Small Pulmonary Vessels Research Articles

Şiddetli COVİD-19 Hastalarında DMAH (Düşük Molekül Ağırlıklı Heparin) Doz Farklılıklarının Etkileri

Objective: The most prominent clinical finding in severe COVID-19 patients is endothelial damage. For these reasons, active administration of anticoagulants (such as heparin) is recommended to patients with severe COVID-19. The purpose of this study is to investigate the effects of different doses of low-molecular weight heparin (LMWH) on severe COVID-19 patients. Methods: This study was performed retrospectively in intensive care unit of a tertiary referral hospital. PCR (polymerase chain reaction) positive (+) patients were included in the study. Patients’ demographic data, length of stay in the hospital and intensive care unit, laboratory values (D-dimer, CRP, creatinine) on the last day of intensive care stay, mortality and invasive mechanical ventilator needs were recorded. Group O: consisted of patients not receiving anticoagulants, and Group 1 received a single daily dose of 40 mg enoxaparin sodium (equivalent to 4000 anti-Xa IU), and Group 2 received 2 daily doses of 1 mg/kg enoxaparin sodium. Results: A total of 191 patients were included in the study. 45% of the patients were female (n: 86), 55% were male. The mean age was found to be 67.6 ± 13.8. Patient numbers; group 0: 12, group 1: 90, group 2: 89. 7-day mortality was 50% in group 0, 22.2% in group 2, and 23.5% in group 3 (p value <0.05). Conclusion: In a recent lung dissection report in critically ill patient with COVID-19; occlusion of pulmonary small vessels and formation of microthrombosis have been demonstrated. Prophylactic doses of LMWH are used more frequently. Some studies have suggested that septic patients may benefit from early diagnosis and specific treatment. As a result; in severe COVID-19 patients with limited mobilization, all doses of LMWH reduce morbidity and mortality.

Imaging of lung pathology in COVID-19 (literature review and own data)

Novel coronavirus infection is predominantly manifests as lung tissue damage. Imaging methods, particularly, chest X-Ray and computed tomography, are of great importance for detecting pulmonary changes and differentiate them with other diseases (mainly other viral pneumonias). In the early disease stages the disease presents on CT with ground glass opacities, consolidations, crazy paving symptom. With time course, they can gradually decrease, evolve into organizing pneumonia or stay stable and even increase in volume with the spread of consolidation and formation of several signs of organizing pneumonia. Although radiological methods show high sensitivity in the detection of pulmonary changes, their specificity and prognostic ability are not so good today. Novel coronavirus infection can be complicated with pulmonary embolism, development thrombosisin situin pulmonary small vessels, acute heart failure and subsequent development of cardiogenic pulmonary edema, bacterial superinfection, exacerbation or worsening of chronic lung disease and several iatrogenic issues (pneumothorax, pneumomediastinum, hematomas).

Quantitative measurement of cross-sectional area of small pulmonary vessels in pulmonary embolism

Objective: The relationship between the percentage of total cross-sectional area (% CSA) of small pulmonary vessels for the lung area in CTPA and the right ventricular function parameters in patients with pulmonary embolism. Methods: 120 patients with PE and 72 healthy subjects underwent CTPA and all date were analyzed Retrospectively. The main pulmonary artery diameter (mPA), the ratio of the main pulmonary artery to the ascending aorta diameter (rPA), right ventricle/left ventricular diameter ratio (RVd/LVd), and the pulmonary artery obstruction index (PAOI) in the PE group were measured for all subjects. The %CSA<5 mm(2) and 5-10 mm(2) for the lung area (%CSA(<5) and %CSA(5-10)) of small pulmonary vessels were measured with Image J image-processing program. According to the risk stratification of the 2018 Guidelines for the Diagnosis and Treatment of Pulmonary Thromboembolism, PE patients were divided into medium-high risk group (RVd/LVd>1) and low-risk group (RVd/LVd<1). The indexes of PE in medium-high risk group, low risk group and control group were compared by ANOVA, and the indexes among PE subgroups were compared by independent sample t-test. Spearman correlation method was used to analyze the correlation between %CSA and right ventricular function parameters of PE patients. Results: %CSA(<5) of medium-high risk group, low-risk group and control group were (0.69±0.19)%, (0.95±0.27)% and (0.99±0.30)% (P<0.01), respectively. %CSA(5-10) of three groups were (0.63±0.15)%, (0.84±0.18)%, and (0.85±0.25)% (P<0.01), respectively; %CSA(<5) and %CSA(5-10) of medium-high risk group were lower than low-risk group and control group. %CSA(<5) and %CSA(5-10) in PE patients correlated negatively with RVd/LVd, rPA and mPA (r=-0.545/-0.549, -0.235/-0.352, -0.239/-0.298, respectively). Conclusion: The measurement of % CSA<(5) and %CSA (5-10) in CTPA were negatively correlated with RVd/LVd in patients with pulmonary embolism, which indirectly reflected the severity of the pulmonary embolism patients.

