Am J Respir Cell Mol Biol. 2023 Jul 4. doi: 10.1165/rcmb.2023-0080OC. Online ahead of print.

ABSTRACT

Idiopathic Pulmonary fibrosis (IPF) is a progressive fatal interstitial lung disease without effective cure. Herein, we explore the role of 3,5,3'-triiodothyronine (T3) administration on lung alveolar regeneration and fibrosis at the single-cell level. T3 supplementation significantly altered the gene expression in fibrotic lung tissues. Immune cells were rapidly recruited into the lung after the injury, M2 macrophages were much than M1 macrophages in bleomycin-treated lungs, and M1 macrophages increased slightly, while M2 macrophages significantly reduced after T3 treatment. T3 enhanced the resolution of pulmonary fibrosis by promoting the differentiation of Krt8+ transitional alveolar type II epithelial cells (AT2) into alveolar type I epithelial cells (AT1) and inhibiting fibroblast activation and extracellular matrix (ECM) production potentially by regulation of Nr2f2. In addition, T3 regulated the crosstalk of macrophages with fibroblasts and the Pros1-Axl signaling axis significantly facilitated the attenuation of fibrosis. The findings demonstrate that administration of a thyroid hormone promotes alveolar regeneration and resolves fibrosis mainly by regulation of the cellular state and cell-cell communication of alveolar epithelial cells, macrophages, and fibroblasts in mouse lungs in comprehensive ways.

PMID:37402274 | DOI:10.1165/rcmb.2023-0080OC

Eur Rev Med Pharmacol Sci. 2023 Jun;27(12):5468-5479. doi: 10.26355/eurrev_202306_32783.

ABSTRACT

OBJECTIVE: Interstitial lung diseases (ILDs) are a group of diffuse parenchymal lung disorders that can be idiopathic [idiopathic pulmonary fibrosis (IPF)] or associated with other diseases and are characterized by varying degrees of inflammation and fibrosis with poor prognosis. Several indicators are essential in diagnosing these individuals and differentiating between IPF and ILD.

PATIENTS AND METHODS: The study involved 44 IPF patients, 22 ILD (non-IPF) patients, and 24 healthy people. We aimed to compare ILD (non-IPF) and IPF patient groups with each other and with healthy people in terms of interleukin (IL)-1, tumor necrosis factor-alpha (TNF-α), matrix metalloproteinase (MMP)-1, MMP-7, galectin (Gal)-3, IL-6, Krebs von den Lungen-6 (KL-6), total antioxidant status (TAS), total oxidant status (TOS), pyruvate kinase (PK), complete blood count (CBC), ferritin, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) features. Furthermore, it was intended to assess the patient groups in terms of visual semi-quantitative score (VSQS) (IPF alone), respiratory function tests (RFT), and 6-minute walk test (6MWT), also potential correlations between these tests and the previously indicated parameters.

RESULTS: MMP-1, MMP-7, Gal-3, IL-6, KL-6, forced vital capacity (FVC), % FVC, forced expiratory volume in 1 second (FEV1), % FEV1, TAS, TOS, and PK values significantly elevated in IPF and ILD. Weight, IL-1, MMP-1, MMP-7, Gal-3, IL-6, KL-6, % FVC, FEV1, % FEV1, eosinophil count, and % red blood cell distribution width (RDW) values differed between IPF and ILD. VSQS, 6MWT, and PK were substantially linked with MMP-1, MMP-7, Gal-3, IL-6, and KL-6 in IPF.

CONCLUSIONS: The factors investigated can be helpful in the diagnosis and distinction of IPF and ILD. In addition to focusing on the inflammatory environment in IPF and ILD patients, oxidant and antioxidant interactions must be studied.

PMID:37401283 | DOI:10.26355/eurrev_202306_32783

BMC Pulm Med. 2023 Jul 3;23(1):242. doi: 10.1186/s12890-023-02536-y.

ABSTRACT

BACKGROUND: Nintedanib is now widely used to treat interstitial lung disease (ILD). Adverse events, which occur in not a few patients, make it difficult to continue nintedanib treatment, but the risk factors for adverse events are not well understood.

METHODS: In this retrospective cohort study, we enrolled 111 patients with ILDs treated with nintedanib and investigated the factors involved in starting dosage reduction, withdrawal, or discontinuation within 12 months, even with appropriate symptomatic treatment. We also examined the efficacy of nintedanib in reducing the frequency of acute exacerbations and the prevention of pulmonary function reduction.

