# Current Insights into Clinical, Molecular, and Therapeutic Approaches to Acute Respiratory Distress Syndrome

**Authors:** Manuel Gonzalez-Plascencia, Margarita L. Martinez-Fierro, Alfredo Salazar de Santiago, Ana G. Castañeda-Miranda, José I. Badillo-Almaraz, Idalia Garza-Veloz

PMC · DOI: 10.3390/medsci14010134 · 2026-03-13

## TL;DR

This review explores the biological basis of ARDS and highlights the need for precision-based treatments to improve patient outcomes.

## Contribution

The paper integrates experimental, clinical, and translational evidence to support a shift toward biologically informed ARDS management.

## Key findings

- ARDS involves epithelial and endothelial injury, dysregulated inflammation, and surfactant dysfunction.
- Emerging biomarker-based stratification may improve therapeutic targeting and prognostic precision in ARDS.
- Evidence supports moving from syndromic management to precision-based approaches for better clinical outcomes.

## Abstract

Acute respiratory distress syndrome (ARDS) remains a leading cause of morbidity and mortality in critically ill patients despite advances in supportive care and lung-protective ventilation. The syndrome is characterized by biological heterogeneity involving epithelial and endothelial injury, dysregulated inflammation, surfactant dysfunction, and impaired alveolar–capillary barrier integrity. This review integrates experimental, translational, and clinical evidence to examine the biological and molecular basis underlying ARDS, with particular emphasis on alveolar–capillary architecture, immune dysregulation, pulmonary mechanics, and the temporal evolution of diffuse alveolar damage. We further discuss emerging concepts in ARDS phenotyping and biomarker-based stratification as tools to address therapeutic heterogeneity and improve prognostic precision. Collectively, the evidence supports a shift from syndromic management toward biologically informed, precision-based approaches that may enable targeted interventions and improved clinical outcomes in ARDS.

## Linked entities

- **Diseases:** Acute respiratory distress syndrome (MONDO:0006502), ARDS (MONDO:0006502)

