Rao AS, Onufer AP, Kumova O
… +4 more, Roberts LTN, Mossabeb R, Pascasio J, Carey AJ
Am J Respir Cell Mol Biol
· 2026 Mar · PMID 42089286
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We previously demonstrated pretreatment with intranasal Lactobacillus rhammosus GG (LGG) prior to influenza viral (IAV) infection protected murine neonates through toll-like receptor (TLR) priming. Based on these results...We previously demonstrated pretreatment with intranasal Lactobacillus rhammosus GG (LGG) prior to influenza viral (IAV) infection protected murine neonates through toll-like receptor (TLR) priming. Based on these results, we hypothesized neonates had impaired TLR activation in response to IAV. However, translational studies with human neonatal monocytes stimulated with IAV exhibited comparable IL-6 production, and sustained TLR2 expression compared to adults. Next, to further investigate the role of TLR2, transgenic mice lacking the TLR2 gene (TLR2-/-) were intranasally infected with IAV. TLR2-/- neonates displayed improved survival over C57BL/6 neonates after IAV infection, with reduced neutrophil recruitment at 6-days post-infection. To test the role of neutrophils in increasing mortality, neutrophil depletion was performed in C57BL/6 neonates; survival was improved. Additionally, treatment with an anti-TLR2 blocking antibody improved survival in the C57BL/6 neonates. Similarly, myeloid-specific TLR2-deficient mice demonstrated enhanced survival with improved histopathology and decreased neutrophil-associated pro-inflammatory cytokines and chemokines (IL-6, TNF-α, MCP-1, CXCL1), despite no changes in immune cell recruitment. Moreover, conditional knockout neonates did not amplify production of pro-inflammatory cytokines and chemokines from 3-days post-infection to 6-days post-infection, compared to the age-matched neonatal control group. These findings suggest that myeloid TLR2 signaling exacerbates neonatal susceptibility to respiratory viral infections by driving increased pulmonary inflammation over the first week of infection. Targeting TLR2 could represent a therapeutic strategy to protect this vulnerable population during respiratory viral infections.
Khan MA, Li DG, Bhusal S
… +2 more, Krupnick AS, Lau CL
Am J Respir Cell Mol Biol
· 2026 Feb · PMID 42089283
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Bronchial anastomotic complications, including stenosis, necrosis, and dehiscence, remain major contributors to morbidity and poor graft outcomes following lung transplantation. These complications are primarily driven b...Bronchial anastomotic complications, including stenosis, necrosis, and dehiscence, remain major contributors to morbidity and poor graft outcomes following lung transplantation. These complications are primarily driven by microvascular disruption, causing hypoxia, epithelial injury, and impaired wound healing at the anastomosis. Tumor necrosis factor-stimulated gene 6 (TSG-6) protein is a secreted anti-inflammatory mediator with immunomodulatory and tissue-reparative properties; however, its role in transplant-associated vascular and epithelial regeneration remains incompletely defined. In this study, we investigated the therapeutic potential of exogenous TSG-6 in preserving airway microvasculature and promoting immunoregulation in a murine orthotopic tracheal transplant model that mimics the clinical setting of bronchial anastomosis following lung transplantation. BALB/cJ→C57BL/6J allografts were treated intranasally with recombinant TSG-6 (5 µg per transplant) on days -1, 2, 5, and 8 post-transplantation. Exogenous TSG-6 therapy significantly increased the recruitment of M2 macrophages, regulatory T cells, and subsets of regulatory B cells, shifting the graft microenvironment toward an IL-10-dominant anti-inflammatory state. These immunoregulatory effects were accompanied by improved microvascular perfusion, increased Fascin-1 and β-catenin expression in CD31 + endothelial cells, and preservation of epithelial architecture with reduced inflammation and airway lumen narrowing, in contrast to untreated allografts that showed epithelial disruption with dense mononuclear infiltration. These findings suggest that TSG-6 coordinates vascular and epithelial repair after transplantation via IL-10-mediated immunoregulation and Fascin-1-dependent endothelial remodeling. These results highlight TSG-6 as a promising immunoregulatory factor with therapeutic potential to mitigate ischemia-related airway injury and offer a novel strategy for preventing bronchial anastomotic complications following lung transplantation.
