Bioenergetics and metabolism of the pulmonary endothelium. Scientific session I: ReSPIRE 2025.

Session I of the inaugural biennial Research Symposium on Pulmonary Injury and Repair of the Endothelium (ReSPIRE) highlighted recent advances in endothelial bioenergetics and metabolism and their role in pulmonary vascular diseases. Emerging evidence suggests that the maladaptation of metabolic pathways in the lung endothelium contributes to the progression of the acute respiratory distress syndrome (ARDS) and pulmonary arterial hypertension (PAH). The conference highlighted several new aspects of endothelial metabolism, including the use of alternative fuel sources such as fructose and fatty acids, inflammatory signaling mediated by mitochondrial depolarization, bioenergetic reprogramming through isoform switching of genes during hypoxia, and feedback regulation of metabolism by hypercapnia.

Lung Single-Cell Transcriptomics Reveal Diverging Pathobiology and Opportunities for Precision Targeting in Scleroderma-Associated Versus Idiopathic Pulmonary Arterial Hypertension.

Background: Pulmonary arterial hypertension (PAH) involves progressive cellular and molecular change within the pulmonary vasculature, leading to increased vascular resistance. Current therapies targeting nitric oxide, endothelin, and prostacyclin pathways yield variable treatment responses. Patients with systemic sclerosis-associated PAH (SSc-PAH) often experience worse outcomes than those with idiopathic PAH (IPAH).

Correction: Bronchoalveolar lavage cell percentages as diagnostic markers of immune checkpoint inhibitor pneumonitis.

[This corrects the article DOI: 10.3389/fmed.2025.

Bronchoalveolar lavage cell percentages as diagnostic markers of immune checkpoint inhibitor pneumonitis.

Introduction: Diagnostic biomarkers for immune checkpoint inhibitor pneumonitis (ICIP) are lacking. Bronchoalveolar lavage (BAL) lymphocytosis has been associated with ICIP, but studies have not evaluated BAL lymphocytosis as a diagnostic biomarker for ICIP.

Purpose: This study aimed to measure the association of BAL immune cell percentage with ICIP and test its performance as a diagnostic biomarker.

Dysregulated Tricarboxylic Acid Cycle Metabolism Is Associated With Right Ventricular Maladaptation in Pulmonary Vascular Disease.

Background: Right ventricular (RV) maladaptation to elevated pulmonary afterload is the primary determinant of outcomes in pulmonary artery (PA) hypertension; however, the pathobiological mechanisms underlying RV decompensation remain poorly understood.

Methods: We performed global untargeted metabolomics on plasma from 55 patients who underwent gold-standard RV-PA coupling measurements using multibeat pressure volume loop assessment in a single-center cohort and from 1027 patients with coupling surrogate measurements in a larger multicenter cohort, the PVDOMICS (Pulmonary Vascular Disease Phenomics) study. Age and sex-adjusted linear regression was performed to identify associations between metabolites and coupling metrics.

Artificial Intelligence-Driven Wireless Sensing for Health Management.

(1) Background: With technological advancements, the integration of wireless sensing and artificial intelligence (AI) has significant potential for real-time monitoring and intervention. Wireless sensing devices have been applied to various medical areas for early diagnosis, monitoring, and treatment response. This review focuses on the latest advancements in wireless, AI-incorporated methods applied to clinical medicine.

Development of a preclinical model of ICU-associated sleep fragmentation and effects on pneumonia recovery in mice.

Patients in the intensive care unit (ICU) experience many ICU-specific factors that could impact their outcomes apart from their underlying acute illness. The precise function of sleep is not clear, but its importance is suggested by the literature on the deleterious effects of poor sleep and sleep deprivation and may represent a modifiable opportunity in ICU patients. Investigation into the role of sleep in critical illness is impeded by a lack of sufficient murine models.

Physiological shear stress suppresses apoptosis in human pulmonary microvascular endothelial cells.

Physiological shear stress contributes to maintaining endothelial cell homeostasis, including suppression of apoptosis. In the pulmonary circulation, diseases such as pulmonary embolism and pulmonary hypertension result in alterations in shear stress. Shear stress has been reported to suppress endothelial apoptosis through phosphatidylinositol 3-kinase (PI3K) activation, but evidence from human pulmonary microvascular endothelial cells (PMVECs) is lacking.

Distinct single-cell transcriptional profile in CD4+ T-lymphocytes among obese children with asthma.

Obesity is a risk factor for asthma morbidity, associated with less responsiveness to inhaled corticosteroids. CD4+ T cells are central to the immunology of asthma and may contribute to the unique obese asthma phenotype. We sought to characterize the single-cell CD4+ transcriptional profile differences in obese children with asthma compared with normal-weight children with asthma.

Single-cell transcriptomics reveal diverging pathobiology and opportunities for precision targeting in scleroderma-associated versus idiopathic pulmonary arterial hypertension.

Introduction: Pulmonary arterial hypertension (PAH) involves progressive cellular and molecular change within the pulmonary vasculature, leading to increased vascular resistance. Current therapies targeting nitric oxide (NO), endothelin, and prostacyclin pathways yield variable treatment responses. Patients with systemic sclerosis-associated PAH (SSc-PAH) often experience worse outcomes than those with idiopathic PAH (IPAH).

Studying the Pulmonary Endothelium in Health and Disease: An Official American Thoracic Society Workshop Report.

