Fibrotic Lung Research Articles

Plumbagin attenuates Bleomycin-induced lung fibrosis in mice

BackgroundIdiopathic pulmonary fibrosis (IPF) is a fatal fibrotic lung disease with limited treatment options. Plumbagin (PL) is an herbal extract with diverse pharmacological effects that have been recently used to treat various types of cancer. This study aims to explore the anti-fibrotic effect of PL and possible underlying mechanisms in IPF.MethodsWe used a bleomycin-induced experimental mouse model of lung fibrosis to assess the potential anti-fibrotic effect of PL. Histological analysis of lung tissue samples by H&E and Masson’s trichrome staining and hydroxyproline assay was performed to evaluate the fibrotic alterations. ELISA and real-time quantitative PCR were conducted to determine the amount of tumor necrosis factor-alpha (TNFα), tumor growth factor-beta (TGF-β), connective tissue growth factor (CTGF), and endothelin-1 (ET-1).ResultsBleomycin exposure induced lung fibrosis, which was indicated by inflammation, collagen deposition, and structural damage. PL remarkably prevented bleomycin-induced lung fibrosis. Furthermore, PL significantly inhibited TNF-α and TGF-β production. PL also diminished the upregulated expression of CTGF and ET-1 induced by bleomycin.ConclusionOverall, our findings suggest PL as an anti-fibrotic agent acting via down-regulation of TGF-β/CTGF or ET-1 axis, as well as TNF-α, to improve lung fibrosis.

Research progress of occupational and environmental exposure and idiopathic pulmonary fibrosis

Occupational and environmental exposure can directly cause specific lung diseases, and can also induce autoimmune diseases that can lead to various types of interstitial lung diseases. In recent years, it was discovered that certain occupational and environmental exposure was related to the increased risk of Idiopathic pulmonary fibrosis (IPF) disease and progression, including metal and mineral dust, wood dust, organic dust, asbestos dust, silica dust, cigarette smoke and air pollution. IPF is a chronic progressive fibrotic lung disease of unknown etiology, with a characteristic imaging and histologic pattern called usual interstitial pneumonia. This article is a review based on the correlation and mechanism of occupational and environmental exposure in the pathogenesis and disease progression of IPF to improve the understanding of the disease and promote the formulation of treatment plans.

Safety and Efficacy of Transbronchial Lung Cryobiopsy Versus Forceps Biopsy in the Diagnosis of Fibrotic Lung Disease: Biopsies and Beyond

Histology is a key element for the multidisciplinary diagnosis of fibrotic diffuse parenchymal lung diseases (f-DPLD) when the clinical–radiological setting of f-DPLD with high-resolution CT features diagnostic of usual interstitial pneumonia (UIP) are not present.

Association of Particulate Matter Exposure With Lung Function and Mortality Among Patients With Fibrotic Interstitial Lung Disease

