ARDS - Papers

PV-K nanoparticles, intrinsically taken up by macrophages, suppressed NLRP3-mediated pyroptosis and mitigated inflammation in LPS and CLP mouse models of acute lung injury. Mechanistically, PV-K upregulated NRF2, enhanced p62-mediated autophagy, and promoted autolysosomal degradation of NLRP3; the effect was lost with impaired NRF2 signaling.

GEn-1124, an analog of UM101, enhances p38α binding and solubility, stabilizes endothelial barriers, and improves survival in murine ALI and influenza pneumonia models. It operates by destabilizing the activated p38α:MK2 complex, rebalancing downstream inflammatory signaling without inhibiting p38 catalytic activity.

This mechanistic study identifies a vagus–α7nAChR–LXA4 axis by which electroacupuncture enhances pro‑resolving lipid mediators, reduces lung permeability, and dampens cytokines in ALI. Macrophages mediate protection, α7nAChR is required, and preliminary patient data suggest symptom alleviation in sepsis-related ARDS.

Using lactylome/proteome profiling and Cut&Tag in septic mice, the authors show that lactate-driven H3K14 histone lactylation in pulmonary endothelial cells enriches at ferroptosis gene promoters (TFRC, SLC40A1), linking hyperglycolysis to endothelial ferroptosis and lung injury. Inhibiting glycolysis reduced H3K14la and EC activation, nominating the glycolysis–H3K14la–ferroptosis axis as a therapeutic target in sepsis-associated ARDS.

A modular, airway-deliverable microcapsule platform enables localized, durable release of IL-10 or IL-1Ra, attenuating inflammation in a rodent ARDS model and improving hypoxemia and structure in pulmonary fibrosis. Single-cell RNA-seq shows myeloid reprogramming, and large-animal testing supports safety, highlighting translational potential for ARDS and other inflammatory lung diseases.

Prospective human data and mechanistic experiments identify extracellular PRDX6 as a DAMP in ALI/ARDS. PRDX6 binds MD2 to activate TLR4/NF-κB, drives macrophage M1 polarization, and correlates with worse prognosis; blocking TLR4–MD2 attenuates inflammation.

This mechanistic study links obesity to aggravated ALI via suppression of ACOD1 in alveolar macrophages, driven by elevated GFI1 and modulated through Nrf2 signaling. ACOD1 overexpression was protective, while its knockdown worsened injury, highlighting the itaconate/Nrf2 pathway as a candidate therapeutic axis.

This mechanistic study shows that PRRSV-2 nsp2 directly engages the NLRP3 NACHT domain, recruits IKKβ, and drives NLRP3 translocation to the dispersed trans-Golgi network, enabling ASC polymerization and inflammasome activation. The IKKβ-dependent dTGN translocation was also required for PRV- and EMCV-induced inflammatory responses, indicating a broader, virus-agnostic pathway.

This mechanistic study identifies a previously unrecognized spleen-derived erythroblast-like population (Ter-cells) originating from megakaryocyte-erythroid progenitors that restrains acute lung injury progression via artemin signaling. It reframes ARDS pathobiology by implicating nonleukocyte cells from a distal organ in modulating lung injury.

Single-cell transcriptomics in COVID-19 identified myeloid mTOR signaling as a key regulator of hyperinflammation. A myeloid-targeted mTOR-inhibiting nanobiologic efficiently homes to myeloid cells and progenitors, and targeting this pathway prevents infection-associated inflammation.

Among 687 adults with moderate-to-severe ARDS, sevoflurane sedation resulted in fewer ventilator-free days through day 28 (median difference −2.1; 95% CI, −3.6 to −0.7) and lower 90-day survival (47.1% vs 55.7%; HR, 1.31; 95% CI, 1.05–1.62) compared with propofol. Sevoflurane also increased 7-day mortality (19.4% vs 13.5%; RR, 1.44) and reduced ICU-free days.

Using multiple Mendelian randomization frameworks across >100,000 participants and >10,000 cis-eQTLs, the authors mapped 50 genes causally linked to sepsis-related ARDS and highlighted four druggable targets (PSMA4, PDK2, RPS18, NDUFV3). They also confirmed a causal relationship between sepsis and ARDS (beta 1.80, SE 0.36, P<0.001).

