Chronic asthma can be associated with secondary pulmonary vascular dysfunction, however, the detailed functional profiling of the asthmatic pulmonary artery remains understudied. In this study, we characterized cardiopulmonary and vascular dysfunction in a chronic mixed allergen (MA) mouse model of asthma. Wild-type mice were intranasally challenged with MA or PBS for four weeks, followed by in vivo respiratory mechanics (flexiVent), ex vivo pulmonary artery wire myography, structural morphometry, and right ventricular analysis (Fulton Index). Chronic MA exposure induced significant airway hyperresponsiveness, evidenced by elevated airway resistance (Rrs) and elastance (Ers) with reduced compliance (Crs). Lung histology revealed increased pulmonary artery medial wall thickness and smooth muscle hyperplasia. Wire myography demonstrated enhanced serotonin (5-HT)-induced vasoconstriction and endothelial dysfunction in MA mice, evidenced by blunted endothelium-dependent relaxation to acetylcholine (ACh) with preserved endothelium-independent relaxation to sodium nitroprusside (SNP). Lastly MA mice had significant right ventricular hypertrophy by Fulton index. Collectively, chronic allergic airway inflammation drives vascular remodeling, endothelial dysfunction, and smooth muscle hyperreactivity in pulmonary arteries. This study demonstrates substantial structural and functional consequences of MA exposure to the pulmonary vasculature that models asthmatic pulmonary vascular dysfunction.
The respiratory chemoreflexes help maintain arterial PCO 2 and PO 2 within a narrow range by adjusting lung ventilation. In any given moment, the sensitivity of the respiratory chemoreflexes to PCO 2 and PO 2 is influenced by internal state, a term that refers to how the brain processes incoming information. This review examines how interactions between neural mechanisms underpinning the respiratory chemoreflexes and internal state account for the respiratory response to exercise, acute psychological stress, pregnancy, and the sensation of air hunger. Together, these examples highlight internal state as a key determinant of homeostatic respiratory motor output and emphasize that the respiratory effects of hypercapnia and hypoxia cannot be understood independently of the state in which they occur.
Idiopathic pulmonary fibrosis (IPF) and lung cancer (LC) are distinct pathological entities; however, growing evidence indicates that they share convergent cellular and molecular mechanisms. As central post-transcriptional regulators microRNAs (miRNAs) orchestrate critical pathogenetic processes including epithelial-mesenchymal transition (EMT), TGF-β signaling, fibroblast activation, and extracellular matrix remodeling. Circulating miRNA signatures represents a promising class of minimally invasive biomarkers for early detection, risk stratification, and disease monitoring, while emerging therapeutic strategies based on miRNA mimics or inhibitors have shown encouraging results in preclinical models. Understanding the complex interplay of miRNAs at the interface between fibrogenesis and oncogenesis may facilitate the development of novel translational approaches, ultimately improving patient outcomes in both IPF and LC. Dysregulation of specific miRNAs has been implicated in both IPF and LC, some of which with concordant expression patterns, such as miR-21,miR-155, and miR-200 promoting fibrosis and tumor progression, and others exhibiting divergent roles, including miR-204 5-p and members of the miR-20a e miR-425, exerting opposing effects in fibrotic and neoplastic contexts. By systematically integrating mechanistic and regulatory evidence, this review provides a framework for understanding miRNA dysregulation in IPF and LC, with direct implications for biomarker validation and therapeutic targeting.