## Full-text entities

- **Genes:** CSF3 (colony stimulating factor 3) [NCBI Gene 1440] {aka C17orf33, CSF3OS, GCSF}, VWF (von Willebrand factor) [NCBI Gene 7450] {aka F8VWF, VWD}, REN (renin) [NCBI Gene 5972] {aka ADTKD4, HNFJ2, RTD}, CLDN3 (claudin 3) [NCBI Gene 1365] {aka C7orf1, CPE-R2, CPETR2, HRVP1, RVP1}, CALCA (calcitonin related polypeptide alpha) [NCBI Gene 796] {aka CALC1, CGRP, CGRP-I, CGRP-alpha, CGRP1, CT}, TJP1 (tight junction protein 1) [NCBI Gene 7082] {aka ZO-1}, TP53 (tumor protein p53) [NCBI Gene 7157] {aka BCC7, BMFS5, LFS1, P53, TRP53}, MSN (moesin) [NCBI Gene 4478] {aka HEL70, IMD50}, CSF2 (colony stimulating factor 2) [NCBI Gene 1437] {aka CSF, GMCSF}, AGRN (agrin) [NCBI Gene 375790] {aka AGRIN, CMS8, CMSPPD}, SFTPD (surfactant protein D) [NCBI Gene 6441] {aka COLEC7, PSP-D, SFTP4, SP-D}, IL1A (interleukin 1 alpha) [NCBI Gene 3552] {aka IL-1 alpha, IL-1A, IL1, IL1-ALPHA, IL1F1}, TREM1 (triggering receptor expressed on myeloid cells 1) [NCBI Gene 54210] {aka CD354, TREM-1}, LPA (lipoprotein(a)) [NCBI Gene 4018] {aka AK38, APOA, LP}, SULT1A3 (sulfotransferase family 1A member 3) [NCBI Gene 6818] {aka HAST, HAST3, M-PST, ST1A3, ST1A3/ST1A4, ST1A4}, LAIR1 (leukocyte associated immunoglobulin like receptor 1) [NCBI Gene 3903] {aka CD305, LAIR-1}, ANGPT1 (angiopoietin 1) [NCBI Gene 284] {aka AGP1, AGPT, AGPT-1, ANG1, HAE5}, SPDL1 (spindle apparatus coiled-coil protein 1) [NCBI Gene 54908] {aka CCDC99}, STAT3 (signal transducer and activator of transcription 3) [NCBI Gene 6774] {aka ADMIO, ADMIO1, APRF, HIES}, SIRPA (signal regulatory protein alpha) [NCBI Gene 140885] {aka BIT, CD172A, MFR, MYD-1, MYD1, P84}, MIR122 (microRNA 122) [NCBI Gene 406906] {aka MIR122A, MIRN122, MIRN122A, hsa-mir-122, miRNA122, miRNA122A}, HLA-A (major histocompatibility complex, class I, A) [NCBI Gene 3105] {aka HLAA}, GPX4 (glutathione peroxidase 4) [NCBI Gene 2879] {aka GPx-4, GSHPx-4, MCSP, PHGPx, SMDS, snGPx}, VCAM1 (vascular cell adhesion molecule 1) [NCBI Gene 7412] {aka CD106, INCAM-100}, S100A9 (S100 calcium binding protein A9) [NCBI Gene 6280] {aka 60B8AG, CAGB, CFAG, CGLB, L1AG, LIAG}, SFTPA1 (surfactant protein A1) [NCBI Gene 653509] {aka COLEC4, ILD1, PSP-A, PSPA, SFTP1, SFTPA1B}, CRP (C-reactive protein) [NCBI Gene 1401] {aka PTX1}, TYMS (thymidylate synthetase) [NCBI Gene 7298] {aka DKCD, HST422, TMS, TS}, ANGPT2 (angiopoietin 2) [NCBI Gene 285] {aka AGPT2, ANG2, LMPHM10}, NLRP7 (NLR family pyrin domain containing 7) [NCBI Gene 199713] {aka CLR19.4, HYDM, NALP7, NOD12, OZEMA25, PAN7}, IFNG (interferon gamma) [NCBI Gene 3458] {aka IFG, IFI, IMD69}, CLDN4 (claudin 4) [NCBI Gene 1364] {aka CPE-R, CPER, CPETR, CPETR1, WBSCR8, hCPE-R}, TGFB1 (transforming growth factor beta 1) [NCBI Gene 7040] {aka CAEND1, CED, DPD1, IBDIMDE, LAP, TGF-beta1}, ESM1 (endothelial cell specific molecule 1) [NCBI Gene 11082] {aka endocan}, CYTH3 (cytohesin 3) [NCBI Gene 9265] {aka ARNO3, GRP1, PSCD3, cytohesin-3}, HMGB1 (high mobility group box 1) [NCBI Gene 3146] {aka HMG-1, HMG1, HMG3, SBP-1}, HIF1A (hypoxia inducible factor 1 subunit alpha) [NCBI Gene 3091] {aka HIF-1-alpha, HIF-1A, HIF-1alpha, HIF1, HIF1-ALPHA, MOP1}, FN1 (fibronectin 1) [NCBI Gene 2335] {aka CIG, ED-B, FINC, FN, FNZ, GFND}, AGER (advanced glycosylation end-product specific receptor) [NCBI Gene 177] {aka RAGE, SCARJ1, sRAGE}, TNFRSF11B (TNF receptor superfamily member 11b) [NCBI Gene 4982] {aka OCIF, OPG, PDB5, TR1}, ACE2 (angiotensin converting enzyme 2) [NCBI Gene 59272] {aka ACEH}, SDC1 (syndecan 1) [NCBI Gene 6382] {aka CD138, SDC, SYND1, syndecan}, NFKB1 (nuclear factor kappa B subunit 1) [NCBI Gene 4790] {aka CVID12, EBP-1, KBF1, NF-kB, NF-kB1, NF-kappa-B1}, IL12B (interleukin 12B) [NCBI Gene 3593] {aka CLMF, CLMF2, IL-12B, IMD28, IMD29, NKSF}, IL4 (interleukin 4) [NCBI Gene 3565] {aka BCGF-1, BCGF1, BSF-1, BSF1, IL-4}, WWOX (WW domain containing oxidoreductase) [NCBI Gene 51741] {aka D16S432E, DEE28, EIEE28, FOR, FRA16D, HHCMA56}, RXRA (retinoid X receptor alpha) [NCBI Gene 6256] {aka NR2B1, RXR-alpha, RXRalpha}, IL18 (interleukin 18) [NCBI Gene 3606] {aka IGIF, IL-18, IL-1g, IL1F4}, ENAH (ENAH actin regulator) [NCBI Gene 55740] {aka ENA, MENA, NDPP1}, ELN (elastin) [NCBI Gene 2006] {aka ADCL1, SVAS, WBS, WS}, CDH5 (cadherin 5) [NCBI Gene 1003] {aka 7B4, CD144}, DFFA (DNA fragmentation factor subunit alpha) [NCBI Gene 1676] {aka DFF-45, DFF1, ICAD}, BTN3A2 (butyrophilin