[Glycoproteins, mucoproteins and collagen metabolites in the assessment of lung inflammation and sclerosis in chronic pneumonia].
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Chronic Disease↗
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Lpb. plantarum inhalation powders for the reduction of lung inflammation and S. aureus growth control in non-CF bronchiectasis.
INTRODUCTION: The reduced diversity of the lung microbiome in respiratory conditions, including bronchiectasis, promotes bacterial infection and inflammation, contributing to worsening clinical outcomes. Traditional treatments often fail to address both infection and inflammation. Because of their potential dual-action, lactic acid bacteria (LAB) directly administered to the lungs could represent an innovative therapeutic approach for these diseases. RESEARCH DESIGN AND METHODS: Two powders for inhalation containing Lpb. plantarum, lactose, l-leucine with and without raffinose, a prebiotic, were produced by spray drying and in vitro tested. The focus was on investigating their potential in vitro anti-inflammatory and anti-microbial activities against S. aureus. RESULTS: The powders showed a fine particle fraction (<5 µm) of >40% and allowed the maintenance of anti -inflammatory activity in vitro for both treatment and prevention. Moreover, both powders led to a significant reduction in S. aureus growth. The stability study of the powders in capsules at different storage conditions showed the preservation of the LAB up to 90 days in refrigerated conditions (4°C/-20°C). CONCLUSIONS: This proof-of-concept study shows that inhalable spray-dried live LABs retain biological activity and are suitable for pulmonary delivery, supporting their potential as a microbiota-modulating therapy, which, however, requires further preclinical validation.
Inhalation↗
[Home care of the child ill with lung inflammation].
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Child↗
[Sodium nucleinate in the therapy of chronic lung inflammation complicated by bronchial asthma].
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Adult↗
Negative regulation of human IL-33 in endothelium during allergic airway inflammation.
Lung IL-33 is involved in pathogen defense, barrier homeostasis, and development of allergic responses. We previously identified a 5 kb noncoding region within a GWAS-defined segment that regulates expression of human IL33 (hIL33) but is absent in the murine locus. To understand how this region affects IL-33 expression in vivo, we engineered 2 BAC-transgenic strains in which 166 kb of the human genome upstream of the hIL33 locus, along with a fluorescent reporter, was inserted into the murine genome, both with and without the 5 kb region. Comparison to a murine Il33 (mIl33) reporter strain revealed species-specific tropism; hIL33 reporter was mostly expressed in the endothelium, while mIl33 reporter was expressed in type 2 alveolar epithelium. hIL33 reporter expression in tracheal basal epithelium, submucosal glands, and lung microvasculature required the 5 kb region. Surprisingly, allergen and exogenous IL-33 downregulated hIL33 reporter in lung endothelium only when the 5 kb region was present. Similar IL-33-dependent downregulation of IL33 transcripts was observed in human endothelial cell lines, validating that our hIL33 reporter strain recapitulated human endothelial biology. Together, these data reveal the importance of the asthma-associated human 5 kb region in regulating human IL33 expression in a cell type- and context-dependent manner.
Interleukin-33↗
MASLD Exacerbates Chronic Low-dose PM2.5-induced Lung Injury, Inflammation, and Fibrosis.
