Bioengineering (Basel). 2023 Jun 17;10(6):727. doi: 10.3390/bioengineering10060727.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) refers to chronic progressive fibrotic interstitial pneumonia. It is called a "tumor-like disease" and cannot be cured using existing clinical drugs. Therefore, new treatment options are urgently needed. Studies have proven that ferroptosis is closely related to the development of IPF, and ferroptosis inhibitors can slow down the occurrence of IPF by chelating iron or reducing lipid peroxidation. For example, the ferroptosis inhibitor deferoxamine (DFO) was used to treat a mouse model of pulmonary fibrosis, and DFO successfully reversed the IPF phenotype and increased the survival rate of mice from 50% to 90%. Given this, we perceive that the treatment of IPF by delivering ferroptosis inhibitors is a promising option. However, the delivery of ferroptosis inhibitors faces two bottlenecks: low solubility and targeting. For one thing, we consider preparing ferroptosis inhibitors into nanomedicines to improve solubility. For another thing, we propose to deliver nanomedicines through pulmonary drug-delivery system (PDDS) to improve targeting. Compared with oral or injection administration, PDDS can achieve better delivery and accumulation in the lung, while reducing the systemic exposure of the drug, and is an efficient and safe drug-delivery method. In this paper, three possible nanomedicines for PDDS and the preparation methods thereof are proposed to deliver ferroptosis inhibitors for the treatment of IPF. Proper administration devices and challenges in future applications are also discussed. In general, this perspective proposes a promising strategy for the treatment of IPF based on inhalable nanomedicines carrying ferroptosis inhibitors, which can inspire new ideas in the field of drug development and therapy of IPF.

PMID:37370658 | DOI:10.3390/bioengineering10060727

BMC Pulm Med. 2023 Jun 27;23(1):230. doi: 10.1186/s12890-023-02496-3.

ABSTRACT

BACKGROUND AND OBJECTIVE: Adherence to antifibrotic medications has been evaluated in a few studies using annual proportion of days covered (PDC), a common adherence metric. However, PDC alone cannot identify and distinguish between different patterns of adherence over time, which can be accomplished using group-based trajectory models (GBTM) of monthly PDC. The objective is to assess nintedanib adherence trajectories using GBTM and identify characteristics of patients within each trajectory group.

METHODS: Individuals with idiopathic pulmonary fibrosis (IPF) who initiated nintedanib during 10/1/2014-12/31/2018 were identified in 100% Medicare claims and enrollment data. The sample consisted of community-dwelling older adults (≥ 66 years) with continuous coverage in Medicare Parts A, B and D for one year before (baseline) and after (follow-up) initiating nintedanib. A series of GBTMs of adherence was estimated to identify the best-fitting specification. Patients were then grouped based on their estimated adherence trajectories. Associations between baseline patient characteristics, including demographics, comorbidities, and health care use, and group membership probabilities were quantified as odds ratios using fractional multinomial logit modeling.

RESULTS: Among the 1,798 patients initiating nintedanib, mean age was 75.4 years, 61.1% were male, and 91.1% were non-Hispanic white. The best-fitting GBTM had five adherence trajectory groups: high adherence (43.1%), moderate adherence (11.9%), high-then-poor adherence (10.4%), delayed-poor adherence (13.2%), and early-poor adherence (21.5%). The principal factors associated with higher odds of being in at least one of the poor-adherence groups were older age, female sex, race and ethnicity other than non-Hispanic white, and number of medications during baseline.

CONCLUSIONS: GBTM identified distinct patterns of nintedanib adherence for the IPF patient cohort. Identifying adherence trajectory groups and understanding the characteristics of their members provide more actionable information to personalize interventions than conventional metrics of medication adherence.

PMID:37370093 | DOI:10.1186/s12890-023-02496-3

Cell Biol Int. 2023 Jun 27. doi: 10.1002/cbin.12062. Online ahead of print.

ABSTRACT

Alveolar epithelial cell (AEC) senescence-induced changes of lung mesenchymal cells are key to starting the progress of pulmonary fibrosis. Follistatin-like 1 (FSTL1) plays a central regulatory role in the complex process of senescence and pulmonary fibrosis by enhancing transforming growth factor-β1 (TGF-β1) signal pathway activity. Activation of Smad4 and Ras relies on SUMO-specific peptidase 1 (SENP1)-mediated deSUMOylation during TGF-β signaling pathway activation. We hypothesized that SENP1-mediated deSUMOylation may be a potential therapeutic target by modulating FSTL1-regulated cellular senescence in pulmonary fibrosis. In verifying this hypothesis, we found that FSTL1 expression was upregulated in the lung tissues of patients with idiopathic pulmonary fibrosis and that SENP1 was overexpressed in senescent AECs. TGF-β1-induced FSTL1 not only promoted AEC senescence but also upregulated SENP1 expression. Interfering with SENP1 expression inhibited FSTL1-dependent promotion of AEC senescence and improved pulmonary fibrosis in mouse lungs. FSTL1 enhancement of TGF-β1 signaling pathway activation was dependent on SENP1 in senescent AEC. Our work identifies a novel mechanism by which FSTL1 is involved in AEC senescence. Inhibition of SENP1 in epithelial cells alleviated pulmonary fibrosis by blocking FSTL1-enhanced TGF signaling.