Particulate matter 2.5 μm or less in diameter (PM2.5) is associated with adverse outcomes for patients with idiopathic pulmonary fibrosis, but its association with other fibrotic interstitial lung diseases (fILDs) and the association of PM2.5 composition with adverse outcomes remain unclear. To investigate the association of PM2.5 exposure with mortality and lung function among patients with fILD. In this multicenter, international, prospective cohort study, patients were enrolled in the Simmons Center for Interstitial Lung Disease Registry at the University of Pittsburgh in Pittsburgh, Pennsylvania; 42 sites of the Pulmonary Fibrosis Foundation Registry; and 8 sites of the Canadian Registry for Pulmonary Fibrosis. A total of 6683 patients with fILD were included (Simmons, 1424; Pulmonary Fibrosis Foundation, 1870; and Canadian Registry for Pulmonary Fibrosis, 3389). Data were analyzed from June 1, 2021, to August 2, 2022. Exposure to PM2.5 and its constituents was estimated with hybrid models, combining satellite-derived aerosol optical depth with chemical transport models and ground-based PM2.5 measurements. Multivariable linear regression was used to test associations of exposures 5 years before enrollment with baseline forced vital capacity and diffusion capacity for carbon monoxide. Multivariable Cox models were used to test associations of exposure in the 5 years before censoring with mortality, and linear mixed models were used to test associations of exposure with a decrease in lung function. Multiconstituent analyses were performed with quantile-based g-computation. Cohort effect estimates were meta-analyzed. Models were adjusted for age, sex, smoking history, race, a socioeconomic variable, and site (only for Pulmonary Fibrosis Foundation and Canadian Registry for Pulmonary Fibrosis cohorts). Median follow-up across the 3 cohorts was 2.9 years (IQR, 1.5-4.5 years), with death for 28% of patients and lung transplant for 10% of patients. Of the 6683 patients in the cohort, 3653 were men (55%), 205 were Black (3.1%), and 5609 were White (84.0%). Median (IQR) age at enrollment across all cohorts was 66 (58-73) years. A PM2.5 exposure of 8 μg/m3 or more was associated with a hazard ratio for mortality of 4.40 (95% CI, 3.51-5.51) in the Simmons cohort, 1.71 (95% CI, 1.32-2.21) in the Pulmonary Fibrosis Foundation cohort, and 1.45 (95% CI, 1.18-1.79) in the Canadian Registry for Pulmonary Fibrosis cohort. Increasing exposure to sulfate, nitrate, and ammonium PM2.5 constituents was associated with increased mortality across all cohorts, and multiconstituent models demonstrated that these constituents tended to be associated with the most adverse outcomes with regard to mortality and baseline lung function. Meta-analyses revealed consistent associations of exposure to sulfate and ammonium with mortality and with the rate of decrease in forced vital capacity and diffusion capacity of carbon monoxide and an association of increasing levels of PM2.5 multiconstituent mixture with all outcomes. This cohort study found that exposure to PM2.5 was associated with baseline severity, disease progression, and mortality among patients with fILD and that sulfate, ammonium, and nitrate constituents were associated with the most harm, highlighting the need for reductions in human-derived sources of pollution.

Non-Invasive Assessment of Right Ventricle to Arterial Coupling for Prognosis Stratification of Fibrotic Interstitial Lung Diseases.

Background: The coupling of the right ventricle (RV) to the pulmonary circulation is an indicator of RV performance that can be non-invasively estimated by echocardiography. There are no data about its use in patients affected by fibrotic interstitial lung diseases (f-ILD). Methods: Fifty f-ILD patients, including 27 cases with idiopathic pulmonary fibrosis (IPF) (M = 37; mean age 67 ± 7 years), were studied with standard and speckle-tracking echocardiography and compared with 30 age-matched healthy volunteers. The mean patient follow-up was 70 ± 4 months. Results: Fibrotic ILD patients had a larger right ventricle (RV) and worse diastolic function because the RV global longitudinal strain (GLS) was significantly lower and the systolic pulmonary artery pressure (sPAP) estimates were higher in comparison with those of controls. Conversely, tricuspid annular systolic excursion (TAPSE) did not differ between controls and patients. Median values of TAPSE/sPAP and RV GLS/sPAP were significantly reduced in f-ILD patients (p < 0.0001). Patients with an RV GLS/sPAP below the median value had a shorter survival time (61 vs. 74 months, p = 0.01); this parameter was an independent predictor of a worse outcome. Conclusion: Low estimates of RV GLS/sPAP are predictive of worse outcomes in f-ILD patients. RV coupling seems to be a promising surrogate biomarker of RV performance to discriminate the patient phenotype with significant management and prognosis implications.

The Emerging Role of Extracellular Vesicles from Mesenchymal Stem Cells and Macrophages in Pulmonary Fibrosis: Insights into miRNA Delivery.

Pulmonary fibrosis is a type of chronic, progressive, fibrotic lung disease of unclear cause with few treatment options. Cell therapy is emerging as a promising novel modality for facilitating lung repair. Mesenchymal stem cell (MSC)-based and macrophage-based cell therapies are regarded as promising strategies to promote lung repair, due to incredible regenerative potential and typical immunomodulatory function, respectively. Extracellular vesicles (EVs), including exosomes and microvesicles, are cell-derived lipid-bilayer membrane vesicles that are secreted from virtually every cell and are involved in intercellular communication by delivering expansive biological cargos to recipients. This review provides a deep insight into the recent research progress concerning the effects of MSC and macrophage-associated EVs on the pathogenesis of pulmonary fibrosis. In addition to discussing their respective vital roles, we summarize the importance of cross-talk, as macrophages are vital for MSCs to exert their protective effects through two major patterns, including attenuating macrophage activation and M1 phenotype macrophage polarization. Moreover, miRNAs are selectively enriched into EVs as essential components, and consideration is given to the particular effects of EV-associated miRNAs.