Invasive ventilation with oxygen supplementation may inadvertently cause ventilator- and hyperoxia-induced lung injury, respectively, but their balance is fairly unaddressed. The concept of mechanical power summarizes factors of ventilation intensity associated with development of ventilator-induced lung injury. More recently, we introduced the theoretical framework for chemical power to estimate risk of hyperoxia-induced injury and allow for integration of both mechanical and chemical energy transfer per unit time. In the current study, we explored the associations of mechanical and chemical power with outcomes in mechanically ventilated patients with acute respiratory distress syndrome. In this secondary analysis of six pooled cohort studies, patients with acute respiratory distress syndrome per Berlin criteria and available data to calculate chemical and mechanical power on days 1 and 2 of invasive ventilation were selected. The primary outcome was all-cause 60-day mortality. A total of 2,117 patients were included in the main analysis. Higher chemical power levels were associated with increased 60-day mortality (P < 0.001), regardless of the mechanical power levels. Increasing mechanical power levels combined with decreasing chemical power levels was associated with a better outcome than vice versa (P < 0.001). There was no interaction between both powers. In this pooled cohort study of acute respiratory distress syndrome patients receiving invasive ventilation, higher chemical power levels were associated with a higher rate of mortality, independent of mechanical power levels. These results support further experimental validation of the concept of chemical power and exploration of its balance with mechanical power to predict outcome of lung injury.NEW & NOTEWORTHY This observational study of a combined cohort of patients with acute respiratory distress syndrome assessed the association of the novel concept of chemical power, a surrogate marker of oxygen exposure intensity, with mortality and its relative weight in this association when compared with mechanical power. Chemical power and mechanical power were independently associated with mortality. An interaction between these powers was not observed. Future experimental studies should aim to validate and optimize this novel concept.
Cough is a purposeful airway-defensive reflex, but in chronic cough it no longer provides a clear physiological benefit and markedly impairs patient's quality of life. Currently available antitussive drugs have limited efficacy and may cause severe side effects. Thus, further research is needed to find reliable treatments. It has been shown that acetylcholine (ACh) downregulates cough via muscarinic ACh receptors (mAChRs) in the rabbit caudal portion of the nucleus tractus solitarii (cNTS), with a major involvement of the M4 receptor subtype. The identification of cholinergic agents modulating Ach-depressant effects on coughing could be of considerable interest for the development of novel therapeutic strategies. Here, we tested the hypothesis that increasing synaptic ACh levels by inhibiting acetylcholinesterase activity may downregulate the cough reflex. In anesthetized, spontaneously breathing rabbits, we investigated the effect of donepezil, a brain-penetrant, potent, and selective acetylcholinesterase inhibitor, on the modulation of the cough reflex induced by mechanical and chemical stimulation of the tracheobronchial tree and on the sneeze reflex. Efferent respiratory and electromyographic activities were recorded from phrenic nerves and abdominal muscles, respectively. Donepezil, either systemically administered (5 mg/kg sc) or bilaterally microinjected (5 mM; 30-50 nL) into the cNTS, induced strong depressant effects up to the complete abolition of the mechanically induced cough, without affecting sneezing. Donepezil also decreased expiratory activity even to complete suppression, whereas transient increases in respiratory frequency were observed only after local application. These findings support further investigation of donepezil and related centrally acting cholinergic agents as candidate antitussive therapies.NEW & NOTEWORTHY Acetylcholine (ACh) downregulates cough in the rabbit caudal portion of the nucleus tractus solitarii (NTS). We show that the acetylcholinesterase inhibitor donepezil markedly suppresses the cough reflex at this site. These findings identify central cholinergic modulation as a promising pathway for the development of novel antitussive strategies.
Pulmonary fibrosis is often framed as a problem of excess collagen causing stiffening of the lung, but that framing misses the more dynamic reality: fibrosis is built through ongoing conversations between fibroblasts, neighboring cells, and extracellular matrix (ECM) that interpret and reinforce injury signals. Over the last 3 years, single-cell, spatial, and multiomics tools, paired with lineage tracing and functional models, have revealed distinct fibroblast states, trajectories, and spatial niches with increasing resolution. Here, we summarize emerging principles from this sharpened point of view. First, lung fibroblasts are not a single "myofibroblast" entity; rather, they include a spectrum of states, ranging from resident niche-supporting lipofibroblasts, to transitional and inflammatory intermediate states, to CTHRC1+ pathological states. These transitions are not strictly linear, potentially reversible, and are context-dependent. Second, fibroblast state transitions are shaped by signals from injury-associated epithelial and immune cell populations within multicellular niches. Third, the ECM is not a passive scar; rather, it is an active signaling hub whose composition, cross linking, and stiffness engage mechanotransduction pathways that reinforce and, in chronic fibrosis, may lock in pathological fibroblast states. These insights motivate more precise therapeutic strategies-targeting fibroblast state-specific vulnerabilities, disrupting the fibrotic niche, and correcting dysregulated mechanosensing-and raise open questions about fibroblast state reversibility and niche plasticity that will shape next-generation approaches.