PMID:37369969 | DOI:10.1002/cbin.12062

J Palliat Med. 2023 Jun 27. doi: 10.1089/jpm.2022.0548. Online ahead of print.

ABSTRACT

Background: Research on health-related quality of life (HRQoL) is crucial for developing comprehensive palliative care in idiopathic pulmonary fibrosis (IPF). Objectives: To study IPF patients' HRQoL compared with general population and its association with dyspnea in a longitudinal follow-up. Design: Assessment of IPF patients' HRQoL by a generic tool. Comparison of baseline data with the general population and a 30-month follow-up with 6 months intervals. Setting/Subjects: In total, 246 IPF patients were recruited from the Finnish nationwide real-life study, FinnishIPF. Measurements: Modified Medical Research Council (MMRC) dyspnea scale for dyspnea and the generic HRQoL tool 15D for the total and dimensional HRQoL were used. Results: At baseline, the mean 15D total score was lower (0.786, standard deviation [SD] 0.116) in IPF patients than in the general population (0.871, SD 0.043) (p < 0.001) and among the IPF patients with MMRC ≥2 compared with those with MMRC <2 (p < 0.001). In patients with MMRC ≥2, significant impairment compared with general population existed in 11 dimensions of HRQoL, such as breathing, usual activities, and sexual activity, whereas this was true in only 4 dimensions in MMRC <2 category. Mental function was not impaired in either group. During the follow-up, 15D total score decreased in both MMRC categories (p < 0.001) but stayed constantly worse in the MMRC ≥2 group. Seven and two dimensions of HRQoL significantly declined in the categories of MMRC <2 and MMRC ≥2, respectively. Conclusions: Patients with IPF, especially if dyspnea limits everyday life, suffer from widely impaired HRQoL, although self-assessed mental capability is preserved. Integrated palliative care is supported to face the multiple needs of IPF patients.

PMID:37366772 | DOI:10.1089/jpm.2022.0548

Am J Physiol Lung Cell Mol Physiol. 2023 Jun 27. doi: 10.1152/ajplung.00083.2023. Online ahead of print.

ABSTRACT

BACKGROUND: Tobacco smoking is an established cause of pulmonary disease whose contribution to interstitial lung disease (ILD) is incompletely characterized. We hypothesized that compared to non-smokers, subjects who smoked tobacco would differ in their clinical phenotype and have greater mortality.

METHODS: We performed a retrospective cohort study of tobacco smoking in ILD. We evaluated demographic and clinical characteristics, time to clinically meaningful lung function decline (LFD) and mortality in patients stratified by tobacco smoking status (ever-versus-never) within a tertiary center ILD registry (2006-2021) and replicated mortality outcomes across four non-tertiary medical centers. Data was analyzed by two-sided t-tests, Poisson generalized linear models, and Cox proportional hazard models adjusted for age, sex, forced vital capacity (FVC), diffusing capacity (DLCO), ILD subtype, antifibrotic therapy, and hospital center.

RESULTS: Of 1163 study participants, 651 were tobacco smokers. Smokers were more likely to be older, male, have idiopathic pulmonary fibrosis (PF), coronary artery disease, CT honeycombing and emphysema, higher FVC, and lower DLCO than non-smokers(P<0.01). Time to LFD in smokers was shorter(19.7±20 months vs. 24.8±29 months;P=0.038] and survival time was decreased [10.75(10.08-11.50) years vs. 20(18.67-21.25) years; adjusted mortality HR=1.50, 95%CI 1.17-1.92;P<0.0001] compared to non-smokers. Smokers had 12% greater odds of death for every additional ten-pack-years of smoking(P<0.0001). Mortality outcomes remained consistent in the non-tertiary cohort (HR=1.51, 95%CI=1.03-2.23;P=0.036).

CONCLUSIONS: Tobacco smokers with ILD have a distinct clinical phenotype strongly associated with the syndrome of combined PF and emphysema, shorter time to LFD, and decreased survival. Smoking prevention may improve ILD outcomes.