BACKGROUND/AIM: Fine particulate matter (PM2.5) and metabolic dysfunction-associated steatotic liver disease (MASLD) are independent risk factors for respiratory disease. However, the combined impact of chronic, low-dose PM2.5 exposure and Western diet (WD)-induced metabolic dysfunction on pulmonary health remains poorly understood. We investigated whether this metabolic state exacerbates PM2.5-driven pathologies using an environmentally relevant PM2.5 dosage (~50 μg/m3). MATERIALS AND METHODS: C57BL/6J mice were fed a WD or normal diet (ND) for 28 weeks and concurrently received intratracheal instillations of PM2.5 (0.5 mg/kg diesel particulate matter) or vehicle three times per week. The MASLD phenotype was confirmed through metabolic and histological analyses. Pulmonary injury, fibrosis, and inflammation were assessed via histology (hematoxylin and eosin, and Masson's trichrome staining) and cytokine quantification in both bronchoalveolar lavage fluid using Luminex multiplex assay and lung tissue using enzyme-linked immunosorbent assay and quantitative polymerase chain reaction. RESULTS: The WD successfully induced MASLD characterized by weight gain, hepatic steatosis, and dyslipidemia. While PM2.5 exposure did not significantly worsen the primary features of MASLD, its combination with a WD markedly exacerbated pulmonary injury and fibrosis compared to PM2.5 exposure alone. This exacerbation was driven by a surge in pro-inflammatory chemokines, including C-X-C motif chemokine ligands 1 and 2 (CXCL1 and CXCL2), and C-C motif chemokine ligand 5 (CCL5), confirmed by Luminex analysis of lavage fluid and mRNA/protein quantification in lung tissue. CONCLUSION: Diet-induced metabolic dysfunction primes the lung for a hyper-inflammatory response to chronic PM2.5 exposure. These findings identify individuals with MASLD as a population with heightened susceptibility to air pollution-related respiratory diseases and underscore the critical interplay between metabolic health and environmental toxicology.
Animals↗
Changes in integrated vagal afferent activity induced by model lung diseases in rats.
An attempt has been made in the present report to evaluate quantitatively the sensory activity in both vagal nerves of control rats and rats with experimental lung inflammation, by employing the integration technique. We evaluated background vagal nerve activity, resting respiration and activity during inflation at constant pressures of 5 to 20 cm of water. It was found that integrated vagal respiratory activity cannot be assessed in absolute units under our experimental conditions, because of the large scatter of data. However, when the integrated values were related, for example, to resting respiration (in percentage), it was possible to compare some respiratory parameters in control, healthy rats of the Wistar strain and rats with lung inflammation. While background activity in control rats represents 75.9% of resting respiration, this parameter is significantly higher both in rats with 2-day carrageenin lung inflammation and those intoxicated with paraquat. Lung inflation at pressures 5, 10, 15, 20 cm H2O increased vagal activity linearly both in control and the two experimental groups with the degree of lung inflation. However, values in experimental animals corresponding to those of the control group were not reached until higher inflation pressures. From the functional aspect, experimental rats had characteristic tachypnoea which returns to control values after bilateral vagotomy. Since it was found that lung compliance was significantly decreased in both carrageenin and paraquat lung processes, it is being suggested that the diminished activity from lung receptors during inflation is due to mechanical properties of the lung tissue, namely lowered lung compliance.
Animals↗
Associations of High Attenuation Area-Related Proteomic Biomarkers with Fibrotic or Subpleural Interstitial Lung Abnormalities.
Rationale: High-attenuation area (HAA) is a computed tomography (CT) tool that correlates with lung inflammation and fibrosis. Systemic molecular correlates of HAA (e.g., plasma proteins) may inform biological processes involved in interstitial lung disease. Objectives: To identify plasma proteins that associate with HAA and correlate with a higher probability of developing new-onset fibrotic or subpleural interstitial lung abnormalities (ILAs). Methods: Plasma protein levels were measured using a semiquantitative aptamer-based platform in MESA (the Multi-Ethnic Study of Atherosclerosis; N = 5,486) and SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study; N = 1,781). Linear regression models identified HAA-associated proteins after adjustment for demographic and socioeconomic factors, CT scanner parameters, study center, and batch. Associations of HAA-related proteins with new-onset fibrotic or subpleural ILAs were examined in MESA participants with ILA assessments on full-lung CT 10 years later. Immunohistochemical staining of select proteins was performed in lung tissue from pulmonary fibrosis cases. Measurements and Main Results: There were 75 proteins detected that were significantly associated with HAA in MESA and SPIROMICS. Gene Ontology analysis of these proteins identified processes involved in immune cell chemotaxis and cellular growth and apoptosis. Seven proteins were associated with a higher probability of new-onset fibrotic or subpleural ILAs in MESA, and two of these, junctional adhesion molecule-like protein and GTP cyclohydrolase 1 feedback regulatory protein, stained in areas of fibrosis in lung tissue from patients with interstitial lung disease. Conclusions: Plasma proteins associated with more HAA are involved in immune and cellular processes and associate with new-onset fibrotic-subpleural ILA.