RESULTS: Patients with high monocyte counts (> 0.454 × 109/L) had a significantly higher frequency of treatment failure, such as dosage reduction, withdrawal, or discontinuation. High monocyte count was as significant a risk factor as body surface area (BSA). Regarding efficacy, there was no difference in the frequency of acute exacerbations or the amount of decline in pulmonary function within 12 months between the normal (300 mg) and reduced (200 mg) starting dosage groups.

CONCLUSION: Our study results indicate that patients with higher monocyte counts (> 0.454 × 109/L) should very careful about side effects with regard to nintedanib administration. Like BSA, a higher monocyte count is considered a risk factor for nintedanib treatment failure. There was no difference in FVC decline and frequency of acute exacerbations between the starting doseage of nintedanib, 300 mg and 200 mg. Considering the risk of withdrawal periods and discontinuation, a reduced starting dosage may be acceptable in the patients with higher monocyte counts or small body sizes.

PMID:37400801 | PMC:PMC10318667 | DOI:10.1186/s12890-023-02536-y

World J Cardiol. 2023 Jun 26;15(6):293-308. doi: 10.4330/wjc.v15.i6.293.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with a high mortality rate. On this basis, exploring potential therapeutic targets to meet the unmet needs of IPF patients is important.

AIM: To explore novel hub genes for IPF therapy.

METHODS: Here, we used public datasets to identify differentially expressed genes between IPF patients and healthy donors. Potential targets were considered based on multiple bioinformatics analyses, especially the correlation between hub genes and carbon monoxide diffusing capacity of carbon monoxide, forced vital capacity, and patient survival rate. The mRNA levels of the hub genes were determined through quantitative real-time polymerase chain reaction.

RESULTS: We found that TDO2 was upregulated in IPF patients and predicted poor prognosis. Surprisingly, single-cell RNA sequencing data analysis revealed significant enrichment of TDO2 in alveolar fibroblasts, indicating that TDO2 may participate in the regulation of proliferation and survival. Therefore, we verified the upregulated expression of TDO2 in an experimental mouse model of transforming growth factor-β (TGF-β)-induced pulmonary fibrosis. Furthermore, the results showed that a TDO2 inhibitor effectively suppressed TGF-β-induced fibroblast activation. These findings suggest that TDO2 may be a potential target for IPF treatment. Based on transcription factors-microRNA prediction and scRNA-seq analysis, elevated TDO2 promoted the IPF proliferation of fibroblasts and may be involved in the P53 pathway and aggravate ageing and persistent pulmonary fibrosis.

CONCLUSION: We provided new target genes prediction and proposed blocking TGF-β production as a potential treatment for IPF.

PMID:37397828 | PMC:PMC10308271 | DOI:10.4330/wjc.v15.i6.293

Nucl Med Commun. 2023 Jul 3. doi: 10.1097/MNM.0000000000001724. Online ahead of print.

ABSTRACT

OBJECTIVE: Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by the accumulation of extracellular matrix. Because there is no effective treatment for advanced IPF to date, its early diagnosis can be critical. Vimentin is a cytoplasmic intermediate filament that is significantly up-regulated at the surface of fibrotic foci with a crucial role in fibrotic morphological changes.

METHODS: In the present study, VNTANST sequence as a known vimentin-targeting peptide was conjugated to hydrazinonicotinic acid (HYNIC) and labeled with 99mTc. The stability test in saline and human plasma and log P determination were performed. Next, the biodistribution study and single photon emission computed tomography (SPECT) integrated with computed tomography (CT) scanning were performed in healthy and bleomycin-induced fibrosis mice models.

RESULTS: The 99mTc-HYNIC-(tricine/EDDA)-VNTANST showed a hydrophilic nature (log P = -2.20 ± 0.38) and high radiochemical purity > 97% and specific activity (336 Ci/mmol). The radiopeptide was approximately 93% and 86% intact in saline and human plasma within 6 h, respectively. The radiopeptide was substantially accumulated in the pulmonary fibrotic lesions (test vs. control = 4.08 ± 0.08% injected dose per gram (ID/g) vs. 0.36 ± 0.01% ID/g at 90 min postinjection). SPECT-CT images in fibrosis-bearing mice also indicated the fibrotic foci and kidneys.