Bufei Yishen Formula Restores Th17/Treg Balance and Attenuates Chronic Obstructive Pulmonary Disease via Activation of the Adenosine 2a Receptor

Bufei Yishen formula (BYF) is a Traditional Chinese Medicine (TCM) reported to ameliorate chronic obstructive pulmonary disease (COPD) by regulating the balance between T helper (Th) 17 and regulatory T (Treg) cells. However, its mechanism remains unknown. Therefore, this study aimed to explore the underlying mechanisms of BYF. Naïve CD4+ T cells were exposed to anti-CD3, anti-CD28, transforming growth factor (TGF)-β, and/or interleukin (IL)-6 to promote their differentiation into Th17 or Treg cells. A rat model of cigarette smoke- and bacterial infection-induced COPD was established and orally treated with BYF and/or an adenosine 2a receptor (A2aR) antagonist. Then, the rats were sacrificed, their lung tissues were removed for histological analysis, and their spleens were collected to evaluate Th17 and Treg cells. The results showed that BYF significantly suppressed Th17 cell differentiation and its related cytokines and enhanced Treg cell differentiation and its related cytokines. In addition, BYF activated the A2aR, increased the levels of p-signal transducer and activator of transcription (STAT)5, and decreased the level of p-STAT3 in Treg and Th17 cells. The A2aR antagonist suppressed the changes induced by BYF treatment in Th17 and Treg cells. Furthermore, the A2aR antagonist diminished the therapeutic effect of BYF on COPD, as indicated by the lung injury scores, bronchiole wall thickness, small pulmonary vessels wall thickness, bronchiole stenosis, alveolar diameters, decrease in inflammatory cytokines, increase in alveolar number, and lung functions. Similarly, the A2aR antagonist reversed the effects of BYF on the proportion of Th17 and Treg cells in the spleen. Additionally, BYF increased the protein and mRNA levels of A2aR and regulated the phosphorylation of STAT3 and STAT5 in spleen and lung tissues, which were inhibited by cotreatment with the A2aR antagonist. In conclusion, this study suggested that BYF exhibited its anti-COPD efficacy by restoring the Th17/Treg balance via activating A2aR, which may provide evidence for the clinical application of BYF in the treatment of COPD.

Evaluation of Image Quality for 7 Iterative Reconstruction Algorithms in Chest Computed Tomography Imaging: A Phantom Study.