Zhan J, Li R, Liang Y
… +3 more, Luo D, Zhou Y, Wei X
Am J Respir Cell Mol Biol
· 2026 Feb · PMID 42089282
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Mast cell (MC) degranulation is associated with allergic rhinitis (AR) progression. Although circMIRLET7BHG has been identified as a promoter of AR development, its potential regulatory role in MC degranulation during AR...Mast cell (MC) degranulation is associated with allergic rhinitis (AR) progression. Although circMIRLET7BHG has been identified as a promoter of AR development, its potential regulatory role in MC degranulation during AR progression has not been clarified. To address this, MCs (LAD2) were co-cultured with ovalbumin (OVA)-induced human nasal mucosa epithelial cells (HNEpC), and an AR mouse model was generated through OVA stimulation. The expression levels of circMIRLET7BHG and interleukin-33 (IL-33) were assessed by qRT-PCR, while cytokine production in MCs was quantified using ELISA. MC degranulation was evaluated by toluidine blue staining, and western blotting was employed to detect the expression of polypyrimidine tract-binding protein 1 (PTBP1) and proteins related to mitochondrial fusion and fission. The interactions of PTBP1 with circMIRLET7BHG and IL-33 were verified by RNA immunoprecipitation and RNA pull-down assays, and IL-33 mRNA stability was determined using the actinomycin D assay. Co-culture of LAD2 cells with OVA-induced HNEpC demonstrated that circMIRLET7BHG knockdown inhibited MC degranulation by suppressing mitochondrial fission. Mechanistically, circMIRLET7BHG enhanced IL-33 mRNA stability through its interaction with PTBP1. IL-33 overexpression promoted mitochondrial fission and accelerated MC degranulation, whereas this effect was reversed upon circMIRLET7BHG knockdown. In OVA-induced AR mouse models, circMIRLET7BHG overexpression increased epithelial thickness, eosinophil infiltration, and apoptosis, thereby aggravating allergic symptoms by enhancing mitochondrial fission and MC degranulation via upregulation of IL-33 expression. In conclusion, these findings demonstrate that circMIRLET7BHG promotes AR progression by enhancing mitochondrial fission and MC degranulation through regulation of the PTBP1/IL-33 axis, suggesting a potential novel therapeutic target for AR treatment.
Buccardi M, Pennati F, Ferrini E
… +5 more, Buseghin D, Polverini E, Sverzellati N, Aliverti A, Stellari FF
Am J Respir Cell Mol Biol
· 2026 Feb · PMID 42089278
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Accurate lung function assessment is essential in preclinical idiopathic pulmonary fibrosis (IPF) research, yet conventional whole-lung endpoints overlook spatial heterogeneity and compensatory mechanisms. We present a µ...Accurate lung function assessment is essential in preclinical idiopathic pulmonary fibrosis (IPF) research, yet conventional whole-lung endpoints overlook spatial heterogeneity and compensatory mechanisms. We present a µCT-based pipeline for longitudinal, regional quantification of structural and functional changes in a murine bleomycin (BLM)-induced fibrosis model to improve evaluation of disease progression and therapeutic effects. C57BL/6 mice received triple oropharyngeal administrations of saline or BLM. Respiratory-gated µCT scans were acquired in free-breathing at baseline and days 7, 14, and 21. A deep-learning algorithm segmented the lungs into left and right lobes, further subdivided into apical and caudal regions using airway landmarks. Regional volumes, aeration compartments, and ventilation maps were extracted to assess structural and functional alterations. Saline-treated mice showed stable metrics over time, with minimal inter-animal variability, demonstrating the robustness and physiological consistency of our segmentation procedure. BLM-treated animals exhibited early and heterogeneous fibrotic changes, with the apical regions appearing as most affected. The caudal-right region displayed a compensatory functional increase of respiratory parameters derived from multivolume µCT. µCT-based regional analysis can detect localized dysfunction and compensatory effects not captured by whole-lung measurements. This strategy is applicable to different models of heterogeneous lung disease and may contribute to reduce the translational gap in IPF research.