This essay addresses the fundamental mechanism underlying the precise regulation of [Formula: see text] during steady states of air-breathing eupnea and hyperpnea. First, an argument is made for CO 2 /H + chemoreception as an important compensatory feedback regulator of breathing and breathing stability, especially during nonrapid eye movement (NREM) sleep. Tonic contributions to respiratory drive occur from the carotid chemoreceptors and retrotrapezoid nucleus (RTN). A case against chemoreception of Pco 2 as the primary homeostatic [Formula: see text] regulator is made based on conditions where precise [Formula: see text] control during air-breathing exists even when ventilatory responsiveness to raised Pco 2 is markedly subnormal or when a measurable [Formula: see text] error signal is nonexistent. Alternatively, a case is made that homeostatic ventilatory control incorporates information critically dependent on pulmonary CO 2 exchange, as revealed when: 1) V̇co 2 , per se, is altered at rest or exercise; 2) V d /V T is raised or lowered; and 3) the resting [Formula: see text] set point is changed, thereby changing respiratory system plant gains. In each of these common conditions, substantial ventilatory adjustments occur to achieve near-proportional V̇a:V̇co 2 linkages at rest and/or exercise with no coincidence changes in CO 2 chemoreception. We view this V̇co 2 -mediated mechanism as a dedicated tracking system for alveolar ventilation that provides an essential underpinning in a traditional hybrid model of homeostatic ventilatory control. Although some potential mediators of these V̇co 2 effects have been suggested, such as an integrative role for the RTN, they remain inadequately explored. It is time to restart enquiry, using modern neuroscience approaches, into the mediation of V̇co 2 as the critical underpinning to [Formula: see text] homeostasis.
Mitophagy is a selective autophagic process that eliminates damaged mitochondria, which is essential for mitochondrial quality control and cellular homeostasis. The most extensively characterized mitophagy pathway involves PTEN-induced kinase 1 (PINK1) and E3 ubiquitin ligase Parkin. Upon mitochondrial depolarization, PINK1 stabilizes on the outer mitochondrial membrane (OMM), where it recruits and phosphorylates Parkin at serine 65 (pParkinS65), activating its E3 ligase activity. Active pParkinS65 initiates the ubiquitination (Ub) of OMM proteins, resulting in the engulfment and lysosomal degradation of damaged (depolarized) mitochondria. Carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP), a mitochondrial uncoupler, is widely used to experimentally induce mitochondrial depolarization and initiate PINK1-Parkin-dependent mitophagy; however, mitophagic responses to FCCP vary across cell types. In the present study, we hypothesized that, in human airway smooth muscle (hASM) cells, FCCP-induced mitochondrial depolarization activates the PINK1-Parkin-mediated mitophagy pathway, culminating in the clearance of damaged mitochondria. We observed that exposing hASM cells to 1 µM FCCP for 6 h induced mitochondrial depolarization and a decrease in the volume of intact mitochondria. This mitochondrial depolarization triggered the accumulation of PINK1 in the mitochondria, which mediated phosphorylation of pParkinS65 and pUbS65. Confocal imaging of labeled mitochondria and lysosomes demonstrated increased colocalization of mitochondria with lysosomes, and mitophagic flux was confirmed using a pH-sensitive mitochondrial reporter mKeima. Collectively, these findings demonstrate that FCCP robustly activates the canonical PINK1-Parkin mitophagy pathway in hASM cells, providing mechanistic insight into mitochondrial quality control, with potential relevance to airway diseases characterized by mitochondrial dysfunction and altered hASM function.NEW & NOTEWORTHY The study establishes the presence of a robust mitophagic response to acute mitochondrial depolarization in hASM cells mediated through the canonical PINK1-Parkin pathway. By integrating quantitative mitochondrial labeling and biochemical analyses, we demonstrate increased mitochondrial damage and remodeling, accompanied by mitochondrial PINK1 accumulation and Parkin activation, resulting in ubiquitin-dependent signaling and lysosomal engulfment. These findings identify mitophagy as a critical adaptive mechanism for maintaining mitochondrial quality control in airway smooth muscle cells during metabolic stress.
