel treatment approaches for PAH.

Abstract 9770: Endothelial Loss of Amphiregulin Drives Inflammation and Endothelial Apoptosis in Pulmonary Hypertension

Pulmonary hypertension (PH) is a vascular disease characterized by elevated pulmonary arterial pressure (PAP), leading to right ventricular failure and death. Pathogenic features of PH include endothelial apoptosis and vascular inflammation, which drive vascular remodeling and increased PAP. Re-analysis of the whole transcriptome sequencing comparing human pulmonary arterial endothelial cells (PAECs) isolated from PH and control patients identified AREG , which encodes amphiregulin, as a key endothelial survival factor. PAECs from PH patients and mice exhibited downregulation of AREG and its receptor epidermal growth factor receptor (EGFR). Moreover, the deficiency of AREG and EGFR in ECs in vivo and in vitro heightened inflammatory leukocyte recruitment, cytokine production and endothelial apoptosis, and diminished angiogenesis. Correspondingly, hypoxic mice lacking Egfr in ECs ( cdh5 cre/+ Egfr fl/fl ) displayed elevated RVSP, Fulton index, and pulmonary remodeling. Computational analysis identified NCOA6, PHB2, and RRP1B as putative genes regulating AREG in endothelial cells. The master transcription factor of hypoxia HIF-1αbinds to the promoter regions of these genes and upregulate their expression in hypoxia. Silencing of these genes in cultured PAECs decreased inflammation and apoptosis, and increased angiogenesis in hypoxic conditions. Our pathway analysis and gene silencing experiments revealed that BCL2-associated agonist of cell death (BAD) is a downstream mediator of AREG . BAD silencing in ECs lacking AREG , mitigated inflammation and apoptosis and suppressed tube formation. In conclusion, loss of amphiregulin and its receptor EGFR in PH is a crucial step in the pathogenesis of PH, promoting pulmonary endothelial cell death, vascular recruitment of inflammatory myeloid cells, and vascular remodeling.

Association between particulate matter containing EPFRs and neutrophilic asthma through AhR and Th17

BackgroundEpidemiological data associate high levels of combustion-derived particulate matter (PM) with deleterious respiratory outcomes, but the mechanism underlying those outcomes remains elusive. It has been acknowledged by the World Health Organization that PM exposure contributes to more than 4.2 million all-cause mortalities worldwide each year. Current literature demonstrates that PM exacerbates respiratory diseases, impairs lung function, results in chronic respiratory illnesses, and is associated with increased mortality. The proposed mechanisms revolve around oxidative stress and inflammation promoting pulmonary physiological remodeling. However, our previous data found that PM is capable of inducing T helper cell 17 (Th17) immune responses via aryl hydrocarbon receptor (Ahr) activation, which was associated with neutrophilic invasion characteristic of steroid insensitive asthma.MethodsIn the present study, we utilized a combination of microarray and single cell RNA sequencing data to analyze the immunological landscape in mouse lungs following acute exposure to combustion derived particulate matter.ResultsWe present data that suggest epithelial cells produce specific cytokines in the aryl hydrocarbon receptor (Ahr) pathway that inform dendritic cells to initiate the production of pathogenic T helper (eTh17) cells. Using single-cell RNA sequencing analysis, we observed that upon exposure epithelial cells acquire a transcriptomic profile indicative of increased Il-17 signaling, Ahr activation, Egfr signaling, and T cell receptor and co-stimulatory signaling pathways. Epithelial cells further showed, Ahr activation is brought on by Ahr/ARNT nuclear translocation and activation of tyrosine kinase c-src, Egfr, and subsequently Erk1/2 pathways.ConclusionsCollectively, our data corroborates that PM initiates an eTh17 specific inflammatory response causing neutrophilic asthma through pathways in epithelial, dendritic, and T cells that promote eTh17 differentiation during initial PM exposure.

T Cells Promote Metastasis by Regulating Extracellular Matrix Remodeling following Chemotherapy.