This study aimed to evaluate the image quality of 7 iterative reconstruction (IR) algorithms in comparison to filtered back-projection (FBP) algorithm. An anthropomorphic chest phantom was scanned on 4 computed tomography scanners and reconstructed with FBP and IR algorithms. Image quality of anatomical details-large/medium-sized pulmonary vessels, small pulmonary vessels, thoracic wall, and small and large lesions-was scored. Furthermore, general impression of noise, image contrast, and artifacts were evaluated. Visual grading regression was used to analyze the data. Standard deviations were measured, and the noise power spectrum was calculated. Iterative reconstruction algorithms showed significantly better results when compared with FBP for these criteria (regression coefficients/P values in parentheses): vessels (FIRST: -1.8/0.05, AIDR Enhanced: <-2.3/0.01, Veo: <-0.1/0.03, ADMIRE: <-2.1/0.04), lesions (FIRST: <-2.6/0.01, AIDR Enhanced: <-1.9/0.03, IMR1: <-2.7/0.01, Veo: <-2.4/0.02, ADMIRE: -2.3/0.02), image noise (FIRST: <-3.2/0.004, AIDR Enhanced: <-3.5/0.002, IMR1: <-6.1/0.001, iDose: <-2.3/0.02, Veo: <-3.4/0.002, ADMIRE: <-3.5/0.02), image contrast (FIRST: -2.3/0.01, AIDR Enhanced: -2.5/0.01, IMR1: -3.7/0.001, iDose: -2.1/0.02), and artifacts (FIRST: <-3.8/0.004, AIDR Enhanced: <-2.7/0.02, IMR1: <-2.6/0.02, iDose: -2.1/0.04, Veo: -2.6/0.02). The iDose algorithm was the only IR algorithm that maintained the noise frequencies. Iterative reconstruction algorithms performed differently on all evaluated criteria, showing the importance of careful implementation of algorithms for diagnostic purposes.

Assessment of Small Pulmonary Blood Vessels in COVID-19 Patients Using HRCT

Rationale and ObjectivesMounting evidence supports the role of pulmonary hemodynamic alternations in the pathogenesis of COVID-19. Previous studies have demonstrated that changes in pulmonary blood volumes measured on computed tomography (CT) are associated with histopathological markers of pulmonary vascular pruning, suggesting that quantitative CT analysis may eventually be useful in the assessment pulmonary vascular dysfunction more broadly.Materials and MethodsBuilding upon previous work, automated quantitative CT measures of small blood vessel volume and pulmonary vascular density were developed. Scans from 103 COVID-19 patients and 107 healthy volunteers were analyzed and their results compared, with comparisons made both on lobar and global levels.ResultsCompared to healthy volunteers, COVID-19 patients showed significant reduction in BV5 (pulmonary blood volume contained in blood vessels of <5 mm2) expressed as BV5/(total pulmonary blood volume; p < 0.0001), and significant increases in BV5-10 and BV 10 (pulmonary blood volumes contained in vessels between 5 and 10 mm2 and above 10 mm2, respectively, p < 0.0001). These changes were consistent across lobes.ConclusionCOVID-19 patients display striking anomalies in the distribution of blood volume within the pulmonary vascular tree, consistent with increased pulmonary vasculature resistance in the pulmonary vessels below the resolution of CT.

Non-invasive prediction of tissue Doppler-derived E/e' ratio using lung Doppler signals.

Lung Doppler signals (LDS) represent the radial movement of small pulmonary blood vessel walls, caused by pulse waves of cardiac origin. We sought to investigate the accuracy and prognostic value of LDS as a predictor of mitral valve early diastolic flow to annular velocity ratio (E/e'), in patients with acute decompensated heart failure (ADHF). We prospectively enrolled patients with ADHF (n = 99, mean age 65 ± 15 years, 61% males) who underwent echocardiographic and simultaneous LDS evaluation at hospital admission. Patients with hospital stay over 72 h underwent a repeat echocardiogram and LDS assessment before discharge. Patients were followed for the occurrence of short-term all-cause mortality and heart failure (HF) hospitalization. Predicted E/e' from LDS correlated with echocardiographic E/e' at admission and discharge (r = 0.67 and 0.83; P < 0.001 for both), respectively. Patients were dichotomized into two groups by the median predicted-E/e'. A high predicted-E/e' was associated with age, hypertension, anaemia, history of HF with preserved ejection fraction (EF), and chronic kidney disease. Over a median follow-up period of 7 months, 22 (22.2%) patients died and 23 (23.2%) patients were rehospitalized for HF. Kaplan-Meier analysis revealed a significantly lower event-free survival in high predicted-E/e' group HF patients with reduced EF (P = 0.0247). No significant differences were observed in HF rehospitalization rates between the two groups. In this single-centre prospective study of patients with ADHF, LDS predicted echocardiographic E/e' measurements and showed prognostic value in predicting all-cause mortality in HF patients with a reduced EF.