Acute respiratory distress syndrome (ARDS) remains a critical condition associated with high morbidity and mortality, particularly when triggered by sepsis. Endothelial dysfunction is a central hallmark of ARDS pathology, but the precise mechanisms underlying pulmonary microvascular dysfunction remain poorly understood. Extracellular vesicles (EVs) have emerged as crucial mediators of cell-cell communication during inflammation; however, their role in endothelial dysfunction in ARDS is less clearly defined. We utilized a human pulmonary microvascular endothelial cell (HPMEC)-based model of sepsis-induced acute lung injury to investigate whether inflammatory EVs (iEVs), derived from endothelial cells treated with bacterial lipopolysaccharide (LPS), impair naïve HPMEC function. EVs were characterized by nanoparticle tracking analysis, transmission electron microscopy, and immunofluorescence, confirming purity and uptake. iEV exposure significantly reduced barrier integrity by electric cell-substrate impedance sensing (ECIS) and increased cell migration; effects partially reversed by the toll-like receptor 4 (TLR4) inhibitor TAK-242. Adhesion and tube formation were unaffected. Pretreatment of donor HPMECs with the neutral sphingomyelinase inhibitor GW4869 attenuated the barrier-disrupting capacity of the resulting iEVs, implicating ceramide-dependent EV biogenesis in generating pathogenic cargo. Trypan Blue staining confirmed that these effects reflect altered signaling rather than cell death. iEV exposure upregulated TLR4, MyD88, interleukin-6 (IL-6), intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), E-selectin, and Jag1 mRNA, with TAK-242 attenuating IL-6 and ICAM-1 induction. Our results highlight endothelial-derived EVs and TLR4-dependent pathways as amplifiers of pulmonary vascular injury in sepsis-induced ARDS, identifying EV biogenesis and EV-mediated signaling as novel therapeutic targets.NEW & NOTEWORTHY EVs released from LPS-stimulated human pulmonary microvascular endothelial cells compromise barrier integrity and enhance migration via TLR4-mediated signaling. Inhibition of ceramide-dependent EV biogenesis with GW4869 attenuated barrier dysfunction, implicating specific EV subpopulations as pathogenic mediators. EV-TLR4 activation upregulates MyD88 and IL-6, suggesting an autocrine loop amplifying vascular injury in sepsis-induced ARDS, and identifying EV biogenesis and EV-mediated TLR4 signaling as novel therapeutic targets.
Bronchopulmonary dysplasia (BPD) is a neonatal lung injury characterized by inflammation, and alveolar and vascular hypoplasia that currently lacks effective treatment. Thrombospondin (TSP)-1 is an angiostatic and pro-inflammatory protein, recently implicated in BPD pathogenesis, that both activates transforming growth factor (TGF)-β1 and suppresses nitric oxide (NO) signaling. In order to gain further insight into the relative importance of downstream effects of TSP-1, our objective in a neonatal rat model of hyperoxia-intermittent hypoxia (H-IH)-induced lung injury was to compare effects of inhibiting: 1) TSP-1-mediated TGF-β1 activation alone (LSKL) or 2) global TSP-1 signaling (soluble CD47 receptor ligand trap; sCD47r). From postnatal days (PND) 1-21, rat pups were exposed to air or to H-IH (PND 1-7 85% O2, PND 7-14 60% O2 and PND 14-21 air with intermittent exposure to 10% O2 for 10 min every 4 hours) while either receiving daily s.c. LSKL (20 mg/kg) or third daily sCD47r (3 mg/kg). Controls were treated with vehicle or were continuously exposed to normoxia. Exposure to H-IH increased lung contents of TSP-1 and active TGF-β1, and caused macrophage influx, alveolar and pulmonary vascular hypoplasia, and pulmonary hypertension (PH). Both strategies prevented H-IH-mediated effects on active TGF-β1 content, macrophage influx, abnormal lung morphology and PH, while only sCD47r increased lung NO content and signaling. These observations in a clinically-relevant model indicate that multiple strategies aimed at suppressing TSP-1 signaling are effective in preventing lung injury and that targeting TSP-1-mediated activation of TGF-β1 is sufficient to achieve these effects.