The Novel Small Molecule BTB Inhibits Pro-Fibrotic Fibroblast Behavior though Inhibition of RhoA Activity.

Idiopathic pulmonary fibrosis (IPF) is a progressive, chronic, interstitial lung disease with a poor prognosis. Although specific anti-fibrotic medications are now available, the median survival time following diagnosis remains very low, and new therapies are urgently needed. To uncover novel therapeutic targets, we examined how biochemical properties of the fibrotic lung are different from the healthy lung. Previous work identified lactate as a metabolite that is upregulated in IPF lung tissue. Importantly, inhibition of the enzyme responsible for lactate production prevents fibrosis in vivo. Further studies revealed that fibrotic lesions of the lung experience a significant decline in tissue pH, likely due to the overproduction of lactate. It is not entirely clear how cells in the lung respond to changes in extracellular pH, but a family of proton sensing G-protein coupled receptors has been shown to be activated by reductions in extracellular pH. This work examines the expression profiles of proton sensing GPCRs in non-fibrotic and IPF-derived primary human lung fibroblasts. We identify TDAG8 as a proton sensing GPCR that is upregulated in IPF fibroblasts and that knockdown of TDAG8 dampens myofibroblast differentiation. To our surprise, BTB, a proposed positive allosteric modulator of TDAG8, inhibits myofibroblast differentiation. Our data suggest that BTB does not require TDAG8 to inhibit myofibroblast differentiation, but rather inhibits myofibroblast differentiation through suppression of RhoA mediated signaling. Our work highlights the therapeutic potential of BTB as an anti-fibrotic treatment and expands upon the importance of RhoA-mediated signaling pathways in the context of myofibroblast differentiation. Furthermore, this works also suggests that TDAG8 inhibition may have therapeutic relevance in the treatment of IPF.

Gut microbiome and metabolites: The potential key roles in pulmonary fibrosis.

There are a wide variety of microbiomes in the human body, most of which exist in the gastrointestinal tract. Microbiomes and metabolites interact with the host to influence health. Rapid progress has been made in the study of its relationship with abenteric organs, especially lung diseases, and the concept the of “gut–lung axis” has emerged. In recent years, with the in-depth study of the “gut–lung axis,” it has been found that changes of the gut microbiome and metabolites are related to fibrotic interstitial lung disease. Understanding their effects on pulmonary fibrosis is expected to provide new possibilities for the prevention, diagnosis and even treatment of pulmonary fibrosis. In this review, we focused on fibrotic interstitial lung disease, summarized the changes the gut microbiome and several metabolites of the gut microbiome in different types of pulmonary fibrosis, and discussed their contributions to the occurrence and development of pulmonary fibrosis.

The fatal trajectory of pulmonary COVID-19 is driven by lobular ischemia and fibrotic remodelling.

SummaryBackgroundCOVID-19 is characterized by a heterogeneous clinical presentation, ranging from mild symptoms to severe courses of disease. 9–20% of hospitalized patients with severe lung disease die from COVID-19 and a substantial number of survivors develop long-COVID. Our objective was to provide comprehensive insights into the pathophysiology of severe COVID-19 and to identify liquid biomarkers for disease severity and therapy response.MethodsWe studied a total of 85 lungs (n = 31 COVID autopsy samples; n = 7 influenza A autopsy samples; n = 18 interstitial lung disease explants; n = 24 healthy controls) using the highest resolution Synchrotron radiation-based hierarchical phase-contrast tomography, scanning electron microscopy of microvascular corrosion casts, immunohistochemistry, matrix-assisted laser desorption ionization mass spectrometry imaging, and analysis of mRNA expression and biological pathways. Plasma samples from all disease groups were used for liquid biomarker determination using ELISA. The anatomic/molecular data were analyzed as a function of patients’ hospitalization time.FindingsThe observed patchy/mosaic appearance of COVID-19 in conventional lung imaging resulted from microvascular occlusion and secondary lobular ischemia. The length of hospitalization was associated with increased intussusceptive angiogenesis. This was associated with enhanced angiogenic, and fibrotic gene expression demonstrated by molecular profiling and metabolomic analysis. Increased plasma fibrosis markers correlated with their pulmonary tissue transcript levels and predicted disease severity. Plasma analysis confirmed distinct fibrosis biomarkers (TSP2, GDF15, IGFBP7, Pro-C3) that predicted the fatal trajectory in COVID-19.InterpretationPulmonary severe COVID-19 is a consequence of secondary lobular microischemia and fibrotic remodelling, resulting in a distinctive form of fibrotic interstitial lung disease that contributes to long-COVID.FundingThis project was made possible by a number of funders. The full list can be found within the Declaration of interests / Acknowledgements section at the end of the manuscript.