Involvement of the pulmonary arteries in patients with Takayasu arteritis: a prospective study from a single centre in China

BackgroundTakayasu arteritis (TA) is a large vessel vasculitis that can involve pulmonary arteries (PAs). We studied multiple clinical characteristics related to pulmonary artery involvement (PAI) in TA patients.MethodsWe enrolled 216 patients with TA from a large prospective cohort. PAI was assessed in each patient based on data from magnetic resonance angiography/computed tomography angiography. Pulmonary hypertension, cardiac function, and pulmonary parenchymal lesions were evaluated further in patients with PAI based on echocardiography, the New York Heart Association Functional Classification, and pulmonary computed tomography, respectively. These abnormalities related to PAI were followed up to evaluate treatment effects.ResultsPAI was detected in 56/216 (25.93%) patients, which involved the pulmonary trunk, main PAs, and small vessels in the lungs. Among patients with PAI, 28 (50%) patients were accompanied by pulmonary hypertension, which was graded as ‘severe’ in 9 (16.07%), ‘moderate’ in 10 (17.86%), and mild in 9 (16.07%). Twenty-six (46.43%) patients showed advanced NYHA function (III, 20, 35.71%; IV, 6, 10.71%). Furthermore, 21 (37.50%) patients presented with abnormal pulmonary parenchymal lesions in the area corresponding to PAI (e.g. the mosaic sign, infarction, bronchiectasis). During follow-up, two patients died due to heart failure and pulmonary thrombosis. In the remaining patients, the abnormalities mentioned above improved partially after routine treatment.ConclusionsPAI is common in TA patients. PAI can cause pulmonary hypertension, cardiac insufficiency, and pulmonary parenchymal lesions, which worsen patients’ prognosis.

A novel rat model of pulmonary hypertension induced by mono treatment with SU5416.

Pulmonary hypertension (PH) is responsible for premature death caused by progressive and severe heart failure. A simple, feasible, and reproducible animal model of PH is essential for the investigation of the pathogenesis and treatment of this condition. Previous studies have demonstrated that the vascular endothelial growth factor receptor 2 (VEGFR-2) inhibitor SU5416 combined with hypoxia could establish an animal model of PH. Here, we investigated whether SU5416 itself could induce PH in rats. The effects of SU5416 treatment followed by 5 weeks of normoxia were examined. Hemodynamic measurements and histological assessments of the pulmonary vasculature and the heart were conducted to evaluate the physiological and pathophysiological characteristics of PH. Compared with the control rats, the SU5416-treated rats showed significantly increased right ventricle systolic pressure, right ventricle mass, total pulmonary vascular resistance, and total pulmonary vascular resistance index, while the cardiac output and cardiac index were substantially decreased. Moreover, the degree of occlusion and the muscularization levels of the distal small pulmonary vessels and the medial wall thickness of larger vessels (OD > 50 μm) simultaneously increased. SU5416 inhibited pulmonary vascular endothelial cell apoptosis in rats, as shown by immunostaining of cleaved caspase-3. Furthermore, changes in the right ventricle, myocardial hypertrophy, myocardial edema, myocardial necrosis, striated muscle cell atrophy, vessel muscularization, neointimal occlusion, and increased collagen deposition were observed in the SU5416 group compared with the control group. Thus, treatment with SU5416 alone plus 5 weeks of normoxia could be sufficient to induce PH in rats, which may provide a good and convenient model for future investigation of PH.

Cannabinoid Receptor Type 2: A Possible Target in SARS-CoV-2 (CoV-19) Infection?