PMID:37366539 | DOI:10.1152/ajplung.00083.2023

Pulm Pharmacol Ther. 2023 Jun 24:102230. doi: 10.1016/j.pupt.2023.102230. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) represents a chronic and progressive tissue repair response that leads to irreversible scarring and lung remodelling. The decoction of bitter almond usually contains amygdalin epimers in traditional clinical application for lung disease. To reveal the differences of cytotoxicity and antifibrotic effect between amygdalin epimers, and potential mechanism is also explored. The cytotoxicity of amygdalin epimers were evaluated with MRC-5 cells in vitro. Their antifibrotic activities were evaluated in bleomycin-induced C57BL/6 mice and TGF-β1-induced MRC-5 cells. Here we demonstrated that L-amygdalin is more toxic of the amygdalin epimers in MRC-5 cells, and D-amygdalin is more effective in anti-pulmonary fibrosis among the amygdalin epimers in bleomycin-induced C57BL/6 mice. Herein, it was observed that D-amygdalin had a stronger inhibitory effect on inflammation than L-amygdalin, and had similar results in inhibiting the mRNA and protein expression levels of fibrosis-related biomarkers. The mechanism of anti-pulmonary fibrosis showed that amygdalin epimers suppressing expression of phosphorylation of Smads2/3, which implying deactivation of the TGF-β1induced Smads2/3 signal pathway. This study evaluates the amygdalin epimers cytotoxicity and antifibrotic effect, and its mechanisms were related to the TGF-β1/Smads2/3 signal pathway. It provides a reference for clinical safety and effectiveness of amygdalin epimers.

PMID:37364767 | DOI:10.1016/j.pupt.2023.102230

Cureus. 2023 May 22;15(5):e39354. doi: 10.7759/cureus.39354. eCollection 2023 May.

ABSTRACT

Hypereosinophilic syndrome is a heterogeneous group of disorders, the majority of which are idiopathic. Cardiac manifestations, particularly eosinophilic myocarditis and endomyocardial fibrosis, are a typical course of morbidity and mortality in hypereosinophilic syndrome. We present a case of a patient with asthma and idiopathic eosinophilia who presented with dyspnea and edema. Cardiac ultrasonography showed pericardial effusion and reduced left ventricular motion, which persisted despite heart failure therapy, although pulmonary congestion improved. The peripheral blood eosinophil count was markedly elevated four days after admission, even though eosinophilia was not present at admission. Parasitic disease, autoimmune disease, and drug-induced cardiomyopathy were excluded as possibilities. A high dose of steroid therapy was started due to eosinophilic myocarditis. Cardiac function improved soon after therapy, along with a reduction in eosinophils. Upon retrospective examination, cardiomegaly and low voltage were observed, along with an elevation in the eosinophil count 15 months before admission. Monitoring chest radiography and electrocardiograms according to fluctuations in eosinophils may enable early detection and treatment of cardiac involvement in patients with hypereosinophilic syndrome, as demonstrated by this case.

PMID:37362537 | PMC:PMC10284668 | DOI:10.7759/cureus.39354

Front Med (Lausanne). 2023 Jun 8;10:1187760. doi: 10.3389/fmed.2023.1187760. eCollection 2023.

ABSTRACT

BACKGROUND: Sarcopenia often occurs as a comorbidity in many diseases which ultimately affects patient prognosis. However, it has received little attention in patients with idiopathic pulmonary fibrosis (IPF). This systematic review and meta-analysis aimed at determining the prevalence and risk factors of sarcopenia in patients with IPF.

METHODS: Embase, MEDLINE, Web of Science, and Cochrane databases were searched using relevant MeSH terms until December 31, 2022. The Newcastle-Ottawa Scale (NOS) was used for quality assessment and data analysis were performed using Stata MP 17.0 (Texas, USA). A random effects model was adopted to account for differences between articles, and the I2 statistic was used to describe statistical heterogeneities. Overall pooled estimates obtained from a random effects model were estimated using the metan command. Forest plots were generated to graphically represent the data of the meta-analysis. Meta-regression analysis was used for count or continuous variables. Egger test was used to evaluate publication bias and, if publication bias was observed, the trim and fill method was used.

MAIN RESULTS: The search results showed 154 studies, and five studies (three cross-section and two cohort studies) with 477 participants were finally included. No significant heterogeneity was observed among studies included in the meta-analysis (I2 = 16.00%) and our study's publication bias is low (Egger test, p = 0.266). The prevalence of sarcopenia in patients with IPF was 26% (95% CI, 0.22-0.31). The risk factors for sarcopenia in patients with IPF were age (p = 0.0131), BMI (p = 0.001), FVC% (p < 0.001), FEV1% (p = 0.006), DLco% (p ≤ 0.001), and GAP score (p = 0.003).