Ghani H, Thillai M, Jenkins D
… +12 more, Bussell E, Ruggiero A, Walsh S, Screaton N, Bunclark K, Cannon J, Sheares K, Taboada D, Graves M, Toshner M, Ng C, Pepke-Zaba J
Am J Respir Cell Mol Biol
· 2025 Oct · PMID 42085489
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Pulmonary blood volumes (PBV), currently not assessed by computed tomography pulmonary angiography (CTPA), could provide additional information to routine investigations performed for chronic thromboembolic pulmonary hyp...Pulmonary blood volumes (PBV), currently not assessed by computed tomography pulmonary angiography (CTPA), could provide additional information to routine investigations performed for chronic thromboembolic pulmonary hypertension (CTEPH). We investigated CTPA-based PBV in evaluating hemodynamic outcome from pulmonary endarterectomy (PEA) surgery. A deep learning-based CTPA vascular segmentation model, differentiating arteries and veins, was applied for automated PBV measurements in CTEPH patients who underwent PEA at U.K.'s national CTEPH service. Pulmonary arteries were compartmentalised into "central" (main pulmonary and proximal lobar) and "intrapulmonary". Mean pulmonary arterial pressure >30 mmHg post-PEA defined "clinically relevant" residual PH. Logistic regression models applying CTPA-based PBV to identify residual PH were trained and tested on the discovery and validation cohorts respectively. Paired pre- and postoperative CTPA, in the discovery (n = 71) and validation (n = 102) cohorts showed that central pulmonary artery volume and total artery to vein volume ratio (A-VR) decreased and pulmonary vein volume increased with hemodynamic improvement post-PEA. Preoperative central pulmonary artery volume and A-VR helped identify patients at risk for clinically relevant residual PH post-PEA (AUROC 0.88 and 0.82 in the discovery and validation cohorts). Postoperative central pulmonary artery volume, A-VR and pulmonary vein volume helped to non-invasively identify patients without clinically relevant residual PH (AUROC 0.91 and 0.88 in the discovery and validation cohorts). Automated quantification of CTPA-based PBV at diagnosis can help stratify risk for residual PH in patients managed with PEA. Utilizing CTPA-derived PBV post-PEA to identify patients without residual PH can potentially reduce the need for routine postoperative right heart catheterization.
Borkar NA, Pfeffer-Kleemann DA, Hamrick SK
… +4 more, Koloko Ngassie ML, Thomspon MA, Pabelick CM, Prakash Y
Am J Respir Cell Mol Biol
· 2026 Mar · PMID 42083982
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Asthma in the elderly (AIE) represents a unique challenge, necessitating better understanding of the mechanisms that drive airway hyperreactivity and remodeling (thickened, fibrotic airways). Normal aging is associated w...Asthma in the elderly (AIE) represents a unique challenge, necessitating better understanding of the mechanisms that drive airway hyperreactivity and remodeling (thickened, fibrotic airways). Normal aging is associated with increased lung stiffness, and thus the influence of mechanical forces on bronchial airways (breathing, sighs, CPAP) likely changes, potentially increasing with AIE and resultant remodeling, overall highlighting the need to understand the importance of mechanobiology in aging and AIE. Here, mechanosensitive Piezo (Pz) channels are highly expressed in the lung, including within airway epithelium and smooth muscle (ASM) but their specific roles particularly with aging remain largely unexplored. In this study, we used human ASM cells from young vs. old (≥65 y) non-asthmatics vs asthmatics to test the hypothesis that normal aging blunts Pz expression and functionality at baseline as well as in response to mechanical stretch, whereas asthma, particularly, AIE ASM leads to enhanced Pz expression promoting fibrosis and remodeling. Both Pz1 and Pz2 were expressed in ASM and increased in AIE. Oscillatory mechanical stretch mimicking breathing with superimposed static stretch increased Pz, especially in AIE: effects exacerbated by Pz activator Yoda1 and blunted by Pz inhibitor GsMTx4. Stretch or Yoda1 increased Wnt3a, β-catenin and GSK3β activation particularly in AIE, while ASM proliferation and extracellular matrix production remained preserved or even heightened in elderly ASM. Conversely, Pz1 inhibition by GsMTx4 potently reduced ECM deposition, particularly in AIE cells, highlighting Pz1's pivotal role in modulating ECM deposition. Overall, our findings indicate Pz1 as a mechanosensitive regulator of airway remodeling in AIE.