In late December 2019, a novel coronavirus (SARS-CoV-2 or CoV-19) appeared in Wuhan, China, causing a global pandemic. SARS-CoV-2 causes mild to severe respiratory tract inflammation, often developing into lung fibrosis with thrombosis in pulmonary small vessels and causing even death. COronaVIrus Disease (COVID-19) patients manifest exacerbated inflammatory and immune responses, cytokine storm, prevalence of pro-inflammatory M1 macrophages and increased levels of resident and circulating immune cells. Men show higher susceptibility to SARS-CoV-2 infection than women, likely due to estrogens production. The protective role of estrogens, as well as an immune-suppressive activity that limits the excessive inflammation, can be mediated by cannabinoid receptor type 2 (CB2). The role of this receptor in modulating inflammation and immune response is well documented in fact in several settings. The stimulation of CB2 receptors is known to limit the release of pro-inflammatory cytokines, shift the macrophage phenotype towards the anti-inflammatory M2 type and enhance the immune-modulating properties of mesenchymal stromal cells. For these reasons, we hypothesize that CB2 receptor can be a therapeutic target in COVID-19 pandemic emergency.

Immune mechanisms of pulmonary intravascular coagulopathy in COVID-19 pneumonia.

SummaryThe lung pathology seen in patients with coronavirus disease 2019 (COVID-19) shows marked microvascular thrombosis and haemorrhage linked to extensive alveolar and interstitial inflammation that shares features with macrophage activation syndrome (MAS). We have termed the lung-restricted vascular immunopathology associated with COVID-19 as diffuse pulmonary intravascular coagulopathy, which in its early stages is distinct from disseminated intravascular coagulation. Increased circulating D-dimer concentrations (reflecting pulmonary vascular bed thrombosis with fibrinolysis) and elevated cardiac enzyme concentrations (reflecting emergent ventricular stress induced by pulmonary hypertension) in the face of normal fibrinogen and platelet levels are key early features of severe pulmonary intravascular coagulopathy related to COVID-19. Extensive immunothrombosis over a wide pulmonary vascular territory without confirmation of COVID-19 viraemia in early disease best explains the adverse impact of male sex, hypertension, obesity, and diabetes on the prognosis of patients with COVID-19. The immune mechanism underlying diffuse alveolar and pulmonary interstitial inflammation in COVID-19 involves a MAS-like state that triggers extensive immunothrombosis, which might unmask subclinical cardiovascular disease and is distinct from the MAS and disseminated intravascular coagulation that is more familiar to rheumatologists.

Valvular endocarditis associated with Helcococcus ovis in a cow in Southern Brazil

ABSTRACT: A 4-year-old cow with a history of breathing difficulty, progressive weight loss, and muffled heart sound was treated for a period of two weeks, but died and underwent necropsy examination. Macroscopic examination revealed heart with vegetative proliferative lesion firmly adhered to pulmonary valve, lungs with marked consolidation, and the presence of thrombus in vessels. There were grade II ulcers in abomasal mucosa associated to blood clots. Microscopic examination revealed marked thickening of the pulmonary valve due to the proliferation of fibrous connective tissue, inflammatory neutrophil infiltration, fibrin deposition, and a significant number of coccoid basophilic bacteria. Septic thromboemboli were present in the large and small pulmonary blood vessels suggestive of embolic pneumonia. The bacterial culture of the valve showed growth of small, nonhemolytic colonies that demonstrated satellitism to coagulase-negative staphylococci contaminating colonies, which were subjected to 16S gene sequencing and were compatible with Helcococcus ovis in GenBank. This was the first report of H. ovis endocarditis in cattle in South America.

Longitudinal changes in structural lung abnormalities using MDCT in chronic obstructive pulmonary disease with asthma-like features.