Metastasis is the main cause of cancer-related mortality. Despite intense efforts to understand the mechanisms underlying the metastatic process, treatment of metastatic cancer is still challenging. Here we describe a chemotherapy-induced, host-mediated mechanism that promotes remodeling of the extracellular matrix (ECM), ultimately facilitating cancer cell seeding and metastasis. Paclitaxel (PTX) chemotherapy enhanced rapid ECM remodeling and mechanostructural changes in the lungs of tumor-free mice, and the protein expression and activity of the ECM remodeling enzyme lysyl oxidase (LOX) increased in response to PTX. A chimeric mouse model harboring genetic LOX depletion revealed chemotherapy-induced ECM remodeling was mediated by CD8+ T cells expressing LOX. Consistently, adoptive transfer of CD8+ T cells, but not CD4+ T cells or B cells, from PTX-treated mice to naïve immunodeprived mice induced pulmonary ECM remodeling. Lastly, in a clinically relevant metastatic breast carcinoma model, LOX inhibition counteracted the metastasis-promoting, ECM-related effects of PTX. This study highlights the role of immune cells in regulating ECM and metastasis following chemotherapy, suggesting that inhibiting chemotherapy-induced ECM remodeling represents a potential therapeutic strategy for metastatic cancer. SIGNIFICANCE: Chemotherapy induces prometastatic pulmonary ECM remodeling by upregulating LOX in T cells, which can be targeted with LOX inhibitors to suppress metastasis.See related commentary by Kolonin and Woodward, p. 197.

Lung Features in Individuals with Biomass Smoke Exposure Characterized by CT Scan and Changes in Pulmonary Function.

Background and ObjectiveTo determine the effects of BSE (biomass smoke exposure) on pulmonary and non-pulmonary changes in patients with COPD compared with normal individuals.MethodsUsing a cohort, we recruited 16 healthy individuals with BSE (BSE normal), 19 patients with BSE+COPD, 13 healthy individuals with cigarette smoke exposure (CSE normal), 25 patients with CSE+COPD, and 25 healthy controls. Patients with GOLD stage I and II COPD were included. Baseline data (demographic data, BSE or CSE, lung function, and CT findings) and follow-up lung function data were collected. CT parameters of emphysema, pulmonary small vessels, airway remodeling, pectoralis muscles, and erector spinae muscle were measured.ResultsIndividuals with BSE were mainly women (32/35, 91.43%). Compared with the CSE+COPD group, the BSE+COPD group demonstrated slower lung function decline, increased lower lung emphysema, narrower airway lumen dimensions and increased airway wall thickening in the moderate and small airways (all P<0.05). Compared with healthy controls, the CSE normal and BSE normal groups exhibited significant reductions in pulmonary small vessel area and obvious airway remodeling in small airways (P<0.05). Compared with the BSE normal group, the BSE+COPD group showed significantly more severe emphysema and airway remodeling, as well as reduced left pectoralis major muscle area (all P<0.05).ConclusionHealthy individuals with BSE had reduced pulmonary small vessel area and evidence of airway remodeling; patients with BSE and COPD showed more severe emphysema, airway remodeling, and reductions in pectoralis major muscle area.Clinical Trial RegistrationChiCTR-OO-14004264.

Thioredoxin system activation is associated with the progression of experimental pulmonary arterial hypertension

In addition to being an antioxidant, thioredoxin (Trx) is known to stimulate signaling pathways involved in cell proliferation and to inhibit apoptosis. The aim of this study was to explore the role of Trx in some of these pathways along the progression of monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH). Male rats were first divided into two groups: monocrotaline (MCT - 60 mg/kg i.p.) and control (received saline), that were further divided into three groups: 1, 2, and 3 weeks. Animals were submitted to echocardiographic analysis. Right and left ventricles were used for the measurement of hypertrophy, through morphometric and histological analysis. The lung was prepared for biochemical and molecular analysis. One week after MCT injection, there was an increase in thioredoxin reductase (TrxR) activity, a reduction in glutathione reductase (GR) activity, and an increase in Trx-1 and vitamin D3 up-regulated protein-1 (VDUP-1) expression. Two weeks after MCT injection, there was an increase in VDUP-1, Akt and cleaved caspase-3 activation, and a decrease in Trx-1 and Nrf2 expression. PAH-induced by MCT promoted a reduction in Nrf2 and Trx-1 expression as well as an increase in Akt and VDUP-1 expression after three weeks. The increase in pulmonary vascular resistance was accompanied by increased TrxR activity, suggesting an association between the Trx system and functional changes in the progression of PAH. It seems that Trx-1 activation was an adaptive response to MCT administration to cope with pulmonary remodeling and disease progression, suggesting a potential new target for PAH therapeutics.