Disruptions during perinatal fetal lung development can lead to postnatal chronic lung diseases such as bronchopulmonary dysplasia (BPD). Along with decreased alveolar and pulmonary vascular growth, abnormal airway growth occurs in BPD. Previous studies in rats have shown that antenatal endotoxin (AN-ETX) mimicking maternal chorioamnionitis causes dysanapsis during the neonatal period. Whether dysanaptic growth alters long-term lung function remains unknown. We hypothesized that antenatal endotoxin causes persistent differences between airway and distal lung growth with age in experimental BPD. Sprague-Dawley rats were exposed to AN-ETX at embryonic day 20 (E20) by intraamniotic injection and delivered on E22, analogous to human preterm 26-28 wk gestation. Pups raised via naive foster dams were evaluated for BPD-associated parameters on postnatal days 14 (D14) and 28 (D28), akin to infancy and childhood human lung development. Lung histologic morphometry, lung mechanics testing, and airway and pulmonary vasculature microcomputed tomography (µCT) evaluations were performed to assess growth at D14 and D28. AN-ETX-exposed rats demonstrated persistent somatic growth failure, decreased alveolarization, decreased vascularization, right ventricular hypertrophy, and impaired lung mechanics at both D14 and D28. AN-ETX exposure decreased large airway size at D14, but also medium airway diameters by D28. AN-ETX exposure caused early airflow obstruction at D14 [decreased forced expiratory volume over 0.1 s to forced vital capacity (FEV0.1/FVC) ratio], which worsened by D28 (decreased FEV0.1 and FEV0.1/FVC ratio). Adverse antenatal stress alone is sufficient to cause sustained abnormalities of lung development beyond the neonatal period. Early dysanapsis may predispose to structural obstructive disease and impair lung function over the lifespan.NEW & NOTEWORTHY Disruptions during perinatal lung development can lead to chronic lung diseases such as bronchopulmonary dysplasia (BPD). Rats exposed to a single intraamniotic endotoxin injection were evaluated for BPD-associated parameters of lung structure and function on postnatal days 14 and 28, akin to human infancy and childhood. Endotoxin-exposed rats demonstrated persistent impairments in lung development and function. This is the first preclinical study to suggest that early dysanaptic growth may predispose to lifelong impaired lung function.
Premature infants exposed to supplemental oxygen (O2) are at increased risk of developing airway diseases such as asthma, hyperoxic lung injury (HLI), and bronchopulmonary dysplasia (BPD). Therefore, it is important to understand how O2 detrimentally impacts developing airways. Previous studies found that severe (80%-90%) O2 exposure increases reactive oxygen species (ROS) and lipid peroxidation, inducing ferroptosis in models of HLI. However, the impact of clinically relevant moderate (<60%) O2 exposure is less understood. Recognizing the importance of smooth muscle in airway dysfunction, the present study uses human fetal airway smooth muscle (fASM) as a model to investigate whether hyperoxia contributes to the establishment of a ferroptotic phenotype. fASM pretreated with or without deferoxamine (DFO; 100 µM) or ferrostatin (Fer-1; 10 µM) was exposed for 48 h to normoxia (21% O2) versus moderate to severe hyperoxia (50%, 70%, or 90% O2). The effects of hyperoxia on antioxidant systems, iron metabolism, and lipid peroxidation, and the alleviating effect of DFO or Fer-1 were examined. Moderate hyperoxia impaired antioxidant systems involved in preventing ferroptosis and dysregulated iron metabolism. Interestingly, only severe hyperoxia (90% O2) induced negative effects on downstream mechanisms involving early onset of ferroptosis such as increased labile iron and lipid peroxidation. DFO and Fer-1 showed no rescue effect on antioxidant systems. However, DFO decreased cytosolic iron, and Fer-1 decreased lipid peroxidation byproducts. Together, these data highlight the impact of supplemental oxygen on premature airways and introduce the concept of a dose-dependent effect of hyperoxia in the context of iron metabolism, lipid peroxidation, and ultimately ferroptosis.NEW & NOTEWORTHY Recognizing that antioxidant systems are impaired in the airways of premature infants, we used human fetal airway cells to explore the impact of oxygen on iron regulation and iron-mediated cell death (ferroptosis). We find moderate hyperoxia impairs antioxidant systems that prevent ferroptosis and dysregulates iron metabolism, while severe hyperoxia has a negative effect on mechanisms driving the early onset of ferroptosis. Inhibitors of ferroptosis decrease iron and lipid peroxidation, demonstrating links between oxygen and iron regulation in developing airways.