CONCLUSION: Because there is no available drug for the treatment of advanced pulmonary fibrosis, early diagnosis is the only chance. The 99mTc-HYNIC-(tricine/EDDA)-VNTANST could be a potential tracer for SPECT imaging of pulmonary fibrosis.

PMID:37395537 | DOI:10.1097/MNM.0000000000001724

Curr Opin Pulm Med. 2023 Jun 29. doi: 10.1097/MCP.0000000000000977. Online ahead of print.

ABSTRACT

PURPOSE OF REVIEW: Idiopathic pulmonary fibrosis (IPF) is the nonmalignant, chronic lung disease with the worst prognosis. Prevalent comorbidities including lung cancer exert a negative impact on patients' survival. However, there is considerable lack of knowledge on the diagnostic and therapeutic management of patients diagnosed with both clinical entities. This review article presents the main challenges in the management of patients with IPF and lung cancer and highlights future perspectives.

RECENT FINDINGS: Recent registries for patients with IPF demonstrated that approximately 10% of patients developed lung cancer. Importantly, incidence of lung cancer was increasing remarkably over time in patients with IPF. Patients with IPF and otherwise technically operable lung cancer who underwent surgical resection had improved survival compared with those who did not undergo surgery. However, specific precautions perioperatively are crucial. Finally, the first randomized-controlled, phase 3 trial (J-SONIC trial) showed no significant difference in exacerbation-free survival for chemotherapy-naive patients with IPF and advanced nonsmall cell lung cancer that were allocated to receive carboplatin and nab-paclitaxel every 3 weeks with or without nintedanib.

SUMMARY: Lung cancer is prevalent in IPF. Management of patients with IPF and lung cancer is challenging. A consensus statement aiming to attenuate confusion is greatly anticipated.

PMID:37395506 | DOI:10.1097/MCP.0000000000000977

Respir Physiol Neurobiol. 2023 Jun 30:104109. doi: 10.1016/j.resp.2023.104109. Online ahead of print.

ABSTRACT

Interstitial lung diseases (ILD) are a heterogenic group of respiratory diseases with complex pathogenesis. A growing number of evidence suggests role of adipose tissue and it's hormones (adipokines) in pathogenesis of various disorders, including lung tissue diseases. The aim of this study was to assess the concentrations of selected adipokines and their receptors (apelin, adiponectin, chemerin, chemerin receptor - CMKLR1) in patients with IPF (idiopathic pulmonary fibrosis) and sarcoidosis in comparison to healthy controls. We found changes in adipokines concentrations in ILD. Adiponectin concentrations were higher in all respiratory diseases patients in comparison to healthy controls. Apelin concentration in ILD patients was higher then those in healthy subjects. The trend of chemerin and CMKLR1 concentrations were similar, with highest concentrations seen in sarcoidosis. The study shows a difference of adipokines concentrations between patients with ILD and healthy controls. Adipokines are a potential marker and therapeutic target in patients with IPF and sarcoidosis.

PMID:37393966 | DOI:10.1016/j.resp.2023.104109

BMC Pulm Med. 2023 Jul 1;23(1):236. doi: 10.1186/s12890-023-02534-0.

ABSTRACT

BACKGROUND: Several markers have been identified to increase the risk for acute exacerbation of interstitial lung disease (AE-ILD) or mortality related to AE-ILD. However, less is known about the risk predictors of ILD patients who have survived AE. The aim of the study was to characterise AE-ILD survivors and investigate prognostic factors in this subpopulation.

METHODS: All AE-ILD patients (n = 95) who had been discharged alive from two hospitals located in Northern Finland were selected from a population of 128 AE-ILD patients. Clinical data related to the hospital treatment and six-month follow-up visit were collected retrospectively from medical records.

RESULTS: Fifty-three patients with idiopathic pulmonary fibrosis (IPF) and 42 patients with other ILD were identified. Two thirds of the patients had been treated without invasive or non-invasive ventilation support. The clinical features of six-month survivors (n = 65) and non-survivors (n = 30) did not differ in terms of medical treatment or oxygen requirements. Of the patients, 82.5% used corticosteroids at the six-month follow-up visit. Fifty-two patients experienced at least one non-elective respiratory re-hospitalisation before the six-month follow-up visit. In a univariate model, IPF diagnosis, high age and a non-elective respiratory re-hospitalisation increased the risk of death, although re-hospitalisation was the only independent risk factor in a multivariate model. In six-month survivors, there was no statistically significant decrease in pulmonary function test results (PFT) examined at the follow-up visit compared with earlier PFT examined near the time of AE-ILD.

