The Roles of S100A4 and the EGF/EGFR Signaling Axis in Pulmonary Hypertension with Right Ventricular Hypertrophy

Pulmonary hypertension (PH) is characterized by increased pulmonary arterial pressure caused by the accumulation of mesenchymal-like cells in the pulmonary vasculature. PH can lead to right ventricular hypertrophy (RVH) and, ultimately, heart failure and death. In PH etiology, endothelial-to-mesenchymal transition (EndMT) has emerged as a critical process governing the conversion of endothelial cells into mesenchymal cells, and S100A4, EGF, and EGFR are implicated in EndMT. However, a potential role of S100A4, EGF, and EGFR in PH has to date not been elucidated. We therefore quantified S100A4, EGF, and EGFR in patients suffering from chronic thromboembolic pulmonary hypertension (CTEPH) and idiopathic pulmonary arterial hypertension (iPAH). To determine specificity for unilateral heart disease, the EndMT biomarker signature was further compared between PH patients presenting with RVH and patients suffering from aortic valve stenosis (AVS) with left ventricular hypertrophy. Reduced S100A4 concentrations were found in CTEPH and iPAH patients with RVH. Systemic EGF was increased in CTEPH but not in iPAH, while AVS patients displayed slightly diminished EGF levels. EGFR was downregulated in all patient groups when compared to healthy controls. Longitudinal data analysis revealed no effect of surgical therapies on EndMT markers. Pulmonary thrombo-endarterectomized samples were devoid of S100A4, while S100A4 tissue expression positively correlated with higher grades of Heath–Edwards histopathological lesions of iPAH-derived lung tissue. Histologically, EGFR was not detectable in CTEPH lungs or in iPAH lesions. Together, our data suggest an intricate role for S100A4 and EGF/EGFR in PH with right heart pathology.

The association of lung function and pulmonary vasculature volume with cardiorespiratory fitness in the community

IntroductionCardiorespiratory fitness is not limited by pulmonary mechanical reasons in the majority of adults. However, the degree to which lung function contributes to exercise response patterns among ostensibly healthy individuals remains unclear.MethodsWe examined 2314 Framingham Heart Study participants who underwent cardiopulmonary exercise testing (CPET) and pulmonary function testing. We investigated the association of FEV1, FVC, FEV1/FVC and DLCO with the primary outcome of peak VO2, along with other CPET parameters using multivariable linear regression. Finally, we investigated the association of total and peripheral pulmonary blood vessel volume with peak VO2.ResultsWe found lower FEV1, FVC and DLCO were associated with lower peak VO2. For example, a one-liter lower FEV1 and FVC were associated with 7.1% (95% CI: 5.1%, 9.1%) and 6.0% (95% CI: 4.3%, 7.7%) lower peak VO2, respectively. By contrast, FEV1/FVC ratio was not associated with peak VO2. Lower lung function was associated with lower oxygen uptake efficiency slope oxygen pulse slope, VO2 at AT, VE at AT and breathing reserve. In addition, lower total and peripheral pulmonary blood vessel volume were associated with a lower peak VO2.ConclusionIn a large, community-based cohort of adults, we found lower FEV1, FVC and DLCO were associated with lower exercise capacity, as well as oxygen uptake efficiency slope and ventilatory efficiency. In addition, lower total and peripheral pulmonary blood vessel volume were associated with lower peak VO2. These findings underscore the importance of lung function and blood vessel volume as contributors to overall exercise capacity.