CONCLUSIONS: The pooled prevalence of sarcopenia in patients with IPF was 26%. The risk factors for sarcopenia in IPF patients were age, BMI, FVC%, FEV1%, DLco%, and GAP score. It is important to identify these risk factors as early as possible to improve the life quality of patients with IPF.

PMID:37359000 | PMC:PMC10285151 | DOI:10.3389/fmed.2023.1187760

Mol Pharm. 2023 Jun 26. doi: 10.1021/acs.molpharmaceut.3c00111. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) causes worsening pulmonary function, and no effective treatment for the disease etiology is available now. Recombinant Human Relaxin-2 (RLX), a peptide agent with anti-remodeling and anti-fibrotic effects, is a promising biotherapeutic candidate for musculoskeletal fibrosis. However, due to its short circulating half-life, optimal efficacy requires continuous infusion or repeated injections. Here, we developed the porous microspheres loading RLX (RLX@PMs) and evaluated their therapeutic potential on IPF by aerosol inhalation. RLX@PMs have a large geometric diameter as RLX reservoirs for a long-term drug release, but smaller aerodynamic diameter due to their porous structures, which were beneficial for higher deposition in the deeper lungs. The results showed a prolonged release over 24 days, and the released drug maintained its peptide structure and activity. RLX@PMs protected mice from excessive collagen deposition, architectural distortion, and decreased compliance after a single inhalation administration in the bleomycin-induced pulmonary fibrosis model. Moreover, RLX@PMs showed better safety than frequent gavage administration of pirfenidone. We also found RLX-ameliorated human myofibroblast-induced collagen gel contraction and suppressed macrophage polarization to the M2 type, which may be the reason for reversing fibrosis. Hence, RLX@PMs represent a novel strategy for the treatment of IPF and suggest clinical translational potential.

PMID:37358639 | DOI:10.1021/acs.molpharmaceut.3c00111

Chem Pharm Bull (Tokyo). 2023 Jun 23. doi: 10.1248/cpb.c23-00216. Online ahead of print.

ABSTRACT

Pirfenidone (PRF) is an anti-fibrotic agent that has been approved by the Food and Drug Administration (FDA) for the treatment of mild to moderate idiopathic pulmonary fibrosis. However, the current oral administration dosing regimen of PRF is complex and requires high doses. Patients are instructed to take PRF three times daily, with each dose consisting of up to three capsules or tablets (600 mg/day or 1.8 g/day of PRF) taken with food. To improve the dosing regimen, efforts are being made to develop an extended-release tablet with a zero-order release pattern. In this study, two types of extended-release matrix tablets were compared: non-channeled extended-release matrix tablets (NChMT) and channeled extended-release matrix tablets (ChMT). In vitro release tests, swelling and erosion index, rheology studies, and X-ray microcomputed tomography (XRCT), were conducted. The results indicated that ChMT maintained a zero-order release pattern with a constant release rate, while NChMT exhibited a decreased release rate in the latter half of the dissolution. ChMT exhibited accelerated swelling and erosion compared to other formulations, and this was made possible by the presence of channels within the tablet. These channels allowed for thorough wetting and swelling throughout the entire depth of the tablet. The formation of channels was confirmed through XRCT images. In conclusion, the presence of channels in ChMT tablets increased the rate of swelling and erosion, resulting in a zero-order release pattern. This development offers the potential to improve the dosage of PRF and reduce its associated side effects.

PMID:37357388 | DOI:10.1248/cpb.c23-00216

Acta Biomater. 2023 Jun 23:S1742-7061(23)00349-5. doi: 10.1016/j.actbio.2023.06.024. Online ahead of print.