Humans↗
IGF1R deficiency mitigates acute lung injury by promoting anti-inflammatory transcriptional profiles.
BACKGROUND: Acute lung injury (ALI), acute respiratory distress syndrome (ARDS) and COVID-19 are characterized by hyperinflammation, commonly referred to as "cytokine storm". The insulin-like growth factor (IGF) pathway, particularly the type 1 receptor (IGF1R), plays a critical role in lung homeostasis and has been implicated in the pathogenesis of pulmonary inflammatory diseases. In mice, widespread Igf1r deficiency attenuates lung inflammation and alveolar damage in bleomycin (BLM)-induced ALI. METHODS: We analyzed single-cell RNA sequencing datasets from lung tissue of COVID-19 cases and control donors as well as mouse lungs to determine Igf1r and IGF family expression across pulmonary cell types. Furthermore, we conducted bulk RNA sequencing on lungs from Igf1r-deficient mice three days after BLM or saline instillation, followed by differential expression and functional enrichment analyses. Findings were further tested through protein detection, assessment of DNA damage and methylation in lung tissues, and functional assays using Igf1r-deficient primary mouse embryonic fibroblasts (MEFs). RESULTS: IGF1R was broadly expressed across multiple cell types in both human and mouse lungs under normal and pathological conditions. Other IGF family members showed cell-type-specific expression, which was modulated by lung injury. Transcriptomic profiling revealed differentially expressed genes between BLM-challenged and control mouse lungs, detecting biological processes and signaling pathways involved in ALI pathobiology. Igf1r deficiency in BLM-challenged mice reversed a large fraction of the transcriptional changes triggered by BLM, including "cytokine storm"-related gene expression. Functional enrichment analysis additionally revealed significant modulation of pathways related to DNA damage, metabolic reprogramming, mitochondrial homeostasis, and epigenetic regulation. In vitro, Igf1r-deficient MEFs exhibited decreased mitochondrial respiration and glycolysis, protection against BLM-induced nuclear damage and mitochondrial accumulation, and decreased histone H3 acetylation. Moreover, Igf1r-deficient mouse lungs displayed increased global DNA methylation following BLM challenge. CONCLUSIONS: IGF1R is a key modulator of the inflammatory and molecular response to ALI pathogenesis. IGF1R deficiency dampens the "cytokine storm", modifies transcriptional and epigenetic profiles and promotes protective cellular responses. These findings highlight IGF1R signaling as a potential therapeutic target in ARDS and related lung injuries.
Animals↗
The alarmin interleukin-33 modulates platelet proteome, function, and biogenesis.
Platelets, traditionally recognized for their involvement in hemostasis and wound healing, also play a central role in immune regulation and inflammation. Their function and production adapt in response to inflammatory cues such as cytokines and danger-associated molecular patterns. Interleukin-33 (IL-33), an alarmin released during tissue damage, particularly in lung inflammation, has been implicated in influencing platelet biology, though its exact effects remain poorly understood. To clarify IL-33's role, we examined its impact on platelet production, proteome, adhesion, secretion, and aggregation using platelets from IL-33-deficient (IL-33 knockout [IL-33KO]) mice and IL-33 stimulation in vivo. Our results reveal that although platelets themselves do not express IL-33, platelets isolated from IL-33KO mice display altered proteomic signatures and reduced adhesion to fibrinogen, podoplanin, and laminin, alongside impaired thrombus formation under shear stress. IL-33 administration in vivo led to proteomic remodeling characterized by increased expression of inflammatory proteins, as well as changes in platelet morphology, including increased size, typically associated with de novo production. Using lung intravital microscopy, we visualized platelet fragmentation within the lung vasculature in real time, and observed enhanced fragmentation following IL-33 stimulation. Interestingly, ST2, the receptor for IL-33, is expressed in subsets of mouse and human megakaryocytes and hematopoietic progenitors, particularly those involved in a noncanonical pathway of thrombopoiesis that enables the rapid replenishment of platelets during inflammation, infection, and aging. Together, these findings identify IL-33 as a pivotal regulator of platelet function and production, linking inflammatory signaling to the dynamic regulation of thrombopoiesis.