Cardiac and Pulmonary Vascular Remodeling in Endurance Open Water Swimmers Assessed by Cardiac Magnetic Resonance: Impact of Sex and Sport Discipline.

Background: The cardiac response to endurance exercise has been studied previously, and recent reports have described the extension of this remodeling to the pulmonary vasculature. However, these reports have focused primarily on land-based sports and few data are available on exercise-induced cardio-pulmonary adaptation in swimming. Nor has the impact of sex on this exercise-induced cardio-pulmonary remodeling been studied in depth. The main aim of our study was to evaluate cardiac and pulmonary circulation remodeling in endurance swimmers. Among the secondary objectives, we evaluate the impact of sex and endurance sport discipline on this cardio-pulmonary remodeling promoted by exercise training.Methods:Resting cardiovascular magnetic resonance imaging was performed in 30 healthy well-trained endurance swimmers (83.3% male) and in 19 terrestrial endurance athletes (79% male) to assess biventricular dimensions and function. Pulmonary artery dimensions and flow as well as estimates of pulmonary vascular resistance (PVR) were also evaluated.Results:In relation to the reference parameters for the non-athletic population, male endurance swimmers had larger biventricular and pulmonary artery size (7.4 ± 1.0 vs. 5.9 ± 1.1 cm2, p < 0.001) with lower biventricular ejection fraction (EF) (left ventricular (LV) EF: 58 ± 4.4 vs. 67 ± 4.5 %, p < 0.001; right ventricular (RV) EF: 60 ± 4 vs. 66 ± 6 %, p < 0.001), LV end-diastolic volume (EDV): 106 ± 11 vs. 80 ± 9 ml/m2, p < 0.001; RV EDV: 101 ± 14 vs. 83 ± 12 ml/m2, p < 0.001). Significantly larger LV volume and lower LV EF were also observed in female swimmers (LV EF: 60 ± 5.3 vs. 67 ± 4.6 %, p = 0.003; LV EDV: 90 ± 17.6 vs. 75± 8.7 ml/m2, p = 0.002). Compared to terrestrial endurance athletes, swimmers showed increased LV indexed mass (75.0 ± 12.8 vs. 61.5 ± 10.0 g/m2, p < 0.001). The two groups of endurance athletes had similar pulmonary artery remodeling.Conclusions: Cardiac response to endurance swimming training implies an adaptation of both ventricular and pulmonary vasculature, as in the case of terrestrial endurance athletes. Cardio-pulmonary remodeling seems to be less extensive in female than in male swimmers.

The role of exosomes from BALF in lung disease.

Exosomes are released from a variety of immune cells and nonimmune cells, the phospholipid vesicle bilayer membrane structure actively secreted into tissues. Recently, exosomes were demonstrated to be effectively delivered proteins, cholesterol, lipids, and amounts of DNA, mRNA, and noncoding RNAs to a target cell or tissue from a host cell. These can be detected in blood, urine, exhaled breath condensates, bronchoalveolar lavage fluid (BALF), ascites, and cerebrospinal fluid. BALF is a clinical examination method for obtaining alveolar cells and biochemical components, reflecting changes in the lungs, so it is also called liquid biopsy. Exosomes from BALF become a new method for intercellular communication and well‐documented in various pulmonary diseases. In chronic obstructive pulmonary disease (COPD), BALF exosomes can predict the degree of COPD damage and serve as an effective monitoring indicator for airflow limitation and airway remodeling. It also mediates antigen presentation in the airways to the adaptive immune system as well as costimulatory effects. Furthermore, BALF exosomes from acute lung injury and infective diseases are closely related to various infections and lack of oxygen status. BALF exosomes play an important role in the diagnosis and prognosis of lung cancer. The effect of immunomodulatory role for BALF exosomes in adaptive and innate immune responses has been studied in sarcoidosis. The intercellular communication in the microenvironment of BALF exosomes in pulmonary fibrosis and lung remodeling have been studied. In this review, we summarize the novel findings of exosomes in BALF, executed function by protein, miRNA, DNA cytokine, and so on in several pulmonary diseases.