ABSTRACT

The progressive formation of fibroblastic foci characterizes idiopathic pulmonary fibrosis (IPF), and excessive oral doses of approved pirfenidone (PFD) always cause gastrointestinal side effects. The fibrotic response driven by activated fibroblasts could perpetuate epithelial damage and promote abnormal extracellular matrix (ECM) deposition. When modified nanoparticles reach their target, it is important to ensure a responsive release of PFD. Hypoxia is a determining factor in IPF, leading to alveolar dysfunction and deeper cellular fibrosis. Herein, a fibroblastic foci-targeting and hypoxia-cleavable drug delivery system (Fn-Azo-BSA@PEG) was established to reprogram the fibrosis in IPF. We have modified the FnBAP5 peptide to enable comprehensive fibroblastic foci targeting, which helps BSA nanoparticles recognize and accumulate at fibrotic sites. Meantime, the hypoxia-responsive azobenzene group allowed for efficient and rapid drug diffusion, while the PEGylated BSA reduced system toxicity and increased circulation in vivo. As expected, the strategy of the fibronectin-targeting-modification and hypoxia-responsive drug release synergistically inhibited activated fibroblasts and reduced the secretion of the fibrosis-related protein. Fn-Azo-BSA@PEG could accumulate in pulmonary tissue and prolong the survival time in bleomycin-induced pulmonary fibrosis mice. Together, the multivalent BSA nanoparticles offered an efficient approach for improving lung architecture and function by regulating the fibroblastic foci and hypoxia. STATEMENT OF SIGNIFICANCE: We established fibroblastic foci-targeting and hypoxia-cleavable bovine serum albumin (BSA) nanoparticles (Fn-Azo-BSA@PEG) to reprogramme the fibroblastic foci in idiopathic pulmonary fibrosis (IPF). Fn-Azo-BSA@PEG was designed to actively target fibroblasts and abnormal ECM with the FnBPA5 peptide, delivering more FDA-approved pirfenidone (PFD) to the cross-talk within the foci. Once the drug reached fibroblastic foci, the azobenzene group acted as a hypoxia-responsive linker to trigger effective and rapid drug release. Hypoxic responsiveness and FnBAP5-modification of Fn-Azo-BSA@PEG synergistically inhibited the secretion of proteins closely related to fibrogenesis. BSA's inherent transport and metabolic pathways in the pulmonary reduced the side effects of the main organs. The multivalent BSA nanoparticles efficiently inhibited IPF-fibrosis progress and preserved the lung architecture by regulating the fibroblastic foci and hypoxia.

PMID:37356783 | DOI:10.1016/j.actbio.2023.06.024

Eur J Pharm Sci. 2023 Jun 23:106509. doi: 10.1016/j.ejps.2023.106509. Online ahead of print.

ABSTRACT

Pirfenidone (PFND) is a recommended oral drug used to treat idiopathic pulmonary fibrosis, but have low bioavailability and high hepatotoxicity. The study, therefore, seeks to improve the therapeutic activities of the drug via increased bioavailability and reduced associated side effects by developing a novel drug delivery system. The electrostatic spray technology was used to prepare a sustained release pirfenidone-loaded microsphere dry powder inhalation with PEG-modified chitosan (PFND-mPEG-CS-MS). The entrapment efficiency, drug loading, and in vitro cumulative drug release rate (at 24 h and with a sustained release effect) of PFND-mPEG-CS-MS were 77.35±3.01 %, 11.45±0.64 %, and 90.4%, respectively. The Carr's index of PFND-mPEG-CS-MS powder was 17.074±2.163 % with a theoretical mass median aerodynamic diameter (MMADt) of 0.99±0.07 μm, and a moisture absorption weight gain rate (Rw) of 4.61±0.72 %. The emptying rate, pulmonary deposition rate (fine particle fraction) and actual mass median aerodynamic diameter (MMADa) were 90%∼95%, 48.72±7.04 % and 3.10±0.16 μm, respectively. MTT bioassay showed that mPEG-CS-MS (200 μg/mL) had good biocompatibility (RGR = 90.25%) and PFND-mPEG-CS-MS (200 μg/mL) had significant inhibitory activity (RGR = 49.82%) on fibroblast growth. The pharmacokinetic data revealed that the t1/2 (5.02 h) and MRT (10.66 h) of PFND-mPEG-CS-MS were prolonged compared with the free PFND (t1/2, 1.67 h; MRT, 2.71 h). The pharmacodynamic results also showed that the formulated-drug group had slight pathological changes, lower lung hydroxyproline content, and reduced hepatotoxicity compared with the free-drug group. The PFND-mPEG-CS-MS further significantly down-regulated TGF-β cytokines, Collagen I, and α-SMA protein expression levels compared with the free drug. The findings indicated that the PFND-mPEG-CS-MS had a good sustained release effect, enhanced bioavailability, decreased toxicity, and increased anti-fibrotic activities.

PMID:37356463 | DOI:10.1016/j.ejps.2023.106509

Respir Investig. 2023 Jun 23;61(5):553-562. doi: 10.1016/j.resinv.2023.05.005. Online ahead of print.

