Daily Respiratory Research Analysis
Analyzed 191 papers and selected 3 impactful papers.
Summary
Three papers stand out today: a single-cell, drug-perturbation study of early-stage IPF airways revealing actionable epithelial–mesenchymal programs with promising response to Src inhibition; a head-to-head preclinical comparison showing baloxavir clearly outperforms oseltamivir, favipiravir, and amantadine against contemporary H5N1; and a large multi-ancestry proteomic analysis identifying over 1,000 circulating proteins associated with lung function. Together, they advance mechanisms, therapeutics, and biomarker discovery in respiratory disease.
Research Themes
- Airway epithelial–mesenchymal programs and drug responsiveness in early-stage IPF
- Antiviral comparative efficacy against contemporary H5N1
- Circulating proteomic determinants of lung function across ancestries
Selected Articles
1. Transcriptomic signatures of IPF in ALI-cultured airway cells and their therapeutic implications.
Using single-cell RNA-seq of air–liquid interface airway cultures from newly diagnosed, treatment-naïve IPF, the authors delineate early epithelial–mesenchymal programs and demonstrate distinct, cell-state–specific responses to antifibrotics and the Src inhibitor saracatinib. Findings position Src pathway modulation as a promising therapeutic angle in early IPF.
Impact: This work shifts IPF investigation upstream to the diagnostic window and links airway-derived single-cell states to drug responsiveness, highlighting saracatinib as a candidate beyond current antifibrotics.
Clinical Implications: Suggests a precision-medicine path for early IPF by targeting Src-driven epithelial–mesenchymal programs and provides a rationale for patient stratification and early-phase trials of saracatinib.
Key Findings
- Single-cell profiling (129,986 transcriptomes) of ALI-cultured IPF airway mucosa identified early epithelial–mesenchymal programs and primed fibroblast states.
- Drug-perturbation revealed distinct, cell-state–specific responses to nintedanib, pirfenidone, and the Src inhibitor saracatinib.
- Data support Src pathway modulation (saracatinib) as a therapeutic strategy at the diagnostic stage of IPF.
Methodological Strengths
- Use of air–liquid interface primary airway cultures with single-cell resolution in newly diagnosed, treatment-naïve IPF
- Direct drug-perturbation testing linking cellular programs to pharmacologic responsiveness
Limitations
- Ex vivo study without clinical outcome data or longitudinal validation
- Patient number not specified; generalizability and between-patient heterogeneity require confirmation
Future Directions: Prospective enrichment trials of Src inhibition with biomarker-defined airway programs; longitudinal sampling to track program dynamics and treatment response in early IPF.
INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with limited treatment options. Most single-cell studies rely on end-stage explant lungs, leaving early disease mechanisms poorly understood. Profiling earlier stages may reveal distinct cellular phenotypes that could be pharmacologically targeted. Recent evidence also implicates airway epithelial cells in IPF disease development and progression. METHODS: To investigate early-stage IPF mechanisms, we profiled the airway mucosa of newly diagnosed, treatment-naïve patients using single-cell RNA-sequencing of air-liquid interface cultures. We further assessed the transcriptional and functional responses of these cells to antifibrotic drugs (nintedanib and pirfenidone) and a Src kinase inhibitor (saracatinib). RESULTS: Profiling of 129 986 transcriptomes identified primed fibroblasts ( CONCLUSIONS: This study defines epithelial-mesenchymal programmes of the airway mucosa at an early, diagnostic stage of IPF and demonstrates distinct drug responses at single-cell resolution. By linking airway-derived phenotypes to antifibrotic efficacy, our findings highlight the therapeutic potential of saracatinib and may inform future treatment strategies.
2. Baloxavir outperforms oseltamivir, favipiravir, and amantadine in treating lethal influenza A(H5N1) HA clade 2.3.4.4b infection in mice.
In a lethal mouse model of contemporary H5N1 (clade 2.3.4.4b), baloxavir single-dose therapy fully protected, suppressed respiratory viral replication, and prevented neuroinvasion, outperforming oseltamivir, favipiravir, and amantadine. These data support prioritizing baloxavir in pandemic response planning for H5N1.
Impact: Provides head-to-head preclinical efficacy data with clear superiority of baloxavir against a high-consequence zoonotic strain, directly informing antiviral prioritization.
