Daily Respiratory Research Analysis
Analyzed 152 papers and selected 3 impactful papers.
Summary
Analyzed 152 papers and selected 3 impactful articles.
Selected Articles
1. Mechanical force-induced tissue remodelling in a clinically relevant microphysiological model of asthmatic human lungs.
This organ-level microphysiological platform demonstrates that dynamic mechanical constriction alone can drive subepithelial fibrosis and increased vascularity in asthma-like airways, and it identifies molecular mediators amenable to pharmacologic modulation. The work bridges mechanobiology with translational targeting in a clinically relevant human model validated in vivo.
Impact: It provides a mechanistic and experimentally controllable human model linking airway mechanics to fibrosis and angiogenesis, revealing druggable mediators of remodeling. This could reshape how we classify and treat asthma endotypes driven by mechanical forces.
Clinical Implications: Reframes asthma as, in part, a mechanobiological disease: therapies targeting mechano-transduction and identified mediators may prevent or reverse subepithelial fibrosis and aberrant vascular remodeling. Offers a human-relevant testbed for precision therapeutics.
Key Findings
- Dynamic airway constriction in a human microphysiological system induces subepithelial fibrosis in distal asthmatic-like airways.
- Vascularized airway constructs revealed airway constriction-driven increases in vascularity via subepithelial fibrosis.
- Proteomics identified mediators of remodeling, and pharmacologic modulation was feasible in the platform.
- Findings were validated with in vivo data, enhancing translational relevance.
Methodological Strengths
- Pneumatically addressable actuators enable precise, dynamic mechanical loading of airway tissues.
- Integration of vascularized constructs and in vivo validation strengthens translational relevance.
- Proteomics-based mediator discovery coupled with pharmacologic testing.
Limitations
- In vitro microphysiological system may not capture full systemic immune and multicellular interactions of in vivo asthma.
- Short- to mid-term remodeling dynamics; long-term reversibility and clinical efficacy remain untested.
Future Directions: Map causal mechano-transduction pathways to specific mediators, test anti-fibrotic/anti-angiogenic strategies, and validate biomarkers/endpoints for early-phase clinical trials targeting mechanically driven asthma endotypes.
Structural remodelling of living tissues due to mechanical forces is a common occurrence that plays an essential role in development, health and disease, but preclinical investigation of this dynamic process in human-relevant conditions remains a challenge. Here we present a microphysiological system integrated with pneumatically addressable soft actuators to emulate dynamic mechanical loading of mucosal tissues in the human respiratory tract. Using this system, we created a clinically relevant model of airway constriction in distal regions of asthmatic lungs to show compressive force-induced fibrotic airway remodelling. Following in vivo validation, we generated vascularized airway constructs in this model to investigate abnormal vascular remodelling in asthma, revealing airway constriction-induced subepithelial fibrosis as a key contributor to increased vascularity of asthmatic airways. Furthermore, we identified molecular mediators of abnormal airway remodelling through proteomics analysis of our microphysiological system and tested the feasibility of pharmacologically modulating their activity. We believe that our technology provides a useful tool for studying biophysical control and dysregulation of dynamic tissue remodelling in lungs and other mechanically active organs.
2. Inhibition of host N-myristoylation compromises the infectivity of SARS-CoV-2 due to Golgi-bypassing egress.
Blocking host N-myristoylation via NMT1 inhibition reduces infectivity of SARS-CoV-2 (and VSV/RSV) across cell lines, primary nasal epithelial cells, and human brain organoids by forcing Golgi-bypassing egress that yields defective progeny virions. This host-directed mechanism could enable broad-spectrum, mutation-resilient antivirals.
Impact: Reveals a unifying, druggable host pathway that controls coronavirus egress and infectivity, validated across multiple human-relevant systems and viruses. It opens a path to broad-spectrum antivirals less susceptible to viral antigenic drift.
Clinical Implications: Host-directed NMT1 inhibition could complement current antivirals for SARS-CoV-2 and RSV, but requires rigorous safety/toxicity profiling and in vivo efficacy. It suggests biomarkers around egress pathways and spike maturation for pharmacodynamic monitoring.
Key Findings
- Pharmacologic inhibition and genetic knockdown of NMT1 significantly reduced infection by SARS-CoV-2, VSV, and RSV.
- Antiviral effects were demonstrated in lung cancer cell lines, primary human nasal epithelial cells, and human choroid plexus–cortical brain organoids.
- NMT1 inhibition induced Golgi-bypassing egress via ER and lysosomal routes, disrupting spike maturation and progeny virion composition, thereby impairing infectivity.
Methodological Strengths
- Convergent evidence across pharmacologic inhibition and genetic knockdown.
- Validation in multiple human-relevant systems including primary airway epithelium and brain organoids.
- Mechanistic mapping of egress rerouting and spike maturation defects.