High-fat diet attenuates the improvement of hypoxia-induced pulmonary hypertension in mice during reoxygenation

BackgroundIt is widely recognized that metabolic disorder is associated with pulmonary hypertension (PH). It is known that hypoxia-induced elevated pulmonary artery pressure in mice returns to normal pressure during reoxygenation. However, it is still unclear how metabolic disorder affects the reverse remodeling of pulmonary arteries. In this study, we investigated the effects of high-fat diet (HFD) on the decrease in pulmonary artery pressure and reverse remodeling of pulmonary arteries in mice with hypoxia-induced PH.MethodsWe used female C57BL/6 mice aged 8 weeks. After being exposed to hypoxia (10% oxygen for four weeks) to induce PH, the mice were returned to normoxic conditions and randomized into a normal diet (ND) group and HFD group. Both groups were fed with their respective diets for 12 weeks.ResultsThe Fulton index and right ventricular systolic pressure measured by a micro-manometer catheter were significantly higher in the HFD group than in the ND group at 12 weeks after reoxygenation. The medial smooth muscle area was larger in the HFD group. Caspase-3 activity in the lung tissue of the HFD group was decreased, and the apoptosis of pulmonary smooth muscle cells was suppressed after reoxygenation. Moreover, the expression levels of peroxisome proliferator-activated receptor-γ and apelin were lower in the HFD group than in the ND group.ConclusionsThe results suggest that metabolic disorder may suppress pulmonary artery reverse remodeling in mice with hypoxia-induced PH during reoxygenation.

Systems Immunology Analysis Reveals the Contribution of Pulmonary and Extrapulmonary Tissues to the Immunopathogenesis of Severe COVID-19 Patients.

As one of the current global health conundrums, COVID-19 pandemic caused a dramatic increase of cases exceeding 79 million and 1.7 million deaths worldwide. Severe presentation of COVID-19 is characterized by cytokine storm and chronic inflammation resulting in multi-organ dysfunction. Currently, it is unclear whether extrapulmonary tissues contribute to the cytokine storm mediated-disease exacerbation. In this study, we applied systems immunology analysis to investigate the immunomodulatory effects of SARS-CoV-2 infection in lung, liver, kidney, and heart tissues and the potential contribution of these tissues to cytokines production. Notably, genes associated with neutrophil-mediated immune response (e.g. CXCL1) were particularly upregulated in lung, whereas genes associated with eosinophil-mediated immune response (e.g. CCL11) were particularly upregulated in heart tissue. In contrast, immune responses mediated by monocytes, dendritic cells, T-cells and B-cells were almost similarly dysregulated in all tissue types. Focused analysis of 14 cytokines classically upregulated in COVID-19 patients revealed that only some of these cytokines are dysregulated in lung tissue, whereas the other cytokines are upregulated in extrapulmonary tissues (e.g. IL6 and IL2RA). Investigations of potential mechanisms by which SARS-CoV-2 modulates the immune response and cytokine production revealed a marked dysregulation of NF-κB signaling particularly CBM complex and the NF-κB inhibitor BCL3. Moreover, overexpression of mucin family genes (e.g. MUC3A, MUC4, MUC5B, MUC16, and MUC17) and HSP90AB1 suggest that the exacerbated inflammation activated pulmonary and extrapulmonary tissues remodeling. In addition, we identified multiple sets of immune response associated genes upregulated in a tissue-specific manner (DCLRE1C, CHI3L1, and PARP14 in lung; APOA4, NFASC, WIPF3, and CD34 in liver; LILRA5, ISG20, S100A12, and HLX in kidney; and ASS1 and PTPN1 in heart). Altogether, these findings suggest that the cytokines storm triggered by SARS-CoV-2 infection is potentially the result of dysregulated cytokine production by inflamed pulmonary and extrapulmonary (e.g. liver, kidney, and heart) tissues.

SVEGFR1 Is Enriched in Hepatic Vein Blood-Evidence for a Provisional Hepatic Factor Candidate?