Werder RB, Homps-Legrand M, Hyatt R
… +6 more, Lindstrom-Vautrin J, Villacorta-Martin C, Bawa P, Cho MH, Zhou X, Wilson AA
Am J Respir Cell Mol Biol
· 2026 May · PMID 42083809
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Impaired lung development and lung function can lead to the development of chronic obstructive pulmonary disease (COPD). Genome wide association studies (GWAS) have identified associations between variants in the gene FA...Impaired lung development and lung function can lead to the development of chronic obstructive pulmonary disease (COPD). Genome wide association studies (GWAS) have identified associations between variants in the gene FAM13A with both lung function and COPD. Of the major FAM13A isoforms expressed in humans, only the shorter isoforms are expressed in mice. This species difference has hindered investigations into whether full-length, human-specific isoforms contribute to human lung development, a question that remains unstudied to date. To functionally address this question, we disrupted the long isoform of FAM13A in human induced pluripotent stem cells (iPSCs). Specific loss of this isoform prevented the emergence in culture of mature airway or alveolar epithelial lineages in directed differentiation protocols. We demonstrate that the FAM13A long isoform is critical to patterning NKX2-1 + lung progenitor cells through dysregulating Wnt/β-catenin signaling during early stages of development in vitro. These findings provide the first evidence that the COPD risk gene FAM13A may be vital in the developing human lung epithelium.
Massara L, Saber Cherif L, Ollivier A
… +11 more, Kervoaze G, Pichavant M, Dufossez C, Fawaz A, Leprêtre E, Le Rouzic O, Deslée G, Pons S, Maskos U, Dormoy V, Gosset P
Am J Respir Cell Mol Biol
· 2026 May · PMID 42082429
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RATIONALE: COPD is the third leading cause of death globally. Although cigarette smoke is the dominant risk factor, only a subset of smokers develop COPD, pointing to a significant role for genetic susceptibility. The α5...RATIONALE: COPD is the third leading cause of death globally. Although cigarette smoke is the dominant risk factor, only a subset of smokers develop COPD, pointing to a significant role for genetic susceptibility. The α5 nicotinic acetylcholine receptor polymorphism (α5SNP; rs16969968), is expressed in the majority of COPD patients and may modulate immune responses to cigarette smoke. OBJECTIVES: To determine how α5SNP influences CS-induced inflammation and COPD pathogenesis in both experimental and clinical settings. METHODS: A murine knock-in model expressing wild-type (WT), heterozygous (HE), or homozygous (HO) α5SNP alleles was exposed to cigarette smoke or ambient air for one or three months. Lung function, histopathology, immune cell profiling, and cytokine expression were evaluated. In a human COPD cohort, we assessed α5SNP prevalence and the cytokine concentrations. MEASUREMENTS AND MAIN RESULTS: Cigarette smoke impaired lung function across all genotypes, but HE mice developed the most severe airflow limitation, inflammation, and airway remodeling. This phenotype was linked to heightened γδ T cell activation and increased TNF-α, associated with altered nAChR signaling in macrophages. Alteration of nicotine-induced cell signaling including adenylate cyclase and protein kinase-C is involved in modulation of cytokine production by macrophages. In humans, α5SNP was highly prevalent among COPD patients and strongly correlated with elevated systemic inflammation. CONCLUSIONS: α5SNP enhances susceptibility to cigarette smoke-driven lung injury and is present in the majority of COPD patients. These findings support α5SNP as a key genetic marker of susceptibility for COPD and its presence should be associated with precise follow-up in smokers.
Regulated cell death is critical in maintaining tissue homeostasis and immune functions. The most common form of physiologic cell death is the highly precise, regulated, and relatively inflammation-free pathway of apopto...Regulated cell death is critical in maintaining tissue homeostasis and immune functions. The most common form of physiologic cell death is the highly precise, regulated, and relatively inflammation-free pathway of apoptosis. In contrast, necrotic or lytic cell death, which involves rapid cell lysis and release of pro-inflammatory mediators, is more often associated with human pathologies. Pyroptosis and necroptosis are two regulated forms of lytic cell death and are increasingly recognized as important mediators of tissue damage in many diseases, including lung diseases. The death of lung cells is a key contributor to disease in multiple respiratory disorders. However, current interventions are limited to targeting downstream effects to help relieve symptoms without addressing the root cause driving tissue damage. Therefore, new strategies directed towards preventing tissue damage caused by detrimental cell death are desperately needed. Emerging evidence strongly implicates regulated necrosis in many acute and chronic lung diseases, but the specific form(s) of cell death driving pathology and cell types involved require nuanced evaluation. Here, we summarize current literature suggesting that pyroptosis and necroptosis facilitate lung injury and inflammation in Chronic Obstructive Pulmonary Disease (COPD) and Idiopathic Pulmonary Fibrosis (IPF) by inducing the death of airway and alveolar epithelial cells and resident immune cells, which leads to alveolar barrier disruption, release of inflammatory mediators, excessive immune cell recruitment, and ultimate lung function decline.