Vasculopathy in COVID-19

COVID-19 is a primary respiratory illness that is frequently complicated by systemic involvement of the vasculature. Vascular involvement leads to an array of complications ranging from thrombosis to pulmonary edema secondary to loss of barrier function. This review will address the vasculopathy of COVID-19 with a focus on the role of the endothelium in orchestrating the systemic response to SARS-CoV-2 infection. The endothelial receptor systems and molecular pathways activated in the setting of COVID-19 and the consequences of these inflammatory and prothrombotic changes on endothelial cell function will be discussed. The sequelae of COVID-19 vascular involvement at the level of organ systems will also be addressed, with an emphasis on the pulmonary vasculature, but with consideration of effects on other vascular beds. The dramatic changes in endothelial phenotypes associated with COVID-19 has enabled the identification of biomarkers that could help guide therapy and predict outcomes. Knowledge of vascular pathogenesis in COVID-19 has also informed therapeutic approaches that may control its systemic sequelae. Since our understanding of vascular response in COVID-19 continues to evolve, we will consider areas of controversy, such as the extent to which SARS-CoV-2 directly infects endothelium and the degree to which vascular responses to SARS-CoV-2 are unique or common to those of other viruses capable of causing severe respiratory disease. This conceptual framework describing how SARS-CoV-2 infection affects endothelial inflammation, prothrombotic transformation, and barrier dysfunction will provide a context for interpreting new information as it arises addressing the vascular complications of COVID-19.

Computed Tomography–Guided Microcoil Localization of Pulmonary Nodules: Effects of Multiple Punctures

Background The aim of the study is to analyze the effect of multiple punctures in computed tomography (CT)-guided microcoil localization of pulmonary nodules with other risk factors for common complications. Methods Consecutive patients who underwent CT-guided microcoil localization and subsequent video-assisted thoracoscopic surgery (VATS) between January 2020 and February 2021 were enrolled. Nodules successfully located after only one puncture were defined as the single puncture group, and nodules requiring two or more punctures were defined as the multiple puncture group. Binary logistic regression analysis was performed to assess the relationship between the number of punctures and pneumothorax and intrapulmonary hemorrhage. Results A total of 121 patients were included. There were 98 (68.1%) pulmonary nodules in the single puncture group compared with 46 (31.9%) nodules in the multiple puncture group. The frequencies of pneumothorax and intrapulmonary hemorrhage were higher in the multiple puncture group than in the single puncture group (p = 0.019 and <0.001, respectively). Binary logistic regression demonstrated that independent risk factors for developing pneumothorax included lateral positioning of the patient (p < .001) and prone positioning (p = 0.014), as well as multiple punctures (p = 0.013). Independent risk factors for intrapulmonary hemorrhage included the distance between the distal end of the coil and the surface of the pleura (p = 0.033), multiple punctures (p = 0.003), and passage through the pulmonary vasculature (p < 0.001). Conclusion Multiple punctures resulted in an increased incidence of pneumothorax and intrapulmonary hemorrhage compared with single puncture during CT-guided microcoil localization of pulmonary nodules and were independently associated with both pneumothorax and intrapulmonary hemorrhage.

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.

Respiratory Support of Infants With Congenital Diaphragmatic Hernia

Optimisation of respiratory support of infants with congenital diaphragmatic hernia (CDH) is critical. Infants with CDH often have severe lung hypoplasia and abnormal development of their pulmonary vasculature, leading to ventilation perfusion mismatch. It is vital that lung protective ventilation strategies are employed during both initial stabilisation and post-surgical repair to avoid ventilator induced lung damage and oxygen toxicity to prevent further impairment to an already diminished gas-exchanging environment. There is a lack of robust evidence for the routine use of surfactant therapy during initial resuscitation of infants with CDH and thus administration cannot be recommended outside clinical trials. Additionally, inhaled nitric oxide has been shown to have no benefit in reducing the mortality rates of infants with CDH. Other therapeutic agents which beneficially act on pulmonary hypertension are currently being assessed in infants with CDH in randomised multicentre trials. The role of novel ventilatory modalities such as closed loop automated oxygen control, liquid ventilation and heliox therapy may offer promise for infants with CDH, but the benefits need to be determined in appropriately designed clinical trials.