Acute respiratory distress syndrome (ARDS) is characterized by robust inflammation in the lungs and systemic circulation. In this context, the toll-like receptor (TLR) signaling pathway plays a major role, driving inflammation that promotes host defense but also causing pathological tissue damage. To limit excessive inflammation, TLR signaling must be tightly controlled. One mechanism that modulates TLR signaling is alternative splicing of TLR pathway pre-mRNAs, which balances production of positively acting inflammatory mediators with alternative splice forms that terminate inflammation. To determine whether altered TLR pathway splicing contributes to pathological inflammation in ARDS, we evaluated two central mediators of the TLR signaling pathway, the MyD88 signaling adapter and the IRAK1 signaling kinase, in leukocytes isolated from bronchoalveolar lavage (BAL) of patients with ARDS. We found that MyD88 gene expression was decreased in BAL immune cells, whereas IRAK1 gene expression was increased. In parallel, we monitored long proinflammatory (MyD88-L and IRAK1) and shorter anti-inflammatory (MyD88-S and IRAK1c) splice forms and determined that IRAK1 splicing was shifted in a proinflammatory direction in patients with ARDS. Finally, we evaluated relationships between MyD88 isoform levels in BAL leukocytes and clinical outcomes. We conclude that pre-mRNA splicing of TLR pathway genes is altered in lung immune cells in patients with ARDS, that monitoring splicing of these genes may provide important prognostic information, and that manipulating splicing of these genes may be a useful novel therapeutic approach that needs further investigation.NEW & NOTEWORTHY We found that MyD88 expression is decreased, that IRAK1 expression is increased, and that IRAK1 splicing is shifted in a proinflammatory direction, in lung immune cells in patients with ARDS. We also find that MyD88 expression levels may correlate with survival in patients with ARDS. Thus, changes in expression and splicing of these two genes offer potential novel prognostic and therapeutic targets for ARDS.
Pulmonary macrophages are central regulators of lung injury and repair following acute inhalation of toxic chemicals. Strategically positioned within the airspaces and lung parenchyma, resident macrophage populations act as first responders that sense epithelial and endothelial injury, initiate sterile inflammatory responses, and coordinate immune cell recruitment, thereby influencing whether injury resolves or progresses to chronic inflammation and fibrosis. Recent advances have revealed substantial heterogeneity and plasticity among lung macrophages shaped by developmental origin, anatomical niche, and local microenvironmental cues. Alveolar and interstitial macrophages engage in extensive bidirectional cross talk with epithelial and endothelial cells through cytokines, growth factors, and extracellular vesicles that collectively maintain pulmonary homeostasis and regulate responses to injury. In experimental models of vesicant, particulate, volatile organic compounds, microbial toxins, and toxic gas exposure, pulmonary macrophages undergo profound transcriptional, metabolic, and functional reprogramming. Early depletion of resident alveolar macrophages coupled with disproportionate recruitment of monocyte-derived macrophages has emerged as a conserved pathogenic feature of severe chemical-induced lung injury. This review summarizes current understanding of pulmonary macrophage ontogeny, functional specialization, and macrophage-epithelial cross talk during acute chemical inhalation injury, and discusses emerging therapeutic strategies aimed at modulating macrophage responses to restore pulmonary homeostasis. Collectively, these insights position pulmonary macrophages as critical gatekeepers of lung injury and repair and as promising targets for intervention in chemical-induced lung disease.