Inhibition of MAD2L1 Mediates Pulmonary Fibrosis through Impairment of Mitochondrial Function and Induction of Cell Senescence.

Idiopathic pulmonary fibrosis (IPF) is a chronic, irreversible, and progressive interstitial lung disease characterized by recurrent alveolar epithelial cell injury, fibroblast hyperproliferation, and cumulative deposition of extracellular matrix leading to alveolar destruction in the lungs. Mitotic arrest deficient 2 like 1 (MAD2L1) is a component of the mitotic spindle assembly checkpoint that prevents the onset of anaphase until all chromosomes are properly aligned at metaphase and is a potential therapeutic target in cancers. However, the role of MAD2L1 in pulmonary fibrosis has not been explored. We analyzed the expression of MAD2L1 in lung tissues from control subjects, IPF patients, and mice with bleomycin-induced fibrosis via IHC, qRT-PCR, and Western blot analysis. We examined the roles of MAD2L1 in ROS production, mitochondrial function, cell senescence, and the establishment of a profibrotic microenvironment. We found that MAD2L1 was highly upregulated in alveolar epithelial cells in fibrotic lung tissues from both patients with IPF and mice with bleomycin-induced fibrosis. Loss of MAD2L1 expression or activity led to decreases of cell viability and proliferation in A549 cells. Subsequent mechanistic investigation demonstrated that inhibition of MAD2L1 damaged mitochondria, which led to augmented ROS production and cellular senescence, and thus promoted the establishment of a profibrotic microenvironment. Taken together, these results reveal that alleviation of alveolar epithelial cell mitochondrial damage arising from augmentation of MAD2L1 may be a novel therapeutic strategy for mitigating pulmonary fibrosis.

DIFFERENTIAL EXPRESSION AND STABILITY OF XIAP AND CIAP-1 MAY INFLUENCE THE APOPTOSIS-RESISTANT PHENOTYPE OF LUNG FIBROBLASTS IN IDIOPATHIC PULMONARY FIBROSIS

DIFFERENTIAL EXPRESSION AND STABILITY OF XIAP AND CIAP-1 MAY INFLUENCE THE APOPTOSIS-RESISTANT PHENOTYPE OF LUNG FIBROBLASTS IN IDIOPATHIC PULMONARY FIBROSIS

A CASE SERIES OF RAPID PROGRESSIVE FIBROTIC LUNG DISEASE AS A SEQUELA OF COVID-19 PNEUMONIA

A CASE SERIES OF RAPID PROGRESSIVE FIBROTIC LUNG DISEASE AS A SEQUELA OF COVID-19 PNEUMONIA

S2743 Mesalamine-Induced Interstitial Lung Disease in a Crohn’s Patient With COVID-19