ABSTRACT

Fibrosis of the lung can occur in idiopathic pulmonary fibrosis, collagen vascular diseases, and hypersensitivity pneumonitis, among other diseases. Transforming growth factor (TGF)-β, vascular epithelial growth factor, fibroblast growth factor, and platelet-derived growth factor contribute to the pathophysiology of fibrosis. TGF-β and other cytokines, including interleukin (IL)-1β, IL-6, and IL-23, activate type-17 immunity, which is involved in pulmonary fibrosis. The components of type-17 immunity include type-17 helper T cells, γδT cells, IL-17A-producing CD8-positive T cells, invariant NKT cells, and group 3 innate lymphoid cells. IL-17A, the main cytokine of type-17 immunity, is able to induce the epithelial-mesenchymal transition in epithelial cells via a production of TGF-β, directly stimulate fibroblasts and fibrocytes, and inhibit autophagy, which otherwise protects against pulmonary fibrosis. IL-23 induces type-17 immunity and plays an important role in the acute exacerbation of pulmonary fibrosis. Clinical studies have also linked type-17 immunity to the pathogenesis of pulmonary fibrosis. Consequently, targeting type-17 immunity may serve as a new therapeutic strategy to prevent the development or exacerbation of pulmonary fibrosis.

PMID:37356133 | DOI:10.1016/j.resinv.2023.05.005

BMC Pulm Med. 2023 Jun 22;23(1):224. doi: 10.1186/s12890-023-02523-3.

ABSTRACT

BACKGROUND: The distinction between hypersensitivity pneumonitis (HP) and idiopathic pulmonary fibrosis (IPF) was thought to be important due to the difference in mortality between the conditions as well as the response to treatment. However, recent work suggests that the clinical diagnosis may matter less than certain radiographic features, namely usual interstitial pneumonia (UIP) pattern. The purpose of this study is to evaluate whether radiographic honeycombing is more predictive of transplant-free survival (TFS) than other clinical, radiographic, or histologic findings that distinguish HP from IPF in the current guidelines and to evaluate the impact of radiographic honeycombing on the efficacy of immunosuppression in fibrotic HP.

METHODS: We retrospectively identified IPF and fibrotic HP patients evaluated between 2003 and 2019. Univariable and multivariable logistic regression was performed for patients with fibrotic HP and IPF to evaluate TFS. To assess the impact of treatment with immunosuppression on TFS in fibrotic HP, a cox proportional hazard model adjusted for known predictors of survival in HP including age, gender, and baseline pulmonary function testing results was constructed, and p-interaction for the presence of honeycombing on high resolution computed tomography and use of immunosuppression was calculated.

RESULTS: Our cohort included 178 with IPF and 198 with fibrotic HP. In a multivariable analysis, the presence of honeycombing had a greater impact on the TFS than the diagnosis of HP vs. IPF. Among the criteria used in the HP diagnostic guidelines, only typical HP scan impacted survival in a multivariable model, while identification of antigen and surgical lung biopsy findings had no impact on survival. We identified a trend toward worse survival on immunosuppression in those with HP with radiographic honeycombing.

CONCLUSION: Our data suggests that honeycombing and baseline pulmonary function testing have a greater impact on TFS than the clinical diagnosis of IPF vs. fibrotic HP and that radiographic honeycombing is a predictor of poor TFS in fibrotic HP. We suggest that invasive diagnostic testing including surgical lung biopsy may not be useful in predicting mortality in HP patients with honeycombing and may potentially increase risk of immunosuppression.

PMID:37349780 | DOI:10.1186/s12890-023-02523-3

Clin Biochem. 2023 Jun 19:110599. doi: 10.1016/j.clinbiochem.2023.110599. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is characterized by excessive extracellular matrix (ECM) remodeling, herein ECM degradation. Fibronectin (FN) is an important component of the ECM that is produced by multiple cell types, including fibroblasts. Extra domain B (EDB) is specific for a cellular FN isoform which is found in the ECM. We sought to develop a non-invasive test to investigate whether matrix metalloproteinase 8 (MMP-8) degradation of EDB in cellular FN results in a specific protein fragment that can be assessed serologically and if levels relate to pulmonary fibrosis.

METHOD: Cellular FN was cleaved in vitro by MMP-8 and a protein fragment was identified by mass spectrometry. A monoclonal antibody (mAb) was generated, targeting a neo-epitope originating from EDB in cellular FN. Utilizing this mAb, a neo-epitope specific enzyme-linked immunosorbent assay (FN-EDB) was developed and technically validated. Serum FN-EDB was assessed in an IPF cohort (n=98), registered at clinicaltrials.gov (NCT02818712), and in healthy controls (n=35).

RESULTS: The FN-EDB assay had high specificity for the MMP-8 degraded neo-epitope and was technically robust. FN-EDB serum levels were not influenced by age, sex, ethnicity, or BMI. Moreover, FN-EDB serum levels were significantly higher in IPF patients (median 31.38 [IQR 25.79-46.84] ng/mL) as compared to healthy controls (median 28.05 [IQR 21.58-33.88] ng/mL, p=0.023).