CONCLUSIONS: The AE-ILD survivors were a heterogeneous group of patients both clinically and in terms of their outcome. A non-elective respiratory re-hospitalisation was identified as a marker of poor prognosis among AE-ILD survivors.

PMID:37393286 | DOI:10.1186/s12890-023-02534-0

Clin Rheumatol. 2023 Jul 1. doi: 10.1007/s10067-023-06689-3. Online ahead of print.

ABSTRACT

Various connective tissue diseases tend to affect specific organs, lungs being the organ with the most serious repercussions and consequences. The diagnosis of interstitial lung disease makes the treatment more difficult and worsens long-term prognosis and overall survival. Positive results from the registration studies of nintedanib led to approval of the drug for the treatment of idiopathic pulmonary fibrosis and chronic fibrosing interstitial lung diseases in connective tissue diseases. After registration, real-world data on the use of nintedanib are being collected in everyday clinical practise. The objective of the study was to collect and analyse real world experience gathered after the registration of nintedanib for the treatment of CTD-ILD and to show if the positive results collected from a homogeneous and "representative" study population can be applied to everyday clinical practice. We are presenting a retrospective observational case-series study of patients treated with nintedanib from the three largest Croatian centers specialised in the treatment of connective tissue diseases with interstitial lung diseases. Stabilisation or improved of lung function tests was reported in 68% of patients when changes in predicted FVC were observed and in 72% of patients when changes in DLco were analysed. Almost all of the reported patients (98%) were treated with nintedanib as an add-on drug to immunosuppressants. The most common side-effects were gastrointestinal symptoms and abnormal liver function tests in less extent. Our real-world data confirm the tolerability, efficacy and similar side-effects of nintedanib as reported in pivotal trials. Key Points • Interstitial lung disease is a common manifestation of several connective tissue diseases and its progressive fibrosing phenotype contributes to high mortality rate and many unmet needs regarding the treatment remain. • Registration studies of nintedanib obtained sufficient data and positive results to support approval of the drug. • Real-world evidence from our CTD-ILD centres confirm the clinical trial data regarding efficacy, tolerability and safety of nintedanib.

PMID:37393200 | DOI:10.1007/s10067-023-06689-3

Aging (Albany NY). 2023 Jul 1;15. doi: 10.18632/aging.204825. Online ahead of print.

ABSTRACT

Cell senescence has recently emerged as a potentially relevant pathogenic mechanism in fibrosing interstitial lung diseases (f-ILDs), particularly in idiopathic pulmonary fibrosis. We hypothesized that senescent human fibroblasts may suffice to trigger a progressive fibrogenic reaction in the lung. To address this, senescent human lung fibroblasts, or their secretome (SASP), were instilled into the lungs of immunodeficient mice. We found that: (1) human senescent fibroblasts engraft in the lungs of immunodeficient mice and trigger progressive lung fibrosis associated to increasing levels of mouse senescent cells, whereas non-senescent fibroblasts do not trigger fibrosis; (2) the SASP of human senescent fibroblasts is pro-senescence and pro-fibrotic both in vitro when added to mouse recipient cells and in vivo when delivered into the lungs of mice, whereas the conditioned medium (CM) from non-senescent fibroblasts lacks these activities; and, (3) navitoclax, nintedanib and pirfenidone ameliorate lung fibrosis induced by senescent human fibroblasts in mice, albeit only navitoclax displayed senolytic activity. We conclude that human senescent fibroblasts, through their bioactive secretome, trigger a progressive fibrogenic reaction in the lungs of immunodeficient mice that includes the induction of paracrine senescence in the cells of the host, supporting the concept that senescent cells actively contribute to disease progression in patients with f-ILDs.