Clinical Implications: Although preclinical, the results justify early consideration of baloxavir in stockpiling and clinical trial designs for emerging H5N1 events.
Key Findings
- Baloxavir (≥10 mg/kg single dose) fully protected mice, reduced respiratory viral replication, and prevented neuroinvasion.
- Oseltamivir reduced lung titers but offered limited survival benefit and did not prevent neuroinvasion.
- Favipiravir conferred partial protection without reducing lung/brain titers; amantadine was ineffective.
- In vitro inhibition did not predict in vivo efficacy except for baloxavir.
Methodological Strengths
- Direct, head-to-head comparison across four antiviral classes in a standardized lethal H5N1 model
- Comprehensive virologic endpoints including neuroinvasion assessment
Limitations
- Preclinical mouse model may not fully recapitulate human pharmacokinetics and disease phenotypes
- Single strain and dosing regimens; generalizability to other clade 2.3.4.4b variants and clinical dosing needs validation
Future Directions: Translate to human dosing simulations and early-phase clinical trials; evaluate combination therapy and resistance emergence under baloxavir pressure.
Intercontinental spread of highly pathogenic avian influenza A(H5N1) viruses poses significant pandemic risks and necessitates strong protective countermeasures. We evaluated the therapeutic efficacy of the neuraminidase inhibitor oseltamivir, the polymerase inhibitors baloxavir and favipiravir, and an ion-channel blocker amantadine, against severe influenza A(H5N1) virus infection in female BALB/c mice. Baloxavir (≥10 mg/kg, 1 dose) fully protected mice from death, significantly reduced virus respiratory replication, and prevented neuroinvasion. Oseltamivir (≥100 mg/kg/day for 5 days) provided limited survival benefits, reduced lung titers but failed to prevent viral neuroinvasion. Favipiravir (≥100 mg/kg/day for 5 days) provided partial protection, although did not reduce viral titers in lungs and brain. Amantadine provided no benefits. Although all drugs inhibited A(H5N1) viruses in vitro, in vivo correlations did not extend beyond baloxavir. Our results indicate that baloxavir is the most reliable treatment to address both respiratory replication and systemic spread of contemporary A(H5N1) viruses in mice and should be considered in pandemic planning.
3. Circulating proteomic landscape of lung function.
Across 20,823 participants from five cohorts and three major ancestries, 1,055 circulating proteins were significantly associated with spirometric traits after stringent correction, providing a comprehensive proteomic atlas of lung function. The work expands candidate biomarkers and potential therapeutic targets for respiratory diseases.
Impact: Provides a large, multi-ancestry proteomic resource directly linked to lung function, enabling biomarker development and mechanistic hypotheses beyond genetics alone.
Clinical Implications: Supports risk stratification and target prioritization by linking circulating proteins to spirometric deficits; may inform future protein-based diagnostics and therapeutic development.
Key Findings
- In 20,823 adults across five cohorts, 1,055 circulating proteins were significantly associated with FEV1/FVC-derived lung function traits after Bonferroni correction.
- Associations were discovered across European, African, and Asian ancestries, enhancing generalizability.
- The proteomic atlas offers a rich set of candidates for biomarker discovery and mechanistic follow-up in respiratory disease.
Methodological Strengths
- Large multi-ancestry sample across five cohorts with uniform proteomic and spirometric phenotyping
- Stringent multiple-testing correction ensuring robust associations
Limitations
- Cross-sectional associations limit causal inference; longitudinal validation and mechanistic studies are needed
- Details on replication and functional validation are pending in the abstract
Future Directions: Integrate proteomics with genomics (pQTL/MR), longitudinal lung function trajectories, and clinical endpoints to prioritize causal proteins and drug targets.
BACKGROUND: Large-scale genetic and epigenetic studies have identified numerous genes linked to lung function. However, proteomics, which can offer more direct insights into pathophysiologic processes, remains underexplored. We aimed to identify circulating proteins related to lung function. METHODS: In 20 823 adults (71% European, 15% African, and 15% Asian ancestries) across five cohorts we investigated spirometry parameters (FEV RESULTS: In this multi-ancestry population, 1055 proteins were significantly associated with a lung function trait after Bonferroni correction (p<1×10 CONCLUSION: This comprehensive investigation identified novel protein-lung function associations that could improve understanding of lung disease pathogenesis, aid in the discovery of circulating biomarkers and accelerate development of new management strategies for respiratory conditions.