CONCLUSION: We developed the neo-epitope specific FN-EDB assay, a competitive ELISA, as a tool for serological assessment of MMP-8 mediated degradation of EDB in cellular FN. This study indicates that degradation of EDB in cellular FN is elevated in IPF and warrants further investigation.

PMID:37343745 | DOI:10.1016/j.clinbiochem.2023.110599

Respir Res. 2023 May 31;24(1):141. doi: 10.1186/s12931-023-02435-0.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is characterized by the accumulation of extracellular matrix in the pulmonary interstitium and progressive functional decline. We hypothesized that integration of multi-omics data would identify clinically meaningful molecular endotypes of IPF.

METHODS: The IPF-PRO Registry is a prospective registry of patients with IPF. Proteomic and transcriptomic (including total RNA [toRNA] and microRNA [miRNA]) analyses were performed using blood collected at enrollment. Molecular data were integrated using Similarity Network Fusion, followed by unsupervised spectral clustering to identify molecular subtypes. Cox proportional hazards models tested the relationship between these subtypes and progression-free and transplant-free survival. The molecular subtypes were compared to risk groups based on a previously described 52-gene (toRNA expression) signature. Biological characteristics of the molecular subtypes were evaluated via linear regression differential expression and canonical pathways (Ingenuity Pathway Analysis [IPA]) over-representation analyses.

RESULTS: Among 232 subjects, two molecular subtypes were identified. Subtype 1 (n = 105, 45.3%) and Subtype 2 (n = 127, 54.7%) had similar distributions of age (70.1 +/- 8.1 vs. 69.3 +/- 7.6 years; p = 0.31) and sex (79.1% vs. 70.1% males, p = 0.16). Subtype 1 had more severe disease based on composite physiologic index (CPI) (55.8 vs. 51.2; p = 0.002). After adjusting for CPI and antifibrotic treatment at enrollment, subtype 1 experienced shorter progression-free survival (HR 1.79, 95% CI 1.28,2.56; p = 0.0008) and similar transplant-free survival (HR 1.30, 95% CI 0.87,1.96; p = 0.20) as subtype 2. There was little agreement in the distribution of subjects to the molecular subtypes and the risk groups based on 52-gene signature (kappa = 0.04, 95% CI= -0.08, 0.17), and the 52-gene signature risk groups were associated with differences in transplant-free but not progression-free survival. Based on heatmaps and differential expression analyses, proteins and miRNAs (but not toRNA) contributed to classification of subjects to the molecular subtypes. The IPA showed enrichment in pulmonary fibrosis-relevant pathways, including mTOR, VEGF, PDGF, and B-cell receptor signaling.

CONCLUSIONS: Integration of transcriptomic and proteomic data from blood enabled identification of clinically meaningful molecular endotypes of IPF. If validated, these endotypes could facilitate identification of individuals likely to experience disease progression and enrichment of clinical trials.

TRIAL REGISTRATION: NCT01915511.

PMID:37344825 | DOI:10.1186/s12931-023-02435-0

Sci China Life Sci. 2023 Jun 16. doi: 10.1007/s11427-022-2314-8. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease with limited therapeutic options. Macrophages, particularly alternatively activated macrophages (M2), have been recognized to contribute to the pathogenesis of pulmonary fibrosis. Therefore, targeting macrophages might be a viable therapeutic strategy for IPF. Herein, we report a potential nanomedicine-based gene therapy for IPF by modulating macrophage M2 activation. In this study, we illustrated that the levels of pleckstrin homology and FYVE domain containing 1 (Plekhf1) were increased in the lungs originating from IPF patients and PF mice. Further functionality studies identified the pivotal role of Plekhf1 in macrophage M2 activation. Mechanistically, Plekhf1 was upregulated by IL-4/IL-13 stimulation, after which Plekhf1 enhanced PI3K/Akt signaling to promote the macrophage M2 program and exacerbate pulmonary fibrosis. Therefore, intratracheal administration of Plekhf1 siRNA-loaded liposomes could effectively suppress the expression of Plekhf1 in the lungs and notably protect mice against BLM-induced lung injury and fibrosis, concomitant with a significant reduction in M2 macrophage accumulation in the lungs. In conclusion, Plekhf1 may play a crucial role in the pathogenesis of pulmonary fibrosis, and Plekhf1 siRNA-loaded liposomes might be a promising therapeutic approach against pulmonary fibrosis.

PMID:37340175 | DOI:10.1007/s11427-022-2314-8

J Inflamm Res. 2023 Jun 14;16:2503-2519. doi: 10.2147/JIR.S414734. eCollection 2023.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a disease with unclear etiology and a poor prognosis. Although the involvement of neutrophils in IPF pathogenesis has been suggested, the exact nature of this relationship remains unclear.