Introduction: Extraintestinal manifestations of Crohn’s disease (CD) generally correlate to the disease activity and may be seen in 1 of 4 patients with CD. Though the prevalence of bronchopulmonary manifestations in CD is 0.4%, subclinical pulmonary changes may be seen in up to half of adults with CD, with involvement of the tracheobronchial tree, lung parenchyma or the pleura. Case Description/Methods: A 61-year-old man, with a history of CD diagnosed 2 years ago, currently in remission with mesalamine, was admitted to the ICU with acute hypoxic respiratory failure due to COVID-19. Inflammatory markers were elevated and he needed high-flow nasal cannula. He was started on a 5-day course of dexamethasone. By HOD-9 O2 requirement and inflammatory markers had trended down. However, around HOD-10 his O2 requirement increased to 6-10 L at rest. CT-chest showed peripherally distributed ground-glass opacities and superimposed early diffuse fibrotic lung changes. Superadded bacterial infection was ruled out. Mesalamine was discontinued and the patient was started on a course of iv methylprednisolone, after which oxygen requirements dramatically declined. He was discharged on HOD 24 with 2L O2 at rest and 4L on ambulation and a prednisone taper. Chest x-ray in 8 weeks showed improving infiltrates. On follow-up 5 months later, he was not on O2 anymore and was doing well. Discussion: Latent interstitial pulmonary involvement is seen in around 20%-55% of patients with IBD, with the most common manifestation being drug-induced lung disease, due to sulfasalazine, mesalamine, methotrexate, or anti-TNF agents. Pulmonary function tests can help in early identification of lung injury since respiratory involvement is latent many times. Onset of drug reaction can occur from 5 days to 44 months after initiation of mesalamine therapy and has been reported in the form of eosinophilic pneumonia, organizing pneumonia, nonspecific interstitial pneumonia and hypersensitivity pneumonitis. The absence of other extra-intestinal manifestations, and the remission of CD itself, can be helpful in excluding other pulmonary manifestations of CD from drug-induced lung disease. Discontinuation of the causative drug, along with a course of steroids, can help in reversing the symptoms. Though the differential of mesalamine-induced lung injury, cannot be confirmed nor excluded here, this patient probably had underlying lung pathology from his CD or its treatment, making his recovery from COVID-19 more complicated (Figure).Figure 1.: A: Portable Chest X-ray showing multifocal pneumonia, low lung volumes with bilateral patchy airspace disease; B, C: CT-Chest showing peripherally distributed ground-glass opacities, distributed in upper and lower lobes. There were superimposed early diffuse lung fibrotic changes, without any evidence of pulmonary thromboembolism; D: CT Chest, 5 months post-discharge, showing improvement in opacities.

Matrix metalloproteinase-7 is increased in lung bases but not apices in idiopathic pulmonary fibrosis.

IntroductionIdiopathic pulmonary fibrosis (IPF) is a progressively fibrotic lung condition with poor prognosis. Matrix metalloproteinase-7 (MMP7) is a protein secreted by epithelial cells in IPF lungs. It is not known if MMP7 expression correlates with fibrotic changes in lung tissue.MethodsTissue samples from lung apices and bases were obtained from 20 IPF patients and 14 non-diseased control (NDC) donors. In formalin-fixed paraffin-embedded sections, histological assessment of fibrosis was performed; overall MMP7 positivity was assessed by immunohistochemistry and MMP7+ cells were quantified using multiplex immunohistochemistry. Protein expression of MMP7 in whole lung lysates was quantified by Western blotting. Bulk tissue transcriptomic profiles of 101 samples were analysed using RNA sequencing technologies.ResultsLung tissue from IPF bases was more fibrotic than in apices. MMP7 protein is elevated in IPF lung base tissue. In IPF whole lung lysates, MMP7 protein levels are increased compared to NDC donors and was increased in IPF lung bases compared to apices. MMP7 protein levels correlated with MMP7 gene expression levels in lung tissue. MMP7 transcript levels were increased in IPF base compared to NDC base lung tissue and increased in IPF base tissue compared to IPF apex tissue.ConclusionsOur cross-sectional study suggests that lung epithelial MMP7 expression increases as the tissue becomes more fibrotic and identifies a potentially nonepithelial or immune-cell source. Mechanisms of disease progression in IPF are still unclear, and our study suggests aberrant MMP7 production may be a histological starting point of lung tissue fibrosis.

IS POST-COVID LUNG FIBROSIS A PROGRESSIVE FIBROSING ILD?

IS POST-COVID LUNG FIBROSIS A PROGRESSIVE FIBROSING ILD?

ABDOMINAL COMPRESSION IN END-STAGE FIBROTIC INTERSTITIAL LUNG DISEASE (ILD) IMPROVES RESPIRATORY COMPLIANCE

ABDOMINAL COMPRESSION IN END-STAGE FIBROTIC INTERSTITIAL LUNG DISEASE (ILD) IMPROVES RESPIRATORY COMPLIANCE

DERIVATION AND VALIDATION OF A SIMPLE MULTIDIMENSIONAL MODEL FOR IDENTIFICATION OF COEXISTING PULMONARY HYPERTENSION IN IDIOPATHIC PULMONARY FIBROSIS

DERIVATION AND VALIDATION OF A SIMPLE MULTIDIMENSIONAL MODEL FOR IDENTIFICATION OF COEXISTING PULMONARY HYPERTENSION IN IDIOPATHIC PULMONARY FIBROSIS