PMID:37393107 | DOI:10.18632/aging.204825

Am J Transplant. 2023 Jun 29:S1600-6135(23)00545-2. doi: 10.1016/j.ajt.2023.06.014. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis lung transplant recipients (IPF-LTRs) are enriched for short telomere length (TL) and telomere gene rare variants. A subset of non-transplant short-TL patients are at increased risk for bone marrow (BM) dysfunction. We hypothesized that IPF-LTRs with short-TL and/or rare variants would be at increased risk for post-transplant hematologic complications. Data were extracted from a retrospective cohort of 72 IPF-LTRs and 72 age-matched non-IPF-LTR controls. Genetic assessment was done using whole genome sequencing or targeted sequence panel. TL was measured using flow cytometry and fluorescence in-situ hybridization (FlowFISH) and TelSeq software. The majority of the IPF-LTR cohort had short-TL and 26% IPF-LTRs had rare variants. Compared to non-IPF controls, short-TL IPF-LTRs were more likely to have immunosuppression agents discontinued due to cytopenias (p=0.0375), and BM dysfunction requiring BM biopsy was more prevalent (29% vs 4%, p=0.0003). IPF-LTRs with short-TL and rare variants had increased requirements for transfusion and growth factor support. Multivariable logistic regression demonstrated short-TL, rare variants and lower pre-transplant platelet counts were associated with BM dysfunction. Pre-transplant TL measurement and genetic testing for telomere gene rare variants identified IPF-LTRs at increased risk for hematologic complications. Our findings, support stratification for telomere-mediated pulmonary fibrosis in lung transplant candidates.

PMID:37392813 | DOI:10.1016/j.ajt.2023.06.014

Biomed Pharmacother. 2023 Jun 29;165:115080. doi: 10.1016/j.biopha.2023.115080. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a type of interstitial pneumonia characterized by chronic and progressive fibrosis with an unknown etiology. Previous pharmacological studies have shown that Sanghuangporus sanghuang possesses various beneficial properties including immunomodulatory, hepatoprotective, antitumor, antidiabetic, anti-inflammatory, and neuroprotective effects. This study used a bleomycin (BLM)-induced IPF mouse model to illustrate the possible benefits of SS in ameliorating IPF. BLM was administered on day 1 to establish a pulmonary fibrosis mouse model, and SS was administered through oral gavage for 21 d. Hematoxylin and eosin (H&E) and Masson's trichrome staining results showed that SS significantly reduced tissue damage and decreased fibrosis expression. We observed that SS treatment resulted in a substantial lowering in the level of pro-inflammatory cytokines like TGF-β, TNF-α, IL-1β, and IL-6 as well as MPO. In addition, we observed a notable increase in glutathione (GSH) levels. Western blot analysis of SS showed that it reduces inflammatory factors (TWEAK, iNOS, and COX-2), MAPK (JNK, p-ERK, and p-38), fibrosis-related molecules (TGF-β, SMAD3, fibronectin, collagen, α-SMA, MMP2, and MMP9), apoptosis (p53, p21, and Bax), and autophagy (Beclin-1, LC3A/B-I/II, and p62), and notably increases caspase 3, Bcl-2, and antioxidant (Catalase, GPx3, and SOD-1) levels. SS alleviates IPF by regulating the TLR4/NF-κB/MAPK, Keap1/Nrf2/HO-1, CaMKK/AMPK/Sirt1, and TGF-β/SMAD3 pathways. These results suggest that SS has a pharmacological activity that protects the lungs and has the potential to improve pulmonary fibrosis.

PMID:37392658 | DOI:10.1016/j.biopha.2023.115080

Ther Adv Respir Dis. 2023 Jan-Dec;17:17534666231181537. doi: 10.1177/17534666231181537.

ABSTRACT

Drug development for idiopathic pulmonary fibrosis (IPF) has been challenging due to poorly understood disease etiology, unpredictable disease progression, highly heterogeneous patient populations, and a lack of robust pharmacodynamic biomarkers. Moreover, because lung biopsy is invasive and dangerous, making the extent of fibrosis as a direct longitudinal measurement of IPF disease progression unfeasible, most clinical trials studying IPF can only assess progression of fibrosis indirectly through surrogate measures. This review discusses current state-of-art practices, identifies knowledge gaps, and brainstorms development opportunities for preclinical to clinical translation, clinical populations, pharmacodynamic endpoints, and dose optimization strategies. This article highlights clinical pharmacology perspectives in leveraging real-world data as well as modeling and simulation, special population considerations, and patient-centric approaches for designing future studies.

PMID:37392011 | DOI:10.1177/17534666231181537

BMC Pulm Med. 2023 Jun 30;23(1):234. doi: 10.1186/s12890-023-02527-z.