Acute lung injury (ALI) is a life-threatening clinical syndrome characterized by intense inflammation and pulmonary physiologic dysfunction. While innate immune cells dominate early ALI pathology, lymphocytes are increas...Acute lung injury (ALI) is a life-threatening clinical syndrome characterized by intense inflammation and pulmonary physiologic dysfunction. While innate immune cells dominate early ALI pathology, lymphocytes are increasingly recognized as important contributors. Prior work demonstrated that natural killer (NK) cells are recruited through CCR5 leading to damage following ischemic lung injury. As endotoxin-induced ALI is an important pre-clinical model for acute respiratory distress syndrome (ARDS), here we asked whether NK cells recruited through CCR5 mediated injury in this clinically relevant model. We examined CCR5 and NK cells in a C57BL/6 mouse model of endotoxin-induced ALI using spectral flow cytometry and genetic knockout animals. We found that CCR5 ligands and CCR5 NK cells were increased during ALI relative to no-injury control mice. CCR5-positive NK cells had markers of tissue residence and CCR5 inhibition reduced NK cell trafficking as measured in the bronchoalveolar lavage. Further, CCR5 inhibition ameliorated lung injury across all domains. CCR5 inhibition had less of an impact on T cell trafficking, and these cells had relatively less CCR5 expression. Adoptive transfer of Ccr5-null NK cells preceding ALI resulted in reduced trafficking and injury compared to wildtype transfers. NK cell depletion and CCR5 inhibition were effective even when administered 2 hours after LPS administration. indicating potential relevance for clinical translation. In summary, this study cements CCR5-positive NK cells as mechanistically important in a clinically relevant acute lung injury model. Inhibition of CCR5-positive NK cells may have translational application for some ARDS endotypes.
RATIONALE: N6-methyladenosine (m6A) modifications are implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD), yet the precise role of the demethylase fat mass and obesity-associated protein (FTO)...RATIONALE: N6-methyladenosine (m6A) modifications are implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD), yet the precise role of the demethylase fat mass and obesity-associated protein (FTO) remains unclear. OBJECTIVES: To identify whether FTO acts as a suppressor of COPD pathogenesis and to elucidate the underlying epitranscriptomic mechanism. METHODS: COPD models were established using cigarette smoke-exposed mice and cigarette smoke extract-stimulated BEAS-2B cells. FTO expression was modulated by lentiviral transduction. m6A epitranscriptomic microarray, RNA immunoprecipitation, m6A methylation analysis, and mRNA stability assays were performed. Inflammation, oxidative stress, mitophagy, and ERK1/2-Drp1 signaling were assessed. RESULTS: FTO expression is reduced in COPD patients and murine models, correlating with elevated m6A levels and disease severity. Overexpression of FTO mitigates inflammation, oxidative stress, and mitochondrial dysfunction by destabilizing S100 calcium-binding protein A9 (S100A9) mRNA via m6A demethylation. Mechanistically, FTO inhibits the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2)- dynamin-related protein 1 (Drp1), thereby suppressing excessive mitophagy and preserving mitochondrial integrity. Notably, S100A9 overexpression abolishes the protective effects of FTO, establishing the FTO/S100A9 axis as a central regulator. CONCLUSIONS: FTO attenuates COPD pathogenesis by demethylating S100A9 mRNA, thereby suppressing ERK1/2-Drp1-driven mitophagy. The FTO/S100A9 axis represents a novel epitranscriptomic mechanism and a potential therapeutic target for COPD.
