{"doi":"10.1165/rcmb.2024-0486ed","title":"Can ENaC “TIP” the Scales to Reduce Endothelial Reactive Oxygen Species and Vascular Leak during Pneumococcal Lung Injury?","abstract":"Can ENaC \"TIP\" the Scales to Reduce Endothelial Reactive Oxygen Species and Vascular Leak during Pneumococcal Lung Injury?Despite the availability of effective vaccines and antibiotics, Streptococcus pneumoniae (S. pneumoniae) remains a clinically important cause of community-acquired pneumonia and severe bacterial infections, which can progress to include the devastating complication of acute respiratory distress syndrome (ARDS).A major component of ARDS pathophysiology is inflammation-induced vascular leak, which leads to alveolar edema and critical oxygenation deficits (1).Unraveling the underlying mechanisms that drive vascular permeability and inflammation is essential for the development of new therapeutics.Extensive prior research has identified that amiloride-sensitive ENaC (epithelial sodium channel) is crucial for alveolar fluid clearance and edema resolution and is a possible therapeutic target in ARDS (2).ENaC is a heterotrimeric protein composed of three main subunits-a, b, and g-and is highly selective for Na 1 cations (3).ENaC activity can be stimulated by the 17 amino acid TIP peptide, which interacts directly with the ENaC a subunit and protects against multiple preclinical models of acute lung injury (ALI) (4).TIP is being evaluated as a therapy in clinical trials of ARDS ( 5) and is an excellent tool to explore the mechanisms by which ENaC-a regulates cellular functions.Although initially believed to be an epithelial channel, ENaC expressed in vascular endothelial cells (ECs) also has important functional effects (6).In a study reported in this issue of the Journal, Romero and colleagues (pp.429-440) build on their prior work to investigate how lung endothelial expression of ENaC-a may modulate oxidative stress responses in lung capillaries during S. pneumoniae-induced ALI (7).They also test whether TIP activation of endothelial ENaC-a exerts protective effects.One crucial mechanism by which S. pneumoniae causes injury is through production and release of the pore-forming toxin PLY (pneumolysin), which contributes to ALI pathogenesis by increasing permeability, cellular toxicity, immune cell activation, and excessive inflammation (8).Romero and colleagues present novel data demonstrating that the injurious effects of PLY can be modulated by the ENaC-a-NOX2 (NADPH oxidase 2) axis in lung endothelium.NOX2 is a key enzyme involved in the production of reactive oxygen species (ROS) in multiple cell types, including those of the pulmonary endothelium (9).NOX2 is upregulated in patients with pneumococcal pneumonia (10) and contributes to inflammatory injury in preclinical models.However, concerns exist about globally suppressing NOX2 activity during infections because of potential detrimental effects on the bactericidal capacity of neutrophils (11).Thus, cell-specific inhibition of NOX2 could be a promising therapeutic approach for pneumonia-induced ARDS.","journal":"American Journal of Respiratory Cell and Molecular Biology","year":2024,"id":482131,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9511,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":402508,"name":"Eleftheria Letsiou","orcid":"0000-0002-9553-4958","position":1,"is_corresponding":false},{"id":388392,"name":"Steven M. Dudek","orcid":"0000-0001-5624-0714","position":2,"is_corresponding":false},{"id":268434,"name":"Alison W. Ha","orcid":"0009-0007-5385-915X","position":0,"is_corresponding":true}],"reference_count":13,"raw_metadata":null,"created_at":"2026-07-19T02:07:14.349221Z","pmid":"39514001","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}