Interleukin-33↗
Single-dose cathepsin L CRISPR nanotherapy mitigates PASC-like lung damage in hamsters.
Respiratory post-acute sequelae of COVID-19 (PASC) persists in many SARS-CoV-2 survivors, yet no therapies specifically address its long-term pulmonary damage. We demonstrate that a single-dose CRISPR-CasRx nanotherapy targeting the host enzyme cathepsin L (SCNC) effectively reduces acute SARS-CoV-2 infection in Syrian hamsters, with antiviral efficacy comparable to Paxlovid. Importantly, SCNC outperforms Paxlovid in alleviating alveolar epithelial hyperplasia and lung inflammation at 31 days post-infection, a recognized PASC time point. Single-cell RNA sequencing reveals that SCNC enhances alveolar repair by promoting the differentiation of alveolar type 2 cells into alveolar type 1 cells and by reducing inflammatory infiltration through multiple signaling pathways. Thus, SCNC exerts a dual mechanism: host-directed viral inhibition and promotion of epithelial repair with reduced inflammation. This distinguishes it from therapies focused solely on viral suppression or symptom relief. These findings support SCNC as a promising therapeutic candidate for acute infection and, particularly, for PASC-related lung injury, where options remain limited.
alveolar epithelial regeneration↗
Pathogenesis of Pseudomonas aeruginosa pneumonia during immunosuppression.
A guinea pig model of immunosuppression was utilized to study the effects of immunosuppressive chemotherapy on lung response to challenge with Pseudomonas aeruginosa. Study groups included normal guinea pigs, as well as guinea pigs that received a one-week course of cortisone acetate (CA, 100 mg/kg per day) plus 15 mg of cyclophosphamide (CTX)/kg per day (CA + LoCTX group) or 30 mg of cyclophosphamide/kg per day (CA + HiCTX group). Separate groups received CA or HiCTX alone. Intratracheal instillation of P. aeruginosa resulted in bilateral hemorrhagic pneumonia in both normal and immunosuppressed animals. Survival was 100% for normal animals and for those given CA alone, 67% in the CA + LoCTX and the HiCTX groups, and 0 in the CA + HiCTX group. Increased mortality correlated with a diminished polymorphonuclear leukocyte inflammatory response in infected lung tissues and also with the addition of CA to CTX. Clearance of viable P. aeruginosa from lung tissue was significantly reduced in animals receiving the combination CA + HiCTX. Thus, decreased lung inflammation and the addition of CA appeared to be important determinants for fatal pseudomonas pneumonia.
Animals↗
Humanizing acidic mammalian chitinase variants establish lung immune conditioning and control environmentally driven inflammation and fibrosis.
Chitin, a widespread environmental particle constituent, triggers lung inflammation but is degraded by chitinases. In humans, single-nucleotide polymorphisms (SNPs) in CHIA (acidic mammalian chitinase; AMCase) are associated with lung disease, suggesting that chitinase variants influence responses to airborne particles. Here, we edit the mouse Chia1 locus to generate humanized (hChia) mice harboring common human SNPs. Compared with controls expressing disease-protective SNPs, hChia mice lack robust chitinase activity and fail to degrade natural chitin substrates. Lung-resident lymphocytes and macrophages are spontaneously primed and sensitive to inflammatory triggering by environmental chitin. Immune cell infiltration correlates with airway chitin following challenge, and hChia mice exhibit exacerbated inflammatory and fibrotic lung disease. In humans with acute respiratory failure, alveolar hemorrhage coincides with environmentally derived chitin particles that are susceptible to chitinase degradation, attenuating inflammatory cell responses. Thus, environmental chitin and chitinase activity are crucial determinants of lung immune conditioning with potential therapeutic applications.