ABSTRACT

BACKGROUND: Following COVID-19 infection, some patients acquired lung injury and fibrosis. Idiopathic pulmonary fibrosis is characterized by lung fibrosis. Both post-COVID lung injury and idiopathic pulmonary fibrosis cause loss of respiratory function and involvement of the lung parenchyma. We aimed to compare respiratory related functional characteristics and radiological involvement between post-COVID lung injury and idiopathic pulmonary fibrosis.

METHODS: A single center, cross-sectional study was applied. Patients with post-COVID lung injury and idiopathic pulmonary fibrosis included in the study. All patients underwent the 6-minute walk test, as well as the Borg and MRC scales. Radiological images were evaluated and scored for lung parenchymal involvement. The impact of post-COVID lung injury and idiopathic pulmonary fibrosis on respiratory functions of were compared. The relationship of functional status and radiological involvement, as well as the effect of potential confounding factors were investigated.

RESULTS: A total of 71 patients were included in the study. Forty-eight (67.6%) of the patients were male and the mean age was 65.4 ± 10.3 years. Patients with post-COVID lung injury had greater 6-minute walk test distance and duration, as well as higher oxygen saturations. The MRC and Borg dyspnea scores were comparable. At radiologic evaluation, ground glass opacity scores were higher in patients with post-COVID lung injury, whereas pulmonary fibrosis scores were higher in patients with idiopathic pulmonary fibrosis. However, the total severity scores were similar. While pulmonary fibrosis score was found to have a negative correlation with 6-minute walk test distance, test duration, and pre- and post-test oxygen saturation levels, there was a positive correlation with oxygen saturation recovery time and MRC score. There was no relationship between ground glass opacity and the functional parameters.

CONCLUSIONS: Despite having equal degrees of radiological involvement and dyspnea symptom severity, PCLI patients exhibited higher levels of functional status. This might be due to different pathophysiological mechanisms and radiological involvement patterns of both diseases.

PMID:37391786 | DOI:10.1186/s12890-023-02527-z

Adv Ther. 2023 Jun 30. doi: 10.1007/s12325-023-02565-3. Online ahead of print.

ABSTRACT

INTRODUCTION: In the European Union (EU), the indication for the antifibrotic pirfenidone prior to April 2023 did not include patients with advanced idiopathic pulmonary fibrosis (IPF). This analysis compared the efficacy and safety of pirfenidone in advanced IPF versus non-advanced IPF.

METHODS: Data were included from the following studies of pirfenidone: ASCEND (NCT01366209); CAPACITY (004 [NCT00287716] and 006 [NCT00287729]); RECAP (NCT00662038; advanced IPF defined as percent predicted forced vital capacity [%FVC] < 50% and/or percent predicted carbon monoxide diffusing capacity [%DLco] < 35% at baseline); PASSPORT (NCT02699879; advanced IPF defined as baseline %FVC < 50%); and SP-IPF (NCT02951429; patients with advanced IPF [defined as %DLco ≤ 40% at screening] at risk of group 3 pulmonary hypertension).

RESULTS: In the pooled ASCEND/CAPACITY studies, the annual mean rate of FVC decline from baseline to Week 52 was significantly lower for pirfenidone versus placebo in advanced (p = 0.0035) and non-advanced IPF (p = 0.0001). Rate of all-cause mortality over 52 weeks was numerically lower for pirfenidone versus placebo in advanced and non-advanced IPF. In RECAP, the mean annual rate of FVC decline from baseline to Week 180 of pirfenidone treatment was similar in patients with advanced (- 141.5 mL) and non-advanced IPF (- 153.5 mL). In SP-IPF, the mean annual rate of FVC decline and rate of all-cause mortality from baseline to Week 52 in patients treated with placebo + pirfenidone were - 93.0 mL and 20.2%, respectively. No new safety signals were identified, and the safety profile of pirfenidone in patients with advanced IPF was generally consistent with that of non-advanced IPF.

CONCLUSIONS: These results highlight the benefit of pirfenidone treatment in patients with advanced and non-advanced IPF. As such, the indication for pirfenidone in the EU has now been updated to include the treatment of adult patients with advanced IPF.

TRIAL REGISTRATIONS: ASCEND (NCT01366209), CAPACITY 004 (NCT00287716), CAPACITY 006 (NCT00287729), RECAP (NCT00662038), PASSPORT (NCT02699879), and SP-IPF (NCT02951429).