Some patients with chronic obstructive pulmonary disease (COPD) have asthma-like features. However, there have been few reports on the structural lung abnormalities found in this patient population. Multi-detector computed tomography (MDCT) can detect emphysematous low-attenuation areas (LAA) within the lung, airway thickness (wall area percentage, WA%), and the loss of pulmonary vasculature as the percentage of small pulmonary vessels with cross-sectional area (CSA) less than 5 mm2 (%CSA<5). We analyzed differences in structural lung changes over time between patients with COPD and those with COPD with asthma-like features using these CT parameters. We performed pulmonary function tests (PFTs), MDCT, and a COPD assessment test (CAT) in 50 patients with COPD and 29 patients with COPD with asthma-like features at the time of enrollment and two years later. We analyzed changes in clinical parameters and CT indices over time and evaluated differences in structural changes between groups. The CAT score and FEV1 did not significantly change during the follow-up period in either group. Emphysematous LAA regions significantly increased in both groups. The %CSA<5 showed a small but significant increase in COPD patients, but a significant decrease in patients with COPD with asthma-like features. The WA% at the distal bronchi was significantly decreased in COPD, but did not significantly change in COPD with asthma -like features. Emphysematous LAA increased in patients with COPD with and without asthma-like features. The %CSA<5 and WA% at the distal bronchi did not change in parallel with LAA. Furthermore, changes in %CSA<5 were significantly different between patients with COPD and those with COPD with asthma-like features. Patients with COPD with asthma-like features may have different longitudinal structural changes than those seen in COPD patients.

An autopsy case of massive pulmonary tumor embolism due to undiagnosed prostatic adenocarcinoma

Adenocarcinoma of the prostate is occasionally associated with pulmonary embolism, occurring as a result of secondary hypercoagulable states or cancer-associated emboli. The objective of this study was to provide a review of clinical, histopathological and immunohistochemical features of poorly differentiated prostatic adenocarcinoma, emphasizing the relevance of undiagnosed malignancy as a cause of pulmonary embolism. The current study describes the case of a 78-year-old male who experienced remarkable clinical symptoms suggestive of pulmonary embolism. Following several diagnostic examinations, the patient was diagnosed with pulmonary embolism, which led to the detection of prostatic adenocarcinoma. Poorly differentiated adenocarcinoma with a Gleason's score of nine was set as a definite diagnosis. Multiple tumor emboli within small and medium-sized pulmonary blood vessels were found in all specimens taken from lung tissue. Immunohistochemical analysis showed diffuse and strong positivity of tumor cells within pulmonary arteries. Hidden malignancy is a diagnostic challenge that should be considered in the differential diagnosis of pulmonary embolism. Laboratory and radiological findings with additional histopathological evaluation are needed for the definite diagnosis.

Pulmonary Intravascular Large B-cell Lymphoma in a Patient Administered Methotrexate for Rheumatoid Arthritis.

A 70-year-old woman with rheumatoid arthritis undergoing methotrexate (MTX) treatment presented with dyspnea and a subfever. Computed tomography (CT) revealed a diffuse minimal ground-glass appearance in both lungs and splenomegaly. The gallium scintigram showed a diffuse, mild uptake in both lungs and the spleen. The lung biopsy specimen revealed the presence of CD20-positive atypical lymphocytes in the small pulmonary vessels. The patient was diagnosed with pulmonary intravascular diffuse large B-cell lymphoma (IVLBCL) and exhibited spontaneous regression after MTX was discontinued. This report describes a rare case of MTX-associated lymphoproliferative disorder expressing pulmonary IVLBCL.

Quantitative computed tomography measurement of cross-sectional area of small pulmonary vessels in asthmatic patients.