AMCase↗
Experimental hypersensitivity lung disease. Chronic pulmonary inflammation and cell-mediated hypersensitivity by exposure to aerosolized antigens in rabbits.
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Aerosols↗
Inhaled vitamin A mitigates hyperoxia-induced acute and chronic lung damage in a neonatal rat model of bronchopulmonary dysplasia.
RATIONALE: Prevention of bronchopulmonary dysplasia (BPD) remains a critical unmet need. OBJECTIVES: We continued evaluating aerosolized vitamin A in a neonatal rat hyperoxia-injury model of BPD, testing whether lung-targeted inhalation yields superior outcomes compared to enteral or intramuscular (IM) delivery. METHODS: Rat pups were exposed to continuous 95% hyperoxia for seven days to induce lung damage. Vitamin A was administered from post-natal day (PD) 1-7 by inhalation, enteral or IM dosing. Persisting effectiveness of inhaled vitamin A was examined at PD 21, dwelling in normoxia after all interventions were discontinued at PD 7. MEASUREMENTS AND MAIN RESULTS: Comprehensive analyses include alveolar morphometrics, in vivo pulmonary function testing, assessment of hepatic vitamin A level, and quantitating gene and protein expression of relevant biomarkers of lung maturation, inflammation and damage/repair, employing singlex and multiplexed assays and whole-genome gene expression. CONCLUSIONS: Inhaled vitamin A suppressed hyperoxia-induced lung damage, with key hallmarks of BPD, including lung morphometrics and biomarkers associated with lung damage and inflammation, being effectively indistinguishable from healthy controls at both PD 7 and 21, Natural reparative processes were enhanced, with normal alveolarization and pulmonary function at PD 21. Despite raising hepatic vitamin A levels, enteral dosing was ineffective in restoring alveolar morphology at PD 7. Consistent with previous reporting, IM dosing yielded modest effect at PD 7 but with little evidence of benefit to pulmonary function at PD 21. Observation of dose-dependent effects with aerosolized vitamin A strengthens the evidence of the benefits of lung-targeted delivery, supporting further development of inhaled vitamin A as a BPD preventive strategy.
Journal Article↗
Prophylactic Inhaled Pattern Recognition Receptor Agonists Reprogram Lung Epithelial Response and Prevent Type 2 Allergic Inflammation.
Prophylactic inhalation of the synergistic agents ODN M362 and Pam2CSK4 ("Pam2ODN") protects mice against allergic lung disease, including allergic inflammation caused by house dust mite (HDM). By preventing sensitization, Pam2ODN reduces HDM-induced eosinophilic and lymphocytic inflammation. How Pam2ODN affects interactions among lung epithelial cells, dendritic cells, and T cells to prevent eosinophilic lung inflammation remains unclear. In the present study, we show that a single inhaled dose of Pam2ODN before HDM sensitization reduces airway Th2 polarization without affecting Th1 or Treg responses. Furthermore, Pam2ODN pretreatment inhibits the recruitment of lung monocyte-derived dendritic cells (moDCs) and conventional Type 2 dendritic cells (DC2s), while preventing the HDM-induced decrease in conventional Type 1 dendritic cells (DC1s). Bulk RNA-seq of the whole lung reveals that Pam2ODN pretreatment restricts the expression of proinflammatory transcripts induced by HDM sensitization. This tolerogenic effect is also reflected at the single-cell level in lung epithelial cells, where proinflammatory transcripts, pathways, and chromatin accessibility are inhibited. These results indicate that Pam2ODN reprograms lung epithelial cells to attenuate allergen-induced Th2-promoting cytokines and DCs while maintaining the population of protective DC1s. These findings suggest a strategy to mitigate chronic allergic lung diseases.
Animals↗
Association of Lung Quantitative CT Scan Textures With Systemic Inflammation and Mortality in COPD.