Park HJ, Cho HJ, Chen P
… +19 more, Pederson WP, Liu B, Yi D, Juarez E, Lorson N, Bruner A, Xia X, Zheng Q, Kheshtchin-Kamel N, Liu T, Raevens S, Beers MF, Li F, Veldhuizen RAW, Zhou H, Ledford JG, Kawut SM, Dai Z, Fallon MB
Hepatopulmonary syndrome (HPS) is a severe complication of cirrhosis characterized by pulmonary microvascular dilation, hypoxemia, and increased mortality. Patients often exhibit unexplained restrictive ventilatory defec...Hepatopulmonary syndrome (HPS) is a severe complication of cirrhosis characterized by pulmonary microvascular dilation, hypoxemia, and increased mortality. Patients often exhibit unexplained restrictive ventilatory defects that correlate with circulating bile acids, suggesting superimposed alveolar dysfunction. To investigate this, we evaluated alveolar function, cell types, and the potential role of altered bile acids in the experimental HPS. Common bile duct ligation (CBDL) mice were assessed for pulmonary and surfactant function. AT2 cell-specific RiboTag RNA sequencing, single-cell RNA sequencing (scRNA-seq), and mass spectrometry-based bile acid profiling were performed. MLE12 cells were treated with bile acids in vitro, and an FXR agonist was administered in vivo to test effects on AT2 cell. CBDL mice developed HPS with restrictive defects due to reduced AT2 cell-derived surfactant-protein-C (SP-C), increased alveolar surface tension, and elevated plasma and bronchoalveolar bile acid levels. ScRNA-seq demonstrated a decrease in AT2 cells and an increase in AT2-to-AT1 transitional cells. AT2-specific RNA-seq revealed upregulated bile acid and cholesterol metabolism and downregulated proliferative pathways. In vitro, bile acids mimicking FXR antagonists reduced SP-C in MLE12 cells, while in vivo FXR agonist decreased circulating bile acids and restored SP-C-producing AT2 cells in CBDL mice. Our data demonstrates alterations in AT2 cell biology, including reduced surfactant expression, in the setting of elevated bile acids. These finding indicate an association between bile acid levels and AT2 cell alterations in cirrhosis and identify bile acid signaling and AT2 cell integrity as areas for future mechanistic investigation.
Vaso M, Dukic M, Pennitz P
… +20 more, Manukyan A, Collum S, Lin W, Winder CL, Dunn WB, Schupp JC, Braubach P, Wygrecka M, Ren D, Suarez EE, Huang HJ, Hussain R, Patel B, Karmouty-Quintana H, Akalin A, Landthaler M, Nouailles G, Ochs M, Lopez-Rodriguez E, Giambelluca S
Am J Respir Cell Mol Biol
· 2026 Feb · PMID 41738296
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Previous research has highlighted dysregulation in lipid metabolism during lung fibrosis. However, the impact of cholesterol immunometabolism during lung fibrosis progression remains unclear but has been related to the N...Previous research has highlighted dysregulation in lipid metabolism during lung fibrosis. However, the impact of cholesterol immunometabolism during lung fibrosis progression remains unclear but has been related to the NLRP3-inflammasome activation in cardiovascular diseases. The main objective of this work was to investigate the link between altered cholesterol metabolism and NLRP3 inflammasome activation in fibrotic lungs. Different pulmonary fibrosis patient cohorts (from 2 centers and a publicly available dataset) and a murine model of lung fibrosis (aged SP-C-/-) were included. Expression of cholesterol metabolism proteins and cholesterol content were determined in lungs from patients and bronchoalveolar lavage fluid (BALF) cells of aging SP-C-/- mice. Metabolomic and lipidomic analyses were conducted in BALF and BALF cells of SP-C-/- versus wild-type (WT) mice. NLRP3 inflammasome components were assessed by immunoblotting, ELISA, and immunofluorescence. Lung samples from fibrosis patients showed higher cholesterol content, altered cholesterol metabolism and higher IL-18 levels, compared to controls. Moreover, key genes related to inflammasome activation and cholesterol metabolism were differentially expressed in alveolar macrophages from IPF patients. Accordingly, BALF cells of SP-C-/- mice showed alteration of their cholesterol metabolism and inflammasome activation with age and fibrosis development. Lipidomic analysis pointed at cholesterol esters as potential activating agent. The molecular mechanism linking cholesterol esters to NLRP3 inflammasome and fibrosis markers was confirmed in vitro in a human macrophage model. In conclusion, altered cholesterol esterification activates the NLRP3 inflammasome in AM during pulmonary fibrosis in a murine model and fibrosis patients.