Background: Pulmonary arteriovenous malformations (PAVMs) are common sequelae of palliated univentricular congenital heart disease, yet their pathogenesis remain poorly defined. In this preliminary study, we used paired patient blood samples to identify potential hepatic factor candidates enriched in hepatic vein blood.Methods: Paired venous blood samples were collected from the hepatic vein (HV) and superior vena cava (SVC) from children 0 to 10 years with univentricular and biventricular congenital heart disease (n = 40). We used three independent protein analyses to identify proteomic differences between HV and SVC blood. Subsequently, we investigated the relevance of our quantified protein differences with human lung microvascular endothelial assays.Results: Two independent protein arrays (semi-quantitative immunoblot and quantitative array) identified that soluble vascular endothelial growth factor receptor 1 (sVEGFR1) is significantly elevated in HV serum compared to SVC serum. Using ELISA, we confirmed the previous findings that sVEGFR1 is enriched in HV serum (n = 24, p < 0.0001). Finally, we studied the quantified HV and SVC serum levels of sVEGFR1 in vitro. HV levels of sVEGFR1 decreased tip cell selection (p = 0.0482) and tube formation (fewer tubes [p = 0.0246], shorter tube length [p = 0.0300]) in vitro compared to SVC levels of sVEGFR1.Conclusions: Based on a small heterogenous cohort, sVEGFR1 is elevated in HV serum compared to paired SVC samples, and the mean sVEGFR1 concentrations in these two systemic veins cause pulmonary endothelial phenotypic differences in vitro. Further research is needed to determine whether sVEGFR1 has a direct role in pulmonary microvascular remodeling and PAVMs in patients with palliated univentricular congenital heart disease.

Pulmonary Fibroelastotic Remodelling Revisited

Pulmonary fibroelastotic remodelling occurs within a broad spectrum of diseases with vastly divergent outcomes. So far, no comprehensive terminology has been established to adequately address and distinguish histomorphological and clinical entities. We aimed to describe the range of fibroelastotic changes and define stringent histological criteria. Furthermore, we wanted to clarify the corresponding terminology in order to distinguish clinically relevant variants of pulmonary fibroelastotic remodelling. We revisited pulmonary specimens with fibroelastotic remodelling sampled during the last ten years at a large European lung transplant centre. Consensus-based definitions of specific variants of fibroelastotic changes were developed on the basis of well-defined cases and applied. Systematic evaluation was performed in a steps-wise algorithm, first identifying the fulcrum of the respective lesions, and then assessing the morphological changes, their distribution and the features of the adjacent parenchyma. We defined typical alveolar fibro-elastosis as collagenous effacement of the alveolar spaces with accompanying hyper-elastosis of the remodelled and paucicellular alveolar walls, independent of the underlying disease in 45 cases. Clinically, this pattern could be seen in (idiopathic) pleuroparenchymal fibro-elastosis, interstitial lung disease with concomitant alveolar fibro-elastosis, following hematopoietic stem cell and lung transplantation, autoimmune disease, radio-/chemotherapy, and pulmonary apical caps. Novel in-transit and activity stages of fibroelastotic remodelling were identified. For the first time, we present a comprehensive definition of fibroelastotic remodelling, its anatomic distribution, and clinical associations, thereby providing a basis for stringent patient stratification and prediction of outcome.

Interleukin-17 aggravates right ventricular remodeling via activating STAT3 under both normoxia and hypoxia

ObjectiveProinflammatory cytokine interleukin 17 (IL-17) is involved in ventricular remodeling, mainly of the left ventricle. This study was designed to explore the role of IL-17 played in the pathogenesis of right ventricular hypertrophy (RVH), aiming to provide a novel treatment target or diagnostic biomarker options for improving the care of RVH patients.MethodsC57BL/6 mice were maintained in 10% O2 chamber or room air for four weeks. Right ventricular hypertrophy index (RVHI), RV/body weight ratio, pulmonary arteriolar remodeling determined by percent media thickness (%MT), and the cardiomyocyte diameter of RV were evaluated. Mice were treated with exogenous recombinant mouse IL-17 (rmIL-17, 1 μg per dose twice a week) for four weeks. H9c2 cardiomyocytes were cultured and treated with IL-17 (10 ng/mL) and STAT3 inhibitor (10 ng/mL) either under normoxia (21% O2, 5% CO2, 74% N2) or under hypoxia (3% O2, 5% CO2, 92% N2). Cardiomyocyte viability was assessed by Cell counting kit 8 (CCK-8) assay. The mRNA level was detected by RT-PCR, where as the protein expression was measured by Western blot, immunohistochemistry, and immunofluorescent analyses.ResultsIn vivo experiments showed that IL-17 did not affect the pulmonary artery under normoxia, after treatment with rmIL-17, %MT was not changed, while RVHI and the RV/body weight ratio were increased, indicating that IL-17 directly induced right ventricular hypertrophy. In a time-course study, the mice were exposed to hypoxia for 0, 1, 2, 3, 4 weeks, respectively. We found that the expression of IL-17 was gradually upregulated in RV tissue in a time-dependent manner after one week of hypoxia exposure, especially at the third and fourth week. Cardiomyocyte hypertrophy and apoptosis were observed after the exposure of the mice to hypoxia for four weeks, rmIL-17 further aggravated the hypoxia-induced cardiomyocyte hypertrophy and apoptosis. The expression of p-STAT3 in the IL-17-deficient mice was lower than in the wild-type mice. In vitro, IL-17 inhibited cardiomyocyte viability and induced cardiomyocyte apoptosis via STAT3 under both normoxic and hypoxic conditions.ConclusionsThese findings support a role for IL-17 as a mediator in the pathogenesis RVH, which might be considered as a potential novel anti-inflammation therapeutic strategy or diagnostic biomarker for RVH.