Background:Cross-sectional area (CSA) for small pulmonary vessels is considered a parameter of pulmonary vessel alterations in patients with chronic obstructive pulmonary disease. This study was to evaluate the correlation of CSA with airflow obstruction parameters in asthma. Furthermore, we aimed to measure the difference in vascular alteration between asthma phenotypes and evaluate its relation with cytokine levels.Methods:We consecutively enrolled 20 adult asthmatic patients (13 women: age range, 26–80 years) and 20 healthy controls (8 women: age range, 23–61 years) from Peking University Third Hospital. Total CSA <5 mm2 (CSA<5) was measured with 64-slice spiral computed tomography, and the percentage CSA <5 for the lung area (%CSA<5) was calculated. Data were corrected for body surface area to obtain sixth-generation airway luminal diameter (LDcor), luminal area (Aicor), and airway wall thickness, and airway wall area percentage (WA%) was calculated. Enzyme-linked immunosorbent assay was used to detect the expression of leptin, total immunoglobulin E, periostin, and transforming growth factor β1 in serum and matrix metalloproteinase 9 in induced sputum supernatant of asthmatic patients. The differences in %CSA<5 between subgroups were assessed by independent samples Student's t test, and Spearman correlation analysis was used to analyze the correlation of %CSA<5 with clinical indexes and inflammatory cytokine levels.Results:Patients with asthma and controls did not differ in %CSA<5. In asthma patients, %CSA<5 was lower with initial onset age ≤12 years old, airflow restriction and uncontrolled Global Initiative for Asthma classification (all P < 0.05). Moreover, it was positively correlated with forced vital capacity ratio in 1 s (FEV1)/forced expiratory volume ratio, FEV1%, LDcor, Aicor, and serum leptin level (all P < 0.05) and negatively with total lung WA% (P = 0.007).Conclusions:%CSA<5 of pulmonary small vessels was well correlated with airflow limitation indexes and sixth-generation airway parameters. It has certain significance in predicting the clinical control of asthma.

Pulmonary Arterial Hypertension Due to NPR-C Mutation: A Novel Paradigm for Normal and Pathologic Remodeling?

Idiopathic Pulmonary Arterial Hypertension (IPAH) is a deadly and disabling disease characterized by severe vascular remodeling of small pulmonary vessels by fibroblasts, myofibroblasts and vascular smooth muscle cell proliferation. Recent studies suggest that the Natriuretic Peptide Clearance Receptor (NPR-C) signaling pathways may play a crucial role in the development of IPAH. Reduced expression or function of NPR-C signaling in pulmonary artery smooth muscle cells may contribute to the pulmonary vascular remodeling, which is characteristic of this disease. The likely mechanisms may involve an impaired interaction between NPR-C, specific growth factors and other signal transduction pathways including but not limited to Gqα/mitogen-activated protein kinase (MAPK)/PI3K and AKT signaling. The resulting failure of growth suppression in pulmonary artery smooth muscle cells provides critical clues to the cellular pathobiology of IPAH. The reciprocal regulation of NPR-C signaling in models of tissue remodeling may thus provide new insights to our understanding of IPAH.

Ambient air pollution and pulmonary vascular volume on computed tomography: the MESA Air Pollution and Lung cohort studies.

Air pollution alters small pulmonary vessels in animal models. We hypothesised that long-term ambient air pollution exposure would be associated with differences in pulmonary vascular volumes in a population-based study. The Multi-Ethnic Study of Atherosclerosis recruited adults in six US cities. Personalised long-term exposures to ambient black carbon, nitrogen dioxide (NO2), oxides of nitrogen (NO x ), particulate matter with a 50% cut-off aerodynamic diameter of <2.5 μm (PM2.5) and ozone were estimated using spatiotemporal models. In 2010-2012, total pulmonary vascular volume was measured as the volume of detectable pulmonary arteries and veins, including vessel walls and luminal blood volume, on noncontrast chest computed tomography (TPVVCT). Peripheral TPVVCT was limited to the peripheral 2 cm to isolate smaller vessels. Linear regression adjusted for demographics, anthropometrics, smoking, second-hand smoke, renal function and scanner manufacturer. The mean±sd age of the 3023 participants was 69.3±9.3 years; 46% were never-smokers. Mean exposures were 0.80 μg·m-3 black carbon, 14.6 ppb NO2 and 11.0 μg·m-3 ambient PM2.5. Mean±sd peripheral TPVVCT was 79.2±18.2 cm3 and TPVVCT was 129.3±35.1 cm3. Greater black carbon exposure was associated with a larger peripheral TPVVCT, including after adjustment for city (mean difference 0.41 (95% CI 0.03-0.79) cm3 per interquartile range; p=0.036). Associations for peripheral TPVVCT with NO2 were similar but nonsignificant after city adjustment, while those for PM2.5 were of similar magnitude but nonsignificant after full adjustment. There were no associations for NO x or ozone, or between any pollutant and TPVVCT. Long-term black carbon exposure was associated with a larger peripheral TPVVCT, suggesting diesel exhaust may contribute to remodelling of small pulmonary vessels in the general population.