Dir B, Mishra R, Hennen N
… +7 more, Mooers E, Teng RJ, Konduri G, Segar JL, Grobe J, Hodges MR, Mouradian GC
Am J Respir Cell Mol Biol
· 2026 Feb · PMID 41738294
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The severity of bronchopulmonary dysplasia (BPD) is defined by the type or amount of respiratory support needed at 36 weeks postmenstrual age, reflecting varying degrees of impairment in the supply and demand systems reg...The severity of bronchopulmonary dysplasia (BPD) is defined by the type or amount of respiratory support needed at 36 weeks postmenstrual age, reflecting varying degrees of impairment in the supply and demand systems regulating arterial oxygenation. However, existing preclinical BPD models fail to account for the comprehensive nature of arterial oxygen regulation (lungs, control mechanisms, and metabolism). Here, based on the predictive power of cumulative supplemental oxygen and BPD severity, we demonstrate that dose dependent increases of CSO limited to the saccular stage of lung development in neonatal mice underlies distinct pathophysiologic features associated with varying degrees of BPD-like phenotypes. Specifically, greater saccular stage CSO levels elicited pathological features commonly associated with severe BPD, including worse alveolar simplification, risk for pulmonary hypertension, hypoventilation, changes in body growth, greater work of breathing, and metabolic acidosis. However, low levels of saccular stage CSO elicited features associated with mild BPD, including mild, though significant, alveolar simplification and pulmonary vascular medial wall thickening with a compensatory ventilatory hyperpnea driven by an increased neural drive to breathe. Thus, we show that different levels of CSO can elicit clinically relevant mild or severe BPD-like phenotypes, expanding the widespread impact CSO has on physiological systems regulating arterial oxygenation. This paradigm enables preclinical testing of therapeutic efficacy across BPD severities, albeit without other common complicating factors. However, this paradigm is amenable to additional insults to align with the more complex clinical course of BPD.
Hoang ON, Chan CE, Brenner JM
… +22 more, Leza-Rincon D, Jaramillo AM, Dolan B, Aziz AW, Cardenas RA, Cardenas GJ, Galvez ED, Hales JB, Nunez-Pena ES, Yang B, Powell RT, Vergara L, Karmouty-Quintana H, Magnusson JM, Hansson GC, Adachi R, Dickinson JD, Evans CM, Courson JA, Burns AR, Tuvim MJ, Dickey BF
Am J Respir Cell Mol Biol
· 2026 Jul · PMID 41738292
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RATIONALE: Finely tuned production and secretion of the polymeric mucins MUC5AC and MUCB are required for lung health, but knowledge of many details between their translation and their packaging into secretory granules i...RATIONALE: Finely tuned production and secretion of the polymeric mucins MUC5AC and MUCB are required for lung health, but knowledge of many details between their translation and their packaging into secretory granules is lacking. OBJECTIVES: To analyze the structure and function of the Golgi apparatus, a key site of mucin glycosylation, folding, polymerization, and packaging, in airway epithelial secretory cells. METHODS: Lung tissue was obtained from mice stimulated or not with IL-13 to upregulate mucin production and from normal human lungs. Golgi elements in mouse and human tissue were imaged by high-resolution immunofluorescence microscopy and electron microscopy. Tissue from mice with deletion of both polymeric mucins was also examined. MEASUREMENTS AND MAIN RESULTS: By immunofluorescence microscopy, both mouse and human airway secretory cells contained approximately 100 dispersed puncta labeled by markers of medial and trans-Golgi cisternae and the trans-Golgi network (TGN), but only a few perinuclear puncta were labeled by markers of cis-Golgi cisternae. By electron microscopy, secretory cells contained both a perinuclear Golgi ribbon and numerous dispersed Golgi stacks, termed satellites. In mucous metaplastic cells, satellites were concentrated among immature mucin granules. Increasing mucin production by cytokine stimulation did not increase the number of TGN puncta, nor did preventing polymeric mucin production by gene deletion reduce TGN puncta. CONCLUSIONS: Mucin-producing airway secretory cells express an unusual Golgi structure consisting of a conventional perinuclear ribbon as well as dispersed satellites. While the Golgi satellites are likely an adaptation for mucin production and packaging, their presence is specified developmentally, independent of mucin production.