The Role of JAK/STAT Molecular Pathway in Vascular Remodeling Associated with Pulmonary Hypertension.

Pulmonary hypertension is defined as a group of diseases characterized by a progressive increase in pulmonary vascular resistance (PVR), which leads to right ventricular failure and premature death. There are multiple clinical manifestations that can be grouped into five different types. Pulmonary artery remodeling is a common feature in pulmonary hypertension (PH) characterized by endothelial dysfunction and smooth muscle pulmonary artery cell proliferation. The current treatments for PH are limited to vasodilatory agents that do not stop the progression of the disease. Therefore, there is a need for new agents that inhibit pulmonary artery remodeling targeting the main genetic, molecular, and cellular processes involved in PH. Chronic inflammation contributes to pulmonary artery remodeling and PH, among other vascular disorders, and many inflammatory mediators signal through the JAK/STAT pathway. Recent evidence indicates that the JAK/STAT pathway is overactivated in the pulmonary arteries of patients with PH of different types. In addition, different profibrotic cytokines such as IL-6, IL-13, and IL-11 and growth factors such as PDGF, VEGF, and TGFβ1 are activators of the JAK/STAT pathway and inducers of pulmonary remodeling, thus participating in the development of PH. The understanding of the participation and modulation of the JAK/STAT pathway in PH could be an attractive strategy for developing future treatments. There have been no studies to date focused on the JAK/STAT pathway and PH. In this review, we focus on the analysis of the expression and distribution of different JAK/STAT isoforms in the pulmonary arteries of patients with different types of PH. Furthermore, molecular canonical and noncanonical JAK/STAT pathway transactivation will be discussed in the context of vascular remodeling and PH. The consequences of JAK/STAT activation for endothelial cells and pulmonary artery smooth muscle cells’ proliferation, migration, senescence, and transformation into mesenchymal/myofibroblast cells will be described and discussed, together with different promising drugs targeting the JAK/STAT pathway in vitro and in vivo.

Chronic Inhaled Nicotine‐Induced Pulmonary Hypertension and Right Ventricular Remodeling are Mediated by Angiotensin‐II Type 1 Receptor

Introduction Use of electronic cigarettes is rapidly increasing among youth and young adults, but little is known regarding the long-term cardiopulmonary impacts of these nicotine-containing devices. Our group previously demonstrated that chronic inhaled nicotine induces pulmonary hypertension and right ventricular (RV) remodeling in mice, characterized by increased RV systolic pressure (RVSP) and RV free wall thickness during diastole (RVFWT;d). These changes were associated with upregulated RV angiotensin converting enzyme (ACE), leading us to hypothesize that these nicotine-induced effects are mediated by the renin-angiotensin system. ACE inhibitor and angiotensin-II receptor blocker use in a large retrospective pulmonary hypertension patient cohort was associated with improved survival. Here, we utilized losartan, a specific antagonist of the angiotensin-II type 1 receptor (AT1R), to further explore nicotine's cardiopulmonary effects. Methods: Male C57BL/6 mice received either nicotine vapor or room air for 12 hours per day, and exposure was measured by serum cotinine (559±57 ng/mL; comparable to human cigarette smokers or electronic cigarette users). A subset of mice was treated with losartan via osmotic mini-pump for 8 weeks. Losartan dosage was approximately 5.0 to 6.5 mg/kg/day due to body weight differences throughout the experiment. Cardiac structure and function were assessed using echocardiography and RV catheterization. Results: Chronic inhaled nicotine significantly increased RVSP (40.7±3.5 mmHg, n=11) versus air exposure (25.6±1.0 mmHg, n=11, p<0.005). Mice receiving both losartan and nicotine had significantly reduced RVSP (24.0±1.3 mmHg, n=12, p<0.005) versus nicotine alone. There was no difference in RVSP between air mice and either losartan-infused group (air-losartan: 23.7±1.2 mmHg, n=14). RVFWT;d was increased in nicotine mice (0.44±0.01 mm, n=12) versus air mice (0.31±0.01 mm, n=10, p<0.0001). Losartan infusion of nicotine mice resulted in significantly decreased RVFWT;d (0.34±0.01 mm, n=8, p<0.0001) versus nicotine alone. There was no difference in RVFWT;d between air mice and either losartan-infused group (air-losartan: 0.32±0.01 mm, n=7). Chronic inhaled nicotine increased RV internal diameter during diastole (RVID;d; 1.56±0.04 mm, n=12) versus air mice (1.24±0.07 mm, n=10, p<0.0001), suggesting RV dilation. RVID;d between air-exposed mice receiving losartan (1.23±0.04, n=7) and nicotine-exposed mice receiving losartan (1.44±0.03, n=8) was not significantly different. Neither nicotine nor losartan exposure resulted in changes to left ventricular structure and function. Conclusion: These findings provide the first preclinical evidence that AT1R antagonism can ameliorate chronic inhaled nicotine-induced pulmonary hypertension and RV remodeling.