EV-bound S100A8/A9 is elevated in sepsis/septic shock, discriminates septic shock from sepsis, and predicts ARDS. Septic shock EVs induce acute lung injury via alveolar macrophage uptake and S100A8/A9–RAGE signaling; neutralizing S100A8/A9 or genetic RAGE deficiency attenuates injury.

Septic plasma EVs carry miRNA/protein cargo that correlates with disease severity and independently predicts septic ARDS, notably LCN2, miR-122-5p, and miR-223-3p. Mechanistically, miR-223-3p in EVs activates Hippo signaling via MEF2C targeting to induce autophagy and ferroptosis in alveolar macrophages; in vivo inhibition attenuated lung injury.

Using an LPS-induced SAPF mouse model and fibroblast–macrophage co-cultures, the authors show that PGC-1α suppression in lung fibroblasts triggers mitochondrial dysfunction and mtDNA-laden migrasome release, which initiates macrophage–myofibroblast transition and accelerates fibrosis. Pharmacologic activation of PGC-1α curtailed migrasome release, inhibited MMT, and attenuated SAPF, revealing a targetable fibroblast–immune crosstalk.

Circulating heme is elevated in COVID-19 ARDS and induces dose-dependent cell death, inflammatory cytokine release, and ECM remodeling in human precision-cut lung slices. The heme-stimulated PCLS model reproduces inflammatory signatures seen in patient blood, providing a human-relevant ex vivo platform for ARDS research.

This ongoing multicenter, double-blind RCT will randomize 130 invasively ventilated ARDS patients to pirfenidone versus placebo for up to 28 days, with ventilator-free days at day 28 as the primary outcome. Secondary endpoints include ICU/hospital-free days, mortality, HRCT fibroproliferation markers, and quality of life.

O-GlcNAcylation dynamically increases during lung I/R and limits epithelial ferroptosis via the Nrf2/G6PDH pathway. Ogt1 deficiency exacerbates ferroptosis markers in vivo, supporting O-GlcNAc-dependent cytoprotection in ALI/ARDS contexts.

Pre-registered meta-analysis of 20 RCTs (n=3459) found that adjunct low-dose, short-course systemic corticosteroids probably reduce short-term mortality in severe pneumonia and ARDS. In severe pneumonia, mortality was reduced (RR 0.73, 95% CI 0.57–0.93); across conditions, hospital-acquired infections were not clearly increased.

This study presents the first coupled fluid-mechanics model of the alveolar capillary–interstitium–alveolus system, deriving simple equations for interstitial pressure and critical capillary pressure at which edema ensues. The model predicts biologically relevant membrane shear stresses and shows how active epithelial reabsorption redirects clearance pathways, with validation against clinical definitions and animal data.

Using gnotobiotic mice, lung epithelial cell assays, and ARDS patient metabolomics, the authors show that gut bacterial metabolites—specifically lactate—stimulate mitochondrial activity in lung epithelium and worsen acute lung injury. Colonization of germ-free mice induced lung mitochondrial gene programs, linking the gut–lung axis to ARDS pathobiology.

In 160 ARDS patients from the ROSE trial, integrated longitudinal plasma metabolomics and whole-blood transcriptomics identified four mortality-associated molecular signatures spanning innate immunity-glycolysis, hepatic/immune dysfunction with impaired beta-oxidation, interferon suppression with altered mitochondrial respiration, and redox/cell proliferation pathways. Signatures persisted to Day 2 and were validated in the EARLI sepsis cohort, highlighting mitochondrial dysfunction as a unifying feature.

In murine ALI, the RIPK1/RIPK3/MLKL necroptosis axis and TLR4 signaling via MYD88 and TRIF drive epithelial injury. A lipid micelle–encapsulated MLKL inhibitor targeted to alveolar type II cells selectively suppressed necroptosis and reduced lung injury and inflammation, highlighting a translational therapeutic strategy for ARDS.

This meta-analysis of five RCTs in TBI (n=1,533) found no mortality differences between liberal and restrictive transfusion strategies, but liberal transfusion increased ARDS risk (RR 1.78) and units transfused while potentially improving favorable neurologic outcomes after sensitivity analysis. The authors advocate reconsidering a 9 g/dL threshold, balancing neurologic benefit against pulmonary complications.