Limitations
- Predominantly in vitro and organoid data; lack of animal model or clinical trial validation.
- Potential on-target/off-target host toxicity with chronic NMT1 inhibition remains to be defined.
Future Directions: Evaluate in vivo efficacy/safety in respiratory models, define therapeutic window and selectivity over NMT2, and explore combination regimens with direct-acting antivirals while developing PD biomarkers of egress disruption.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which caused the coronavirus disease 2019 (COVID-19) pandemic, remains a global health concern despite vaccines, neutralizing antibodies, and antiviral drugs. The emergence of viral mutations that diminish the effectiveness of current interventions underscores the importance of alternative, host-directed strategies. Here, we show that pharmacological inhibition or knockdown of host N-myristoyltransferase 1 (NMT1), one of the two human enzymes that mediates protein N-myristoylation, significantly impairs SARS-CoV-2, Vesicular Stomatitis Virus (VSV) and Respiratory syncytial virus (RSV) infections. We demonstrate the antiviral efficacy and safety of this host-directed therapeutic strategy across multiple viral tropic sites, including human lung adenocarcinoma cell lines, primary nasal epithelial cells, and human choroid plexus-cortical brain organoids. NMT1 inhibition triggers a Golgi-bypassing pathway for SARS-CoV-2 progeny virion egress, through endoplasmic reticulum and lysosomal structures, which leads to perturbed progeny virion composition and spike maturation, impairing progeny virion infectivity.
3. Mortality in relation to smoke exposure 9 years after the Hazelwood coal mine fire.
In a 2,872-person cohort exposed to the Hazelwood coal mine fire, all-cause and cancer mortality were not associated with modeled PM2.5, but cardiac mortality increased 18% per 10 µg/m3 increase in fire-related PM2.5. PM2.5 also amplified the effect of tobacco on respiratory mortality, underscoring long-term cardiovascular and respiratory risks from smoke.
Impact: Provides rare, individual-level, long-term mortality data linking fire-related PM2.5 to cardiac death risk, informing preparedness and mitigation policies for wildfires and industrial fires.
Clinical Implications: Prioritize smoke exposure mitigation and cardiovascular risk monitoring after large fires; integrate air quality alerts, filtration, and risk communication, and intensify smoking cessation and respiratory follow-up in exposed populations.
Key Findings
- No association between modeled fire-related PM2.5 exposure and all-cause or cancer mortality over long-term follow-up.
- Cardiac mortality increased by 18% (95% CI 2%–37%) per 10 µg/m3 increase in daily mean fire-related PM2.5.
- PM2.5 exposure exacerbated the risk of respiratory mortality attributable to tobacco use.
- Highlights persistent cardiovascular risk many years after a major smoke event.
Methodological Strengths
- Individual-level exposure assessment integrating time-location diaries with high-resolution PM2.5 modeling.
- Linkage to national mortality registry with competing risks modeling for cause-specific outcomes.
Limitations
- Observational design with potential residual confounding and exposure misclassification.
- Cause-specific mortality beyond 2021 required prediction to mid-2023, introducing uncertainty.
Future Directions: Replicate in wildfire-exposed cohorts, refine cardiovascular phenotyping, evaluate interventions (e.g., air filtration, sheltering) on hard outcomes, and model policy scenarios for smoke mitigation.
BACKGROUND: In 2014, a coal mine fire in rural Australia shrouded nearby towns in smoke for several weeks. In response to community concerns and a lack of available evidence, the Victorian Department of Health commissioned a long-term health study. This article evaluates smoke effects on mortality 9 years after the fire. METHODS: In 2016-17, 2872 individuals living near the mine during the fire were recruited into a cohort study and consented to linkage of their data. Time-location diaries were blended with estimates of hourly fire-related fine particulate matter ≤2.5 µm (PM2.5) to generate individual exposure measures. Mortality data were obtained up to mid-2023 by linkage with the National Death Index. Cardiac, cancer, and respiratory-related deaths were identifiable up to December 2021 and predicted thereafter to mid-2023. All-cause mortality effects were evaluated with Cox proportional-hazards models and cause-specific mortality with a competing risk survival model. RESULTS: Nine years post-fire, 318 (11%) of the sample had died. All-cause mortality was not associated with PM2.5 exposure. There was no detectable effect on cancer deaths. However, a 10 µg/m3 increase in daily mean exposure to fire-related PM2.5 was associated with an 18% (95% CI: 2%-37%) higher risk of cardiac mortality, while PM2.5 exacerbated risk of respiratory mortality from tobacco use. CONCLUSION: Fire-related PM2.5 increased cardiac mortality and smoking effects on respiratory mortality years after the event. These findings concord with a growing body of evidence on the deadly risks of wildfire smoke. Protecting communities and individuals from smoke during and after large fire events should be a public health priority.