Longitudinal effects of elexacaftor/tezacaftor/ivacaftor on sputum viscoelastic properties, airway infection and inflammation in patients with cystic fibrosis

European Respiratory Journal, Год журнала: 2023, Номер 62(2), С. 2202153 - 2202153

Опубликована: Июль 6, 2023

Recent studies demonstrated that the triple combination cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy elexacaftor/tezacaftor/ivacaftor (ETI) improves lung function and reduces pulmonary exacerbations in (CF) patients with at least one F508del allele. However, effects of ETI on downstream consequences CFTR dysfunction, i.e. abnormal viscoelastic properties airway mucus, chronic infection inflammation have not been studied. The aim this study was to determine longitudinal mucus rheology, microbiome CF or two alleles aged ≥12 years throughout first 12 months therapy.In prospective observational study, we assessed sputum microbiome, markers proteome before 1, 3 after initiation ETI.In total, 79 allele 10 healthy controls were enrolled study. improved elastic modulus viscous (all p<0.01). Furthermore, decreased relative abundance Pseudomonas aeruginosa increased α-diversity all time points. In addition, reduced interleukin-8 (p<0.05) free neutrophil elastase activity points p<0.001), shifted towards healthy.Our data demonstrate restoration by properties, over therapy; however, levels close reached.

Язык: Английский

---

The future of cystic fibrosis treatment: from disease mechanisms to novel therapeutic approaches

The Lancet, Год журнала: 2023, Номер 402(10408), С. 1185 - 1198

Опубликована: Сен. 1, 2023

Язык: Английский

---

Cystic fibrosis

Nature Reviews Disease Primers, Год журнала: 2024, Номер 10(1)

Опубликована: Авг. 8, 2024

Язык: Английский

---

Mucus Structure, Viscoelastic Properties, and Composition in Chronic Respiratory Diseases

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(3), С. 1933 - 1933

Опубликована: Фев. 5, 2024

The respiratory mucus, a viscoelastic gel, effectuates primary line of the airway defense when operated by mucociliary clearance. In chronic diseases (CRDs), such as asthma, obstructive pulmonary disease (COPD), and cystic fibrosis (CF), mucus is overproduced its solid content augments, changing structure properties determining derangement essential mechanisms against opportunistic microbial (virus bacteria) pathogens. This ensues in damaging airways, leading to vicious cycle obstruction infection responsible for harsh clinical evolution these CRDs. Here, we review features normal pathological (i.e., sputum CF, COPD, asthma), i.e., mucin content, (mesh size), micro/macro-rheology, pH, osmotic pressure, ending with awareness that biomarkers (mucins, inflammatory proteins peptides, metabolites) might serve indicate acute exacerbation response therapies. There are some indications old novel treatments may change structure, properties, biomarker sputum; however, wealth work still needed embrace measures correlates severity association (or even substitutes of) functional tests.

Язык: Английский

---

Pharmacological Improvement of Cystic Fibrosis Transmembrane Conductance Regulator Function Rescues Airway Epithelial Homeostasis and Host Defense in Children with Cystic Fibrosis

American Journal of Respiratory and Critical Care Medicine, Год журнала: 2024, Номер 209(11), С. 1338 - 1350

Опубликована: Янв. 23, 2024

Pharmacological improvement of cystic fibrosis transmembrane conductance regulator (CFTR) function with elexacaftor/tezacaftor/ivacaftor (ETI) provides unprecedented improvements in lung and other clinical outcomes patients (CF). However, ETI effects on impaired mucosal homeostasis host defense at the molecular cellular levels airways CF remain unknown.

Язык: Английский

---

Inhalable siRNA Targeting IL-11 Nanoparticles Significantly Inhibit Bleomycin-Induced Pulmonary Fibrosis

ACS Nano, Год журнала: 2025, Номер unknown

Опубликована: Янв. 10, 2025

For idiopathic pulmonary fibrosis (IPF), interleukin 11 (IL-11) is a pivotal cytokine that stimulates the transformation of fibroblasts into myofibroblasts, thus accelerating progression fibrosis. Here, we develop an innovative inhalable small interfering RNA (siRNA) delivery system termed PEI-GBZA, which demonstrates impressive efficiency in loading siIL-11 targeting IL-11 (siIL-11) and substantially suppresses differentiation myofibroblasts epithelial-mesenchymal transition (EMT), reduces neutrophil macrophage recruitment, ultimately relieves established fibrotic lesions IPF model. PEI-GBZA prepared by modifying low-molecular-weight polyethylenimine (PEI) with 4-guanidinobenzoic acid (GBZA). The resulting may effectively encapsulate through variety interactions such as hydrophobic, hydrogen bonding, electrostatic interactions, creating stable carrier/siIL-11 nanoparticles (PEI-GBZA/siIL-11 NPs). Upon inhalation, PEI-GBZA/siIL-11 NPs demonstrate effective retention lesions, leading to marked mitigation disease bleomycin-induced Impressively, this inhalation therapy exhibits negligible systemic toxicity. This work provides universal noninvasive therapeutic platform holds significant promise for respiratory diseases. potential clinical application substantial, offering frontier treatment potentially other disorders.