subfamily 3 member A2) [NCBI Gene 11118] {aka BT3.2, BTF4, BTN3.2, CD277}, MUC1 (mucin 1, cell surface associated) [NCBI Gene 4582] {aka ADMCKD, ADMCKD1, ADTKD2, CA 15-3, CD227, Ca15-3}, B2M (beta-2-microglobulin) [NCBI Gene 567] {aka AMYLD6, IMD43, MHC1D4}, SFTPB (surfactant protein B) [NCBI Gene 6439] {aka PSP-B, SFTB3, SFTP3, SMDP1, SP-B}, AGT (angiotensinogen) [NCBI Gene 183] {aka ANHU, SERPINA8, hFLT1}, OCLN (occludin) [NCBI Gene 100506658] {aka BLCPMG, PPP1R115, PTORCH1}, LTBR (lymphotoxin beta receptor) [NCBI Gene 4055] {aka D12S370, LT-BETA-R, TNF-R-III, TNFCR, TNFR-RP, TNFR2-RP}, AKT1 (AKT serine/threonine kinase 1) [NCBI Gene 207] {aka AKT, PKB, PKB-ALPHA, PRKBA, RAC, RAC-ALPHA}
- **Diseases:** septic (MESH:D001170), alveolar (MESH:D002282), critical illness (MESH:D016638), cytotoxicity (MESH:D064420), immune dysfunction (MESH:D007154), pancreatitis (MESH:D010195), Inhalation injury (MESH:D015208), pulmonary infiltrates (MESH:D017254), aspergillosis (MESH:D001228), Alveolar Damage (MESH:D055370), organizing pneumonia (MESH:D000092124), microvascular dysfunction (MESH:D017566), DAD (MESH:D000070625), COPD (MESH:D029424), impaired ventilation (MESH:D053717), Instability (MESH:D043171), dyspnea (MESH:D004417), bronchiectasis (MESH:D001987), Lung (MESH:D008171), myocardial damage (MESH:D009202), hypercapnia (MESH:D006935), Acute Respiratory Distress Syndrome (MESH:D012128), Tachycardia (MESH:D013610), perfusion abnormalities (MESH:D000014), alveolar collapse (MESH:D001261), alveolar opacities (MESH:D003318), immune or oncologic disorders (MESH:D000072716), vasoplegia (MESH:D056987), exchange (MESH:D001816), metabolic acidosis (MESH:D000138), acute eosinophilic pneumonia (MESH:D015472), idiopathic pulmonary fibrosis (MESH:D054990), Vascular Dysregulation (MESH:D021081), endotoxic shock (MESH:D012772), fungal superinfection (MESH:D015163), AEC2 injury (MESH:D014947), coronavirus pneumonia (MESH:D018352), cardiogenic (MESH:D013575), CT (MESH:C000719218), intra-alveolar hemorrhage (MESH:D006470), infection (MESH:D007239), acute injury (MESH:D001930), mechanical (MESH:D041781), Pulmonary contusion (MESH:D003288), gastric aspiration (MESH:D011015), fungal (MESH:D009181), dysfunction (MESH:D006331), peritonitis (MESH:D010538), Death (MESH:D003643), Pneumonia (MESH:D011014), bacterial infection (MESH:D001424), fluid overload (MESH:D019190), platelet aggregate (MESH:D001791), Endothelial Injury (MESH:D057772), neuromuscular blockade (MESH:D020879), obesity (MESH:D009765), thoracic trauma (MESH:D013896), burns (MESH:D002056), cardiac failure (MESH:D006333), neutrophil (MESH:C564275)
- **Chemicals:** Pv (MESH:D010404), Heparin (MESH:D006493), MDA (MESH:D015104), prostacyclin (MESH:D011464), Vincristine (MESH:D014750), Hyaluronic acid (MESH:D006820), Vitamin E acetate (MESH:D024502), lipids (MESH:D008055), Bleomycin (MESH:D001761), mitomycin-C (MESH:D016685), calcium (MESH:D002118), Amiodarone (MESH:D000638), tocilizumab (MESH:C502936), aldehydes (MESH:D000447), ACM (-), NO (MESH:D009569), carbon (MESH:D002244), volatile organic compounds (MESH:D055549), O3 (MESH:D010126), malondialdehyde (MESH:D008315), O2 (MESH:D010100), imatinib (MESH:D000068877), paquinimod (MESH:C573440), bicarbonate (MESH:D001639), steroid (MESH:D013256), LPS (MESH:D008070), Desmosine (MESH:D003895), CO2 (MESH:D002245), simvastatin (MESH:D019821), water (MESH:D014867), CO (MESH:D002248), DPPC (MESH:D015060), Nitrofurantoin (MESH:D009582), gemcitabine (MESH:D000093542), cytarabine (MESH:D003561), ROS (MESH:D017382), vinca alkaloids (MESH:D014748), Tetrahydrocannabinol (MESH:D013759), SO2 (MESH:D013458), bilirubin (MESH:D001663), PO2 (MESH:C093415), NO2 (MESH:D009585), GSH (MESH:D005978)
- **Species:** Homo sapiens (human, species) [taxon 9606], Mus musculus (house mouse, species) [taxon 10090], Severe acute respiratory syndrome coronavirus 2 (no rank) [taxon 2697049]
- **Mutations:** AUC of 0, -1082 G/G
- **Cell lines:** AEC2 — Bos taurus (Bovine), Telomerase immortalized cell line (CVCL_T048), MLE-12 — Mus musculus (Mouse), Transformed cell line (CVCL_3751), HARP-2 — Homo sapiens (Human), Colon carcinoma, Cancer cell line (CVCL_A628), C57BL/6 — Mus musculus (Mouse), Transformed cell line (CVCL_C0MU)

## Figures

4 figures with captions in the complete paper: https://tomesphere.com/paper/PMC13027457/full.md

---
Source: https://tomesphere.com/paper/PMC13027457