PMID:37391667 | DOI:10.1007/s12325-023-02565-3

Cell Death Dis. 2023 Jun 30;14(6):389. doi: 10.1038/s41419-023-05889-8.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a devastating fibrotic lung disease characterized by scarring and destruction of the lung architecture, with limited treatment options. Targeted gene therapy to restore cell division autoantigen-1 (CDA1) expression may be a potential treatment approach to delay the progression of pulmonary fibrosis (PF). Here, we focused on CDA1, which was significantly decreased in human IPF, in a mouse model of bleomycin (BLM)-induced PF, and in transforming growth factor (TGF-β)-challenged lung fibroblasts. In vitro, CDA1 overexpression by lentivirus infection in human embryonic lung fibroblasts (HFL1 cells) inhibited the production of pro-fibrotic and pro-inflammatory cytokines, lung fibroblast-to-myofibroblast transition, and extracellular matrix protein expression induced by exogenous TGF-β1 treatment, whereas CDA1 knockdown with small interfering RNA promoted this effect. CDA1 overexpression also inhibited cell proliferation and migration. In a mouse model of BLM-induced PF, we provided novel evidence that the intratracheal delivery of adeno-associated virus serotype 9 carrying the mouse Tspyl2 gene reduced lung tissue inflammation and fibrosis. Mechanistically, CDA1, as a transcription regulator, could repress the TGF-β signal transduction in vivo and in vitro. In conclusion, our results show that Tspyl2 gene therapy plays an antifibrotic role by inhibiting the lung fibroblast-to-myofibroblast transition and downstream TGF-β/Smad3 signaling transduction in BLM-induced PF in mice, suggesting that CDA1 is an appropriate and promising therapeutic target for PF.

PMID:37391440 | DOI:10.1038/s41419-023-05889-8

Chem Biomed Eng. 2023 May 22;1(3):268-285. doi: 10.1021/cbmi.3c00023. eCollection 2023 Jun 26.

ABSTRACT

Chronic lung diseases, such as idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD), are major leading causes of death worldwide and are generally associated with poor prognoses. The heterogeneous distribution of collagen, mainly type I collagen associated with excessive collagen deposition, plays a pivotal role in the progressive remodeling of the lung parenchyma to chronic exertional dyspnea for both IPF and COPD. To address the pressing need for noninvasive early diagnosis and drug treatment monitoring of pulmonary fibrosis, we report the development of human collagen-targeted protein MRI contrast agent (hProCA32.collagen) to specifically bind to collagen I overexpressed in multiple lung diseases. When compared to clinically approved Gd3+ contrast agents, hProCA32.collagen exhibits significantly better r1 and r2 relaxivity values, strong metal binding affinity and selectivity, and transmetalation resistance. Here, we report the robust detection of early and late-stage lung fibrosis with stage-dependent MRI signal-to-noise ratio (SNR) increase, with good sensitivity and specificity, using a progressive bleomycin-induced IPF mouse model. Spatial heterogeneous mapping of usual interstitial pneumonia (UIP) patterns with key features closely mimicking human IPF, including cystic clustering, honeycombing, and traction bronchiectasis, were noninvasively detected by multiple MR imaging techniques and verified by histological correlation. We further report the detection of fibrosis in the lung airway of an electronic cigarette-induced COPD mouse model, using hProCA32.collagen-enabled precision MRI (pMRI), and validated by histological analysis. The developed hProCA32.collagen is expected to have strong translational potential for the noninvasive detection and staging of lung diseases, and facilitating effective treatment to halt further chronic lung disease progression.

PMID:37388961 | PMC:PMC10302889 | DOI:10.1021/cbmi.3c00023

Chin Med J Pulm Crit Care Med. 2023 Jun;1(2):77-83. doi: 10.1016/j.pccm.2022.12.002. Epub 2023 Jan 23.