Lung endothelium resides at the interface between the circulation and the underlying tissue, where it senses biochemical and mechanical properties of both the blood as it flows through the vascular circuit and the vessel wall. The endothelium performs the bidirectional signaling between the blood and tissue compartments that is necessary to maintain homeostasis while physically separating both, facilitating a tightly regulated exchange of water, solutes, cells, and signals. Disruption in endothelial function contributes to vascular disease, which can manifest in discrete vascular locations along the artery-to-capillary-to-vein axis.

Aquaporin 1 confers apoptosis resistance in pulmonary arterial smooth muscle cells from the SU5416 hypoxia rat model.

Pulmonary hypertension (PH) arises from increased pulmonary vascular resistance due to contraction and remodeling of the pulmonary arteries. The structural changes include thickening of the smooth muscle layer from increased proliferation and resistance to apoptosis. The mechanisms underlying apoptosis resistance in PH are not fully understood.

A novel interaction between aquaporin 1 and caspase-3 in pulmonary arterial smooth muscle cells.

Pulmonary hypertension (PH) is a condition in which remodeling of the pulmonary vasculature leads to hypertrophy of the muscular vascular wall and extension of muscle into nonmuscular arteries. These pathological changes are predominantly due to the abnormal proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs), enhanced cellular functions that have been linked to increases in the cell membrane protein aquaporin 1 (AQP1). However, the mechanisms underlying the increased AQP1 abundance have not been fully elucidated.

Pulmonary toxicity of immune checkpoint immunotherapy.

Cancer remains a leading cause of mortality on a global scale. Lung cancer, specifically non-small cell lung cancer (NSCLC), is a prominent contributor to this burden. The management of NSCLC has advanced substantially in recent years, with immunotherapeutic agents, such as immune checkpoint inhibitors (ICIs), leading to improved patient outcomes.

Fatty acid metabolism promotes TRPV4 activity in lung microvascular endothelial cells in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a morbid disease characterized by significant lung endothelial cell (EC) dysfunction. Prior work has shown that microvascular endothelial cells (MVECs) isolated from animals with experimental PAH and patients with PAH exhibit significant abnormalities in metabolism and calcium signaling. With regards to metabolism, we and others have shown evidence of increased aerobic glycolysis and evidence of increased utilization of alternate fuel sources (such as fatty acids) in PAH EC.

Spatial and temporal resolution of metabolic dysregulation in the Sugen hypoxia model of pulmonary hypertension.

Although PAH is partially attributed to disordered metabolism, previous human studies have mostly examined circulating metabolites at a single time point, potentially overlooking crucial disease biology. Current knowledge gaps include an understanding of temporal changes that occur within and across relevant tissues, and whether observed metabolic changes might contribute to disease pathobiology. We utilized targeted tissue metabolomics in the Sugen hypoxia (SuHx) rodent model to investigate tissue-specific metabolic relationships with pulmonary hypertensive features over time using regression modeling and time-series analysis.

Metabolic profiling of in vivo right ventricular function and exercise performance in pulmonary arterial hypertension.

Right ventricular (RV) adaptation is the principal determinant of outcomes in pulmonary arterial hypertension (PAH), however, RV function is challenging to assess. RV responses to hemodynamic stressors are particularly difficult to interrogate without invasive testing. This study sought to identify metabolomic markers of in vivo right ventricular function and exercise performance in PAH.

Society for Immunotherapy of Cancer (SITC) consensus definitions for immune checkpoint inhibitor-associated immune-related adverse events (irAEs) terminology.

Immune-related adverse events (irAEs) associated with immune checkpoint inhibitor (ICI) therapy may vary substantially in their clinical presentation, including natural history, outcomes to treatment, and patterns. The application of clinical guidelines for irAE management can be challenging for practitioners due to a lack of common or consistently applied terminology. Furthermore, given the growing body of clinical experience and published data on irAEs, there is a greater appreciation for the heterogeneous natural histories, responses to treatment, and patterns of these toxicities, which is not currently reflected in irAE guidelines.

MK2 nonenzymatically promotes nuclear translocation of caspase-3 and resultant apoptosis.

We have previously identified mitogen-activated protein kinase-activated protein kinase 2 (MK2) is required for caspase-3 nuclear translocation in the execution of apoptosis; however, little is known of the underlying mechanisms. Therefore, we sought to determine the role of kinase and nonkinase functions of MK2 in promoting nuclear translocation of caspase-3. We identified two non-small cell lung cancer cell lines for use in these experiments based on low MK2 expression.

Tumor MK2 transcript levels are associated with improved response to chemotherapy and patient survival in non-small cell lung cancer.

Non-small cell lung cancers (NSCLCs) demonstrate intrinsic resistance to cell death, even after chemotherapy. Previous work suggested defective nuclear translocation of active caspase-3 in observed resistance to cell death. We have identified mitogen-activated protein kinase-activated protein kinase 2 (MK2; encoded by the gene ) is required for caspase-3 nuclear translocation in the execution of apoptosis in endothelial cells.

Transpulmonary amino acid metabolism in the sugen hypoxia model of pulmonary hypertension.

In pulmonary artery hypertension (PAH), emerging evidence suggests that metabolic abnormalities may be contributing to cellular dysfunction in PAH. Metabolic abnormalities such as glycolytic shift have been observed intracellularly in several cell types in PAH, including microvacular endothelial cells (MVECs). Concurrently, metabolomics of human PAH samples has also revealed a variety of metabolic abnormalities; however the relationship between the intracellular metabolic abnormalities and the serum metabolome in PAH remains under investigation.