METHODS: We analyzed data from the Gene Expression Omnibus (GEO) using immune infiltration analysis, weighted gene co-expression network analysis (WGCNA), and consensus cluster analysis. Neutrophil-related genes and hub genes related to neutrophils were identified and differentially expressed between IPF patients and healthy controls. We also validated the expression differences of hub genes in a bleomycin-induced mice model.

RESULTS: Immune infiltration analysis revealed a significantly decreased percentage of neutrophils in the lung tissue of IPF patients compared with healthy controls (P<0.001) in both the train and validation sets. Neutrophil-related genes in IPF were identified by WGCNA, and functional enrichment analysis showed that these genes were mainly involved in the cytokine-cytokine receptor interaction pathway and correlated with lung disease, consistent with DEGs between IPF and healthy controls. Eight hub genes related to neutrophils were identified, including MMP16, ARG1, IL1R2, PROK2, MS4A2, PIR, and ZNF436. Consensus cluster analysis revealed a low neutrophil-infiltrating cluster that was correlated with IPF (P<0.001), and a principal component analysis-generated score could distinguish IPF patients from healthy controls, with an area under the curve of 0.930 in the train set and 0.768 in the validation set. We also constructed a diagnostic model using hub genes related to neutrophils, which showed a reliable diagnostic value with an area under the curve of 0.955 in the train set and 0.995 in the validation set.

CONCLUSION: Our findings provide evidence of a low neutrophil-infiltrating characteristic in the IPF microenvironment and identify hub genes related to neutrophils that may serve as diagnostic biomarkers for the disease.

PMID:37337515 | PMC:PMC10277023 | DOI:10.2147/JIR.S414734

Aging (Albany NY). 2023 Jun 16;15. doi: 10.18632/aging.204805. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a fibrosing interstitial pneumonia of unknown cause. The most typical characteristic of IPF is gradual weakening of pulmonary elasticity and increase in hardness/rigidity with aging. This study aims to identify a novel treatment approach for IPF and explore mechanism of mechanical stiffness underlying human umbilical cord mesenchymal stem cells (hucMSCs) therapy. Target ability of hucMSCs was examined by labeling with cell membrane dye Dil. Anti-pulmonary fibrosis effect of hucMSCs therapy by reducing mechanical stiffness was evaluated by lung function analysis and MicroCT imaging system and atomic force microscope in vivo and in vitro. Results showed that stiff environment of fibrogenesis caused cells to establish a mechanical connection between cytoplasm and nucleus, initiating expression of related mechanical genes such as Myo1c and F-actin. HucMSCs treatment blocked force transmission and reduced mechanical force. For further exploration of mechanism, ATGGAG was mutated to CTTGCG (the binding site of miR-136-5p) in the full-length sequence of circANKRD42. Wildtype and mutant plasmids of circANKRD42 were packaged into adenovirus vectors and sprayed into lungs of mice. Mechanistic dissection revealed that hucMSCs treatment repressed circANKRD42 reverse splicing biogenesis by inhibiting hnRNP L, which in turn promoted miR-136-5p binds to 3'-Untranslated Region (3'-UTR) of YAP1 mRNA directly, thus inhibiting translation of YAP1 and reducing YAP1 protein entering nucleus. The condition repressed expression of related mechanical genes to block force transmission and reduce mechanical forces. The mechanosensing mechanism mediated directly by circANKRD42-YAP1 axis in hucMSCs treatment, which has potential general applicability in IPF treatment.

PMID:37335082 | DOI:10.18632/aging.204805

Front Immunol. 2023 Jun 2;14:1207641. doi: 10.3389/fimmu.2023.1207641. eCollection 2023.

ABSTRACT

Chronic inflammatory diseases of the lung are some of the leading causes of mortality and significant morbidity worldwide. Despite the tremendous burden these conditions put on global healthcare, treatment options for most of these diseases remain scarce. Inhaled corticosteroids and beta-adrenergic agonists, while effective for symptom control and widely available, are linked to severe and progressive side effects, affecting long-term patient compliance. Biologic drugs, in particular peptide inhibitors and monoclonal antibodies show promise as therapeutics for chronic pulmonary diseases. Peptide inhibitor-based treatments have already been proposed for a range of diseases, including infectious disease, cancers and even Alzheimer disease, while monoclonal antibodies have already been implemented as therapeutics for a range of conditions. Several biologic agents are currently being developed for the treatment of asthma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis and pulmonary sarcoidosis. This article is a review of the biologics already employed in the treatment of chronic inflammatory pulmonary diseases and recent progress in the development of the most promising of those treatments, with particular focus on randomised clinical trial outcomes.

PMID:37334374 | PMC:PMC10272527 | DOI:10.3389/fimmu.2023.1207641