Asthma is a chronic respiratory disease affecting over 230 million people worldwide, with higher prevalence in women. Environmental allergens such as house dust mite (HDM) trigger airway inflammation and hyperresponsiveness (AHR), yet the epigenetic mechanisms underlying these responses remain poorly understood. Furthermore, the role of estrogen receptors in the context of asthma is understudied. We aimed to investigate whether estrogen receptor-specific DNA methylation contributes to HDM-induced airway remodeling and hyperresponsiveness. Male and female C57BL/6J wild-type mice and estrogen receptor α and β knockout mice (Esr1-/- and Esr2-/-) were exposed to HDM or phosphate-buffered saline for 5 wk. DNA methylation and RNA sequencing data were obtained from snap-frozen whole lung tissues. HDM exposure resulted in widespread differential methylation of genes associated with inflammation and AHR, including Itgal, Tmem267, Rap1b, Bmf, Mid1, Fgd1, Ddx4, Comtd1, Filip1l, Grb10, and Chst7. Notably, the absence of estrogen receptor β (in Esr2-/- mice) produced the most pronounced methylation patterns, particularly in females. Pathway enrichment analysis revealed asthma-relevant processes such as extracellular matrix remodeling, leukocyte adhesion and migration, airway smooth muscle contraction, and inflammatory signaling. Integration of methylation and gene expression data confirmed significant correlations (P < 0.05) for Itgal, Rap1b, and Tmem267, and a marginal correlation for Chst7 (P < 0.1), implicating these genes in allergic asthma pathogenesis. Our findings demonstrate that HDM exposure induces sex-specific epigenetic changes mediated by estrogen receptor status, highlighting a potential mechanism for increased asthma susceptibility in women. These results can inform estrogen receptor-targeted treatment strategies for allergic airway diseases.NEW & NOTEWORTHY Understanding estrogen receptor-mediated epigenetic regulation provides a foundation for developing sex-specific interventions for asthma, addressing the higher prevalence and severity observed in women. In this study, we demonstrate that exposure to house dust mite in the mouse lung is associated with epigenetic alterations in genes linked to airway hyperresponsiveness and lung inflammation. These alterations were dependent on the presence or absence of estrogen receptors.
Coronaviruses can cause serious disease in humans and animals. They are often difficult to study due to the variability of the disease as well as safety concerns related to biosafety requirements. Here, we use a biological safety level (BSL) 2-compatible murine betacoronavirus (MHV-A59), which infects multiple organs, to study the respiratory phase of disease and subsequent systemic dissemination. We asked whether inducible epithelial resistance, activated by the combination of pattern recognition receptor agonists Pam2CSK4 (Pam2), synthetic diacylated lipopeptide, + oligodeoxynucleotide (ODN) M362, can limit both pulmonary infection and systemic spread of disease. Prophylactic exposure with Pam2 + ODN improves survival and reduces extrapulmonary viral burden, including in the liver, consistent with limited systemic spread. Stopping the infection at the level of the lungs is associated with improved physiological outcomes and increased protection for the mice. We further characterize the response of the epithelial cells to infection and treatment and demonstrate modulation of epithelial gene expression, including attenuation of virus-induced responses, to better understand the mechanisms of protection and how these responses may be leveraged against future infectious agents.NEW & NOTEWORTHY This study establishes a BSL 2-compatible murine betacoronavirus model to investigate respiratory and systemic disease. We show that inducible epithelial resistance via Pam2 + ODN improves survival, preserves lung function, and reduces extrapulmonary viral burden. Mechanistically, Pam2 + ODN reprograms lung epithelial gene expression, reversing virus-induced transcriptional responses. These findings support epithelial-targeted, pathogen-agnostic strategies to limit both pulmonary and systemic consequences of respiratory viral infection.
Asthma heterogeneity remains a defining challenge driven by multiple factors, including hormonal influences that contribute to distinct phenotypic and endotypic manifestations during the menopausal transition. Fluctuations in sex hormones such as estrogen and progesterone during this period do not merely alter reproductive physiology but they fundamentally modulate immune regulation, airway homeostasis, and inflammatory thresholds in ways that give rise to distinct clinically underrecognized asthma phenotypes and endotypes. This review examines how the hormonal milieu during the menopausal transition, defined as the period marked by changes in menstrual cycle regularity and ending 12 mo after the final menstrual period (menopause), may influence the classical asthma subtypes. We highlight the hormonal dynamics, clinical features of asthma, asthma endotypes and phenotypes, and therapeutic modifiers of asthma during the menopausal transition. Collectively, this review underscores the need to reframe menopause-associated asthma as hormonally driven, biologically distinct subtypes while highlighting the critical gaps in knowledge that must be addressed to develop effective therapeutic strategies for this vulnerable and understudied population.