BACKGROUND: COPD is characterized by persistent inflammation that is responsible for remodeling the bronchovascular bundles (BVBs), which may lead to poor quality of life. Quantitative CT (QCT) scan textures of the lung can capture local disease patterns of inflammation and related respiratory morbidity. RESEARCH QUESTION: Are BVB textures, obtained from the adaptive multiple feature method, associated with systemic inflammation, morbidity, and mortality in COPD? STUDY DESIGN AND METHODS: We analyzed data from the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS; n = 2,981) and the Genetic Epidemiology of COPD (COPDGene) study (n = 10,305). The predictors included 2 QCT scan biomarkers, the BVB and CT density gradient (CTDG) textures, age, sex, BMI, race, smoking status, pack-years of smoking, CT scan-detected emphysema, and square root of the wall area of a hypothetical airway with a 10-mm lumen perimeter (Pi10). Outcomes included plasma biomarker concentrations from Meso Scale Discovery proteomics assays and CBC counts, both as markers of inflammation, along with FEV1, FEV1 to FVC ratio, St. George's Respiratory Questionnaire score, 6-minute walk distance, and modified Medical Research Council dyspnea scale score. Associations of these QCT scan textures with FEV1 decline and all-cause mortality also were investigated. RESULTS: Increased BVB texture was associated significantly with elevated neutrophil and monocyte counts and the neutrophil to lymphocyte ratio, independent of clinical covariates, CT scan-detected emphysema, and Pi10. Elevated CTDG was associated with increased neutrophil count, NLR, and tumor necrosis factor α. Increased CTDG and BVB textures also were associated with a lower FEV1 and 6-minute walk distance. CTDG at baseline was also associated with decline in FEV1 at the 5-year follow-up in the COPDGene study. We observed a significant association of both BVB texture (SPIROMICS: hazard ratio [HR], 1.084 [95% CI, 1.035-1.135; P < .001]; COPDGene: HR, 1.106 [95% CI, 1.080-1.131; P < .001]) and CTDG texture (SPIROMICS: HR, 1.033 [95% CI, 1.003-1.064; P = .03]; COPDGene: HR, 1.079 [95% CI, 1.061-1.096; P < .001]) with all-cause mortality independent of CT scan-detected emphysema and Pi10. INTERPRETATION: QCT scan textures may provide imaging evidence of the spatial heterogeneity of lung inflammation and overall disease burden in COPD. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; Nos.: NCT01969344 (SPIROMICS) and NCT00608764 (COPDGene); URL: www. CLINICALTRIALS: gov.
Humans↗
Human airspace macrophage signatures are conserved during sterile lung injury and repair.
RATIONALE: Airspace macrophages (AM) are implicated in both persistent inflammation and tissue repair following acute lung injury. Distinct subsets of AM are associated with lung pathology in humans but whether unique AM signatures are specific to disease states or represent a conserved response to lung inflammation is unknown. OBJECTIVES: We sought to test the hypothesis that conserved subsets of inflammatory and reparative AM could be identified by transcriptional programing in a human model of self-resolving acute lung injury. METHODS: Fifteen subjects underwent bronchoscopic lavage (BAL) before and at a pre-assigned time point after endobronchial exposure to bacterial endotoxin. BAL cells were subjected to single cell RNA sequencing and longitudinal assessment of AM programing during resolution of inflammation and lung repair was performed. MEASUREMENTS AND MAIN RESULTS: We identify transcriptionally distinct subsets of tissue resident and recruited AM present at all time points, in all subjects. Two recruited AM populations increase following inflammation, one which aligns with classical monocytes (MoAM) and one with interstitial macrophages (IAM). AM subsets display unique patterns of gene expression throughout the time course. Comparison of subset-specific markers to those identified in disease states reveals that IAM express many so-called "pathogenic" markers during normal lung repair. CONCLUSIONS: By applying a uniform inflammatory stimulus to healthy adults and examining BAL cells obtained at precise time points thereafter, we construct a time-resolved kinetic of AM transcriptional programing during typical lung repair. Our data demonstrate that IAM share transcriptional similarity to AM identified in disease states and suggest they may reflect a conserved cellular response to tissue injury.
Journal Article↗