Research and Application of Stem Cell-Based Therapy in Idiopathic Pulmonary Fibrosis: A Review

Idiopathic pulmonary fibrosis (IPF) is a type of pulmonary disease that progresses acutely or slowly into irreversible pulmonary diseases, resulting in the end severe damages to patients' lung functions, as well as deaths. At present, the pathogenesis of pulmonary fibrosis is still not clear and there is no effective therapeutic measure available to control the progression of the disease. Research findings indicate that stem cells, being the origin of all cells of organisms, participate in the development of individuals at various stages and play an important role in repairing pulmonary tissue damage. Stem cells are attracting growing attention in the field of regenerative medicine, providing new ideas for treating IPF with transplanted stem cells. Herein, in order to better explore the potential applications of stem cell transplantation in treating IPF, we attempt to summarize preliminary studies of stem cell-mediated pulmonary remodeling after IPF, as well as cutting-edge clinical trials in stem cell-based IPF therapy.

Hydrogen regulates the M1/M2 polarization of alveolar macrophages in a rat model of chronic obstructive pulmonary disease

Objective Chronic obstructive pulmonary disease (COPD) is a respiratory disease with high morbidity and mortality worldwide, so far there is no ideal treatment method. Previous studies have shown that hydrogen (H2) is involved in the treatment of COPD as an antioxidant. In this study, the effect of H2 on M1/M2 polarization of alveolar macrophages in COPD rats was observed, and its anti-inflammatory mechanism was further elucidated. Methods: Twenty-four Sprague-Dawley rats were randomly divided into three groups including the control, COPD and H2 group. A rat model of COPD was established by cigarette exposure combined with lipopolysaccharide (LPS) induction. H2 therapy was administered 2 hours per day for 14 days. Lung function and pathology were assessed. The levels of interleukin (IL)-6, tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β1 and IL-10 in bronchoalveolar lavage fluid (BALF) and lung tissue were measured by enzyme-linked immunosorbent assay. The mRNA, protein expression and immunoreactivity of inducible nitric oxide synthase (iNOS) and arginase (Arg)-1 in lung were observed by quantitative real-time PCR, western blot and immunohistochemistry. Results: Compared with the control rats, there were a significant decline in lung function, a marked inflammatory infiltration and pulmonary parenchymal remodeling and the increases of IL-6, TNF-α and TGF-β1 levels in BALF and lung tissue, but a lower expression of IL-10 in COPD rats. The iNOS mRNA and protein expression, as well as its optical density (OD), were increased significantly in lung tissue, while those of Arg-1 decreased significantly. H2 treatment improved the lung function and the parenchymal inflammation, reversed the increased levels of IL-6, TNF-α and TGF-β1, and the lower IL-10. Meanwhile, H2 also down-regulated the expression of iNOS, but up-regulated expression of Arg-1 in lung tissue. Conclusion: H2 reduces inflammation in the lung of COPD, which may be related to its inhibition of M1 type polarization and activation of M2 type polarization of alveolar macrophage.