Interferon-induced transmembrane protein 3 (IFITM3) limits lethality of SARS-CoV-2 in mice

Interferon-induced transmembrane protein 3 (IFITM3) is a host antiviral protein that alters cell membranes to block fusion of viruses. Published reports have identified conflicting pro- and anti-viral effects of IFITM3 on SARS-CoV-2 in cultured cells, and its impact on viral pathogenesis in vivo remains unclear. Here, we show that IFITM3 knockout (KO) mice infected with mouse-adapted SARS-CoV-2 experienced extreme weight loss and lethality, while wild type (WT) mice lost minimal weight and recovered. KO mice had higher lung viral titers and increases in lung inflammatory cytokine levels, CD45-positive immune cell infiltration, and histopathology, compared to WT mice. Mechanistically, we observed disseminated viral antigen staining throughout the lung tissue and pulmonary vasculature in KO mice, while staining was observed in confined regions in WT lungs. Global transcriptomic analysis of infected lungs identified upregulation of gene signatures associated with interferons, inflammation, and angiogenesis in KO versus WT animals, highlighting changes in lung gene expression programs that precede severe lung pathology and fatality. Corroborating the protective effect of IFITM3 in vivo, K18-hACE2/IFITM3 KO mice infected with non-adapted SARS-CoV-2 showed enhanced, rapid weight loss and early death compared to control mice. Increased heart infection was observed in both mouse models in the absence of IFITM3, indicating that IFITM3 constrains extrapulmonary dissemination of SARS-CoV-2. Our results establish IFITM3 KO mice as a new animal model for studying severe SARS-CoV-2 infection of the lung and cardiovascular system, and overall demonstrate that IFITM3 is protective in SARS-CoV-2 infections of mice.

Smouldering fire or conflagration? An illustrated update on the concept of inflammation in pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a rare condition that is characterised by a progressive increase of pulmonary vascular resistances that leads to right ventricular failure and death, if untreated. The underlying narrowing of the pulmonary vasculature relies on several independent and interdependent biological pathways, such as genetic predisposition and epigenetic changes, imbalance of vasodilating and vasoconstrictive mediators, as well as dysimmunity and inflammation that will trigger endothelial dysfunction, smooth muscle cell proliferation, fibroblast activation and collagen deposition. Progressive constriction of the pulmonary vasculature, in turn, initiates and sustains hypertrophic and maladaptive myocardial remodelling of the right ventricle. In this review, we focus on the role of inflammation and dysimmunity in PAH which is generally accepted today, although existing PAH-specific medical therapies still lack targeted immune-modulating approaches.

Vascular Remodeling in Pulmonary Arterial Hypertension: The Potential Involvement of Innate and Adaptive Immunity

Pulmonary arterial hypertension (PAH) is a severe disease with high morbidity and mortality. Current therapies are mainly focused on vasodilative agents to improve prognosis. However, recent literature has shown the important interaction between immune cells and stromal vascular cells in the pathogenic modifications of the pulmonary vasculature. The immunological pathogenesis of PAH is known as a complex interplay between immune cells and vascular stromal cells, via direct contacts and/or their production of extra-cellular/diffusible factors such as cytokines, chemokines, and growth factors. These include, the B-cell—mast-cell axis, endothelium mediated fibroblast activation and subsequent M2 macrophage polarization, anti-endothelial cell antibodies and the versatile role of IL-6 on vascular cells. This review aims to outline the major pathophysiological changes in vascular cells caused by immunological mechanisms, leading to vascular remodeling, increased pulmonary vascular resistance and eventually PAH. Considering the underlying immunological mechanisms, these mechanisms may be key to halt progression of disease.

PULMONARY HYPERTENSION IN INFANTS WITH BRONCHOPULMONARY DYSPLASIA: CAUSES, DIAGNOSIS, TREATMENT

Bronchopulmonary dysplasia (BPD) is a leading chronic pathology of premature infants, which changes the structure of the lungs and disrupts the development of pulmonary vessels. The most important cardiovascular complication of BPD is the development of pulmonary hypertension, which is diagnosed in about 25 % of severely ill infants. Pulmonary hypertension associated with BPD develops due to lung vascular abnormalities and remodeling of the pulmonary vasculature, both of which lead to an increase in vascular resistance and the development of right ventricular heart failure. The occurrence of this complication worsens the prognosis of survival in infants with BPD, prolongs the total duration of hospital stay, adversely affects long-term somatic and neurological development and increases the frequency of re-hospitalizations. All this justifies the need for timely diagnosis and treatment of pulmonary hypertension in children with BPD. This review presents new data, for the definition, diagnosis, and treatment of pulmonary hypertension associated with BPD.