Post-COVID corticosteroid use and pulmonary fibrosis: 1 year follow-up

Purpose: Depending on the prevalence and severity of COVID-19 disease, pulmonary sequelae and fibrotic lung disease continue to pose significant problems for patients in the post-COVID period. In our study, we aimed to determine the risk factors for pulmonary sequelae and fibrosis with post-COVID patient management.&#x0D; Materials and Methods: The study comprised 67 post-COVID patients who were released from the hospital after receiving low-dose corticosteroids (0.5 mg/kg daily methylprednisolone) as a result of COVID-19. Socio-demographic data, radiological and laboratory findings of the patients were recorded. All patients were followed up at 3, 6, and 12 months after discharge, and the diagnosis of pulmonary fibrosis was made according to high resolution computed tomography (HRCT) findings, by evaluating with detailed biochemical blood tests and HRCT.&#x0D; Results: Thirtyfour (50.7%) of the 67 patients were male and the mean age was 57±16.33 (min.19–max.90). At 3 months, there were 59 patients (88.1%) with aberrant thoracic computed tomography (CT) findings, 28 (41.8%) at 6 months, and 21 (31.3%) at 12 months. In the 12th month follow-up, pulmonary fibrosis was detected in a total of 9 (13.4%) patients according to thorax CT findings. &#x0D; Conclusion: In our study, the most important risk factors for the development of post-COVID pulmonary fibrosis were intensive care unit (ICU) follow-up, lymphocyte count

Chitinase 3 like 1 contributes to the development of pulmonary vascular remodeling in pulmonary hypertension.

Chitinase 3 like 1 (CHI3L1) is the prototypic chitinase-like protein mediating inflammation, cell proliferation, and tissue remodeling. Limited data suggest CHI3L1 is elevated in human pulmonary arterial hypertension (PAH) and is associated with disease severity. Despite its importance as a regulator of injury/repair responses, the relationship between CHI3L1 and pulmonary vascular remodeling is not well understood. We hypothesize that CHI3L1 and its signaling pathways contribute to the vascular remodeling responses that occur in pulmonary hypertension (PH). We examined the relationship of plasma CHI3L1 levels and severity of PH in patients with various forms of PH, including group 1 PAH and group 3 PH, and found that circulating levels of serum CHI3L1 were associated with worse hemodynamics and correlated directly with mean pulmonary artery pressure and pulmonary vascular resistance. We also used transgenic mice with constitutive knockout and inducible overexpression of CHI3L1 to examine its role in hypoxia-, monocrotaline-, and bleomycin-induced models of pulmonary vascular disease. In all 3 mouse models of pulmonary vascular disease, pulmonary hypertensive responses were mitigated in CHI3L1-null mice and accentuated in transgenic mice that overexpress CHI3L1. Finally, CHI3L1 alone was sufficient to induce pulmonary arterial smooth muscle cell proliferation, inhibit pulmonary vascular endothelial cell apoptosis, induce the loss of endothelial barrier function, and induce endothelial-mesenchymal transition. These findings demonstrate that CHI3L1 and its receptors play an integral role in pulmonary vascular disease pathobiology and may offer a target for the treatment of PAH and PH associated with fibrotic lung disease.

Development of nintedanib nanosuspension for inhaled treatment of experimental silicosis.

Silicosis is an irreversible and progressive fibrotic lung disease caused by massive inhalation of crystalline silica dust at workplaces, affecting millions of industrial workers worldwide. A tyrosine kinase inhibitor, nintedanib (NTB), has emerged as a potential silicosis treatment due to its inhibitory effects on key signaling pathways that promote silica-induced pulmonary fibrosis. However, chronic and frequent use of the oral NTB formulation clinically approved for treating other fibrotic lung diseases often results in significant side effects. To this end, we engineered a nanocrystal-based suspension formulation of NTB (NTB-NS) possessing specific physicochemical properties to enhance drug retention in the lung for localized treatment of silicosis via inhalation. Our NTB-NS formulation was prepared using a wet-milling procedure in presence of Pluronic F127 to endow the formulation with nonadhesive surface coatings to minimize interactions with therapy-inactivating delivery barriers in the lung. We found that NTB-NS, following intratracheal administration, provided robust anti-fibrotic effects and mechanical lung function recovery in a mouse model of silicosis, whereas a 100-fold greater oral NTB dose given with a triple dosing frequency failed to do so. Importantly, several key pathological phenotypes were fully normalized by NTB-NS without displaying notable local or systemic adverse effects. Overall, NTB-NS may open a new avenue for localized treatment of silicosis and potentially other fibrotic lung diseases.