Язык: Английский

---

Airway mucins promote immunopathology in virus-exacerbated chronic obstructive pulmonary disease

Journal of Clinical Investigation, Год журнала: 2022, Номер 132(8)

Опубликована: Март 3, 2022

The respiratory tract surface is protected from inhaled pathogens by a secreted layer of mucus rich in mucin glycoproteins. Abnormal accumulation cardinal feature chronic diseases, but the relationship between and during exacerbations poorly understood. We identified elevations airway 5AC (MUC5AC) MUC5B concentrations spontaneous experimentally induced obstructive pulmonary disease (COPD) exacerbations. MUC5AC was more sensitive to changes expression exacerbation therefore predictably associated with viral load, inflammation, symptom severity, decrements lung function, secondary bacterial infections. functionally related as Muc5ac-deficient (Muc5ac-/-) mice had attenuated RV-induced (RV-induced) exogenous glycoprotein administration augmented inflammatory responses increased release extracellular adenosine triphosphate (ATP) human epithelial cell cultures. Hydrolysis ATP suppressed augmentation inflammation mice. Therapeutic suppression production using an EGFR antagonist ameliorated immunopathology mouse COPD model. coordinated virus induction suggests that non-Th2 mechanisms trigger hypersecretion Our data proinflammatory role for infection suggest inhibition may ameliorate

Язык: Английский

---

Mucus Penetration of Surface-Engineered Nanoparticles in Various pH Microenvironments

ACS Nano, Год журнала: 2023, Номер 17(3), С. 2813 - 2828

Опубликована: Янв. 31, 2023

The penetration behavior of nanoparticles in mucous depends on physicochemical properties the and mucus microenvironment, due to particle–mucin interactions presence mucin mesh space filtration effect. To date, it is still unclear how surface influence their behaviors various physiological pathophysiological conditions. In this study, we have prepared a comprehensive library amine-, carboxyl-, PEG-modified silica (SNPs) with controlled ligand densities. Using multiple particle tracking, studied mechanism responsible for these SNPs. It was found that PEG- amine-modified SNPs exhibited pH-independent immobilization under iso-density conditions, while carboxyl-modified enhanced movement only weakly alkaline mucus. Biophysical characterizations demonstrated amine- were trapped electrostatic hydrogen bonding mucin. contrast, high-density PEGylated formed brush conformation shields interactions. We further investigated property-dependent using murine airway distribution model. This study provides insights designing efficient transmucosal nanocarriers prevention treatment pulmonary diseases.

Язык: Английский

---

Epithelial Barrier in the Nasal Mucosa, Related Risk Factors and Diseases

International Archives of Allergy and Immunology, Год журнала: 2023, Номер 184(5), С. 481 - 501

Опубликована: Янв. 1, 2023

As the first line of defense against risk factors, nasal epithelial barrier maintains homeostasis in mucosa. The composition contains physical, chemical, immune, and microbiological barriers. Together, these barriers form irritations. Risk factors from both internal external environments can disrupt them. External contain allergens containing proteases, bacteria, virus, particulate matter, diesel exhaust particles, cigarette smoke. In meantime, inflammatory cytokines also increase load on barrier. Taking into account role mucosa, some studies focus treatment allergic rhinitis (AR) chronic rhinosinusitis (CRS) by restoring barrier, progress has been made. Among therapeutic approaches, histone deacetylase (HDAC) inhibitor steroid corticosteroids are considered two more studied categories, their roles repairing have demonstrated AR CRS. underlying mechanism HDAC may be related to transcription factor p63. And protection associated with disease susceptibility gene, protocadherin-1. Notably, manipulation a positive effect Lactococcus probiotics categories that worth being explored continuously. We here review discuss compositions Furthermore, novel promising approaches restore defective diseases were mentioned.

Язык: Английский

---

Chronic airway epithelial hypoxia exacerbates injury in muco-obstructive lung disease through mucus hyperconcentration

Science Translational Medicine, Год журнала: 2023, Номер 15(699)

Опубликована: Июнь 7, 2023

Unlike solid organs, human airway epithelia derive their oxygen from inspired air rather than the vasculature. Many pulmonary diseases are associated with intraluminal obstruction caused by aspirated foreign bodies, virus infection, tumors, or mucus plugs intrinsic to disease, including cystic fibrosis (CF). Consistent requirements for luminal O 2 , surrounding in chronic obstructive disease (COPD) lungs hypoxic. Despite these observations, effects of hypoxia (CH) on epithelial host defense functions relevant have not been investigated. Molecular characterization resected individuals a spectrum muco-obstructive lung (MOLDs) COVID-19 identified molecular features hypoxia, increased EGLN3 expression, lining mucus-obstructed airways. In vitro experiments using cultured chronically hypoxic revealed conversion glycolytic metabolic state maintenance cellular architecture. Chronically unexpectedly exhibited MUC5B mucin production and transepithelial Na + fluid absorption mediated HIF1α/HIF2α-dependent up-regulation β γENaC (epithelial channel) subunit expression. The combination generated hyperconcentrated predicted perpetuate obstruction. Single-cell bulk RNA sequencing analyses transcriptional changes involved wall remodeling, destruction, angiogenesis. These results were confirmed RNA–in situ hybridization studies MOLD. Our data suggest that may be central pathogenesis persistent accumulation MOLDs damage.

Язык: Английский

---