Adverse effect of smoking on cross-sectional area of small pulmonary vessel and arterial stiffness in healthy smokers without COPD.

Because it induces systemic inflammation, smoking is a risk factor of atherosclerosis and pulmonary hypertension. The brachial-ankle pulse wave velocity (baPWV) and cross-sectional area (CSA) of small pulmonary vessels can be useful markers to assess early changes of arterial stiffness and pulmonary vascular alteration in smokers. This study aimed to explore association between the CSA of small pulmonary vessel and arterial stiffness in healthy male smokers. We enrolled 90 male non-smokers and 90 male smokers (age: 51.5±9.7 years and 52.1±7.9 years, respectively). All subjects underwent chest computed tomography (CT), pulmonary function test and baPWV measurement. We evaluated the total CSAs less than 5 mm2 using ImageJ software and divided by the total lung area (%CSA<5). We compared the association between baPWV and %CSA<5 in two groups as well as correlations among the amount of smoking, baPWV and %CSA<5. Multiple linear regression analysis using %CSA<5 as the dependent variable was also performed. The mean baPWV and mean %CSA<5 were significantly different between the smokers and non-smokers. The pack-years was significantly correlated with %CSA<5 (r=-0.631, P<0.001) and baPWV (r=0.534, P<0.001) in smokers. In multiple linear regression analysis, age, pack-years, FEV1 /FVC and baPWV were associated with %CSA<5, regardless of body mass index, blood pressure and heart rate. There is a dose-response relationship between cigarette smoking and the CSA of small pulmonary vessels and arterial stiffness, respectively. Arterial stiffness, age, pack-years and mild airflow impairment are independent predictors of small pulmonary vascular destruction in smokers.

A novel cyclic biased agonist of the apelin receptor, MM07, is disease modifying in the rat monocrotaline model of pulmonary arterial hypertension.

Background and PurposeApelin is an endogenous vasodilatory and inotropic peptide that is down‐regulated in human pulmonary arterial hypertension, although the density of the apelin receptor is not significantly attenuated. We hypothesised that a G protein‐biased apelin analogue MM07, which is more stable than the endogenous apelin peptide, may be beneficial in this condition with the advantage of reduced β‐arrestin‐mediated receptor internalisation with chronic use.Experimental ApproachMale Sprague–Dawley rats received either monocrotaline to induce pulmonary arterial hypertension or saline and then daily i.p. injections of either MM07 or saline for 21 days. The extent of disease was assessed by right ventricular catheterisation, cardiac MRI, and histological analysis of the pulmonary vasculature. The effect of MM07 on signalling, proliferation, and apoptosis of human pulmonary artery endothelial cells was investigated.Key ResultsMM07 significantly reduced the elevation of right ventricular systolic pressure and hypertrophy induced by monocrotaline. Monocrotaline‐induced changes in cardiac structure and function, including right ventricular end‐systolic and end‐diastolic volumes, ejection fraction, and left ventricular end‐diastolic volume, were attenuated by MM07. MM07 also significantly reduced monocrotaline‐induced muscularisation of small pulmonary blood vessels. MM07 stimulated endothelial NOS phosphorylation and expression, promoted proliferation, and attenuated apoptosis of human pulmonary arterial endothelial cells in vitro.Conclusion and ImplicationsOur findings suggest that chronic treatment with MM07 is beneficial in this animal model of pulmonary arterial hypertension by addressing disease aetiology. These data support the development of G protein‐biased apelin receptor agonists with improved pharmacokinetic profiles for use in human disease.