ABSTRACT

The pandemic of coronavirus disease 2019 (COVID‑19), caused by a novel severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2), has caused an enormous impact on the global healthcare. SARS-CoV-2 infection primarily targets the respiratory system. Although most individuals testing positive for SARS-CoV-2 present mild or no upper respiratory tract symptoms, patients with severe COVID-19 can rapidly progress to acute respiratory distress syndrome (ARDS). ARDS-related pulmonary fibrosis is a recognized sequelae of COVID-19. Whether post-COVID-19 lung fibrosis is resolvable, persistent, or even becomes progressive as seen in human idiopathic pulmonary fibrosis (IPF) is currently not known and remains a matter of debate. With the emergence of effective vaccines and treatments against COVID-19, it is now important to build our understanding of the long-term sequela of SARS-CoV-2 infection, to identify COVID-19 survivors who are at risk of developing chronic pulmonary fibrosis, and to develop effective anti-fibrotic therapies. The current review aims to summarize the pathogenesis of COVID-19 in the respiratory system and highlights ARDS-related lung fibrosis in severe COVID-19 and the potential mechanisms. It envisions the long-term fibrotic lung complication in COVID-19 survivors, in particular in the aged population. The early identification of patients at risk of developing chronic lung fibrosis and the development of anti-fibrotic therapies are discussed.

PMID:37388822 | PMC:PMC9988550 | DOI:10.1016/j.pccm.2022.12.002

Pol Arch Intern Med. 2023 Jun 30:16520. doi: 10.20452/pamw.16520. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive and life-threatening interstitial lung disease of familial or sporadic onset. The incidence and prevalence of IPF is in the range of 0.09-1.30 and 0.33-4.51 per 10,000 persons, respectively. IPF has a poor prognosis, and death usually occurring within 2-5 years following the diagnosis due to secondary respiratory failure. Currently, there are two drugs available to treat IPF, prirfenidone and nintedanib, both only slow the disease progression and, in addition, have unfavorable safety profiles. IPF bears the histology of usual interstitial pneumonia, which is characterized by bronchiolization of distal airspaces, honeycombing, fibroblastic foci, and abnormal epithelial hyperplasia. In the last years, alterations in metabolic pathways, in particular, those associated with fatty acid (FA) metabolism have been link to the pathogenesis of lung fibrosis. Changes in FA profiles have been reported in lung tissue, plasma, and bronchoalveolar lavage fluid of IPF patients and have been found to correlate with the disease progression and outcome. In addition, they have been associated with the development of a pro-fibrotic phenotype of epithelial cells, macrophages, and fibroblasts/myofibroblasts contributing to their (trans)differentiation and production of disease relevant mediators. Furthermore, strategies focusing on the correction of FA profiles in experimental models of lung fibrosis brought advances in understanding tissue scarring processes and contributed to the transition of new molecules into clinical development. This review highlights the role of FA and their metabolites in IPF and provides evidence for therapeutic potential of lipidome manipulations in the treatment of this disease.

PMID:37387676 | DOI:10.20452/pamw.16520

Clin Exp Rheumatol. 2023 Aug;41(8):1670-1678. doi: 10.55563/clinexprheumatol/icr6hy. Epub 2023 Jun 29.

ABSTRACT

OBJECTIVES: Studies identifying nonspecific interstitial pneumonia (NSIP) as the predominant histopathology in systemic sclerosis-associated interstitial lung disease (SSc-ILD) have primarily utilised surgical lung biopsies in early disease. These case series may only reflect the histopathology of early disease and differ from the histopathology of advanced disease in those with respiratory failure.

METHODS: Patients receiving a lung transplant for a diagnosis of SSc at a single centre from 2000-2021 were included for retrospective analysis. All explanted lungs underwent histopathology review as part of routine care.

RESULTS: 127 patients with SSc received a native lung transplant during the study period. Usual interstitial pneumonia (UIP) was identified in 111 explants (87.4%), NSIP in 45 (35.4%) explants, organising pneumonia in 11 explants (8.7%), and lymphocytic bronchitis in 2 explants (1.6%). Areas of both UIP and NSIP were identified in 37 explants (29.1%), with only 9 explants (7.1%) showing neither UIP nor NSIP. Aspiration was identified on histology in 49 (38.6%) explants. Pathology results were available from a prior surgical lung biopsy for 19 patients, with 11 patients maintaining the same primary pathology on biopsy and explant (2 NSIP, 9 UIP) and 8 patients showing different pathology at the timepoints, all of whom had UIP on explant. Most patients (101, 79.5%) had evidence of pulmonary hypertension and vasculopathy on explant.

CONCLUSIONS: UIP is the predominant histopathology in patients with SSc receiving a lung transplant, with many patients concurrently having both NSIP and UIP or showing progression from NSIP to UIP over time before transplant.

PMID:37382449 | DOI:10.55563/clinexprheumatol/icr6hy