N Engl J Med. 2022 Mar 17;386(11):1058-1069. doi: 10.1056/NEJMra2116777.

NO ABSTRACT

PMID:35294814 | DOI:10.1056/NEJMra2116777

Respirology. 2022 Mar 15. doi: 10.1111/resp.14245. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: The development of clinically progressive fibrosis complicates a wide array of interstitial lung diseases (ILDs). However, there are limited data regarding its prevalence and prognosis.

METHODS: We analysed consecutive patients seen for initial evaluation of a fibrosing form of ILD (FILD). Patients were evaluated for evidence of progressive fibrosis over the first 24 months of follow-up. We defined a progressive phenotype as the presence of at least one of the following: a relative decline in forced vital capacity (FVC) of ≥10%; a relative decline in FVC of ≥5%-<10% with a relative decline in diffusing capacity of the lung for carbon monoxide of ≥15%, increased fibrosis on HRCT or progressive symptoms.

RESULTS: Eight hundred and forty-four patients (397 with idiopathic pulmonary fibrosis [IPF] and 447 non-IPF FILD) made up the final analysis cohort. Three hundred and fifty-five patients (42.1%) met the progressive phenotype criteria (59.4% of IPF patients and 26.6% of non-IPF FILD patients, p <0.01). In both IPF and non-IPF FILD, transplantation-free survival differed between patients with a progressive phenotype and those without (p <0.01). Multivariable analysis showed that a progressive phenotype was an independent predictor of transplantation-free survival (hazard ratio [HR]: 3.36, 95% CI: 2.68-4.23, p <0.01). Transplantation-free survival did not differ between non-IPF FILD with a progressive phenotype and IPF (HR: 1.12, 95% CI: 0.85-1.48, p = 0.42).

CONCLUSION: Over one-fourth of non-IPF FILD patients develop a progressive phenotype compared to approximately 60% of IPF patients. The survival of non-IPF FILD patients with a progressive phenotype is similar to IPF.

PMID:35293077 | DOI:10.1111/resp.14245

J Biomech Eng. 2022 Mar 16. doi: 10.1115/1.4054106. Online ahead of print.

ABSTRACT

Pulmonary function is tightly linked to the lung mechanical behavior, especially large deformation during breathing. Interstitial lung diseases, such as Idiopathic Pulmonary Fibrosis (IPF), have an impact on the pulmonary mechanics and consequently alter lung function. However, IPF remains poorly understood, poorly diagnosed and poorly treated. Currently, the mechanical impact of such diseases is assessed by pressure-volume curves, giving only global information. We developed a poromechanical model of the lung that can be personalized to a patient based on routine clinical data. The personalization pipeline uses clinical data, mainly CT-images at two time steps and involves the formulation of an inverse problem to estimate regional compliances. The estimation problem can be formulated both in terms of "effective", i.e., without considering the mixture porosity, or "rescaled", i.e., where the first-order effect of the porosity has been taken into account, compliances. Regional compliances are estimated for one control subject and three IPF patients, allowing to quantify the IPF-induced tissue stiffening. This personalized model could be used in the clinic as an objective and quantitative tool for IPF diagnosis.

PMID:35292805 | DOI:10.1115/1.4054106

EBioMedicine. 2022 Mar 12:103912. doi: 10.1016/j.ebiom.2022.103912. Online ahead of print.

ABSTRACT

BACKGROUND: α-Klotho is a geroprotective protein that can attenuate or alleviate deleterious changes with ageing and disease. Declines in α-Klotho play a role in the pathophysiology of multiple diseases and age-related phenotypes. Pre-clinical evidence suggests that boosting α-Klotho holds therapeutic potential. However, readily clinically-translatable, practical strategies for increasing α-Klotho are not at hand. Here, we report that orally-active, clinically-translatable senolytics can increase α-Klotho in mice and humans.

METHODS: We examined α-Klotho expression in three different human primary cell types co-cultured with conditioned medium (CM) from senescent or non-senescent cells with or without neutralizing antibodies. We assessed α-Klotho expression in aged, obese, and senescent cell-transplanted mice treated with vehicle or senolytics. We assayed urinary α-Klotho in patients with idiopathic pulmonary fibrosis (IPF) who were treated with the senolytic drug combination, Dasatinib plus Quercetin (D+Q).

FINDINGS: We found exposure to the senescent cell secretome reduces α-Klotho in multiple nonsenescent human cell types. This was partially prevented by neutralizing antibodies against the senescence-associated secretory phenotype (SASP) factors, activin A and Interleukin 1α (IL-1α). Consistent with senescent cells' being a cause of decreased α-Klotho, transplanting senescent cells into younger mice reduced brain and urine α-Klotho. Selectively removing senescent cells genetically or pharmacologically increased α-Klotho in urine, kidney, and brain of mice with increased senescent cell burden, including naturally-aged, diet-induced obese (DIO), or senescent cell-transplanted mice. D+Q increased α-Klotho in urine of patients with IPF, a disease linked to cellular senescence.

INTERPRETATION: Senescent cells cause reduced α-Klotho, partially due to their production of activin A and IL-1α. Targeting senescent cells boosts α-Klotho in mice and humans. Thus, clearing senescent cells restores α-Klotho, potentially opening a novel, translationally-feasible avenue for developing orally-active small molecule, α-Klotho-enhancing clinical interventions. Furthermore, urinary α-Klotho may prove to be a useful test for following treatments in senolytic clinical trials.

FUNDING: This work was supported by National Institute of Health grants AG013925 (J.L.K.), AG062413 (J.L.K., S.K.), AG044271 (N.M.), AG013319 (N.M.), and the Translational Geroscience Network (AG061456: J.L.K., T.T., N.M., S.B.K., S.K.), Robert and Arlene Kogod (J.L.K.), the Connor Group (J.L.K.), Robert J. and Theresa W. Ryan (J.L.K.), and the Noaber Foundation (J.L.K.). The previous IPF clinical trial was supported by the Claude D. Pepper Older Americans Independence Centers at WFSM (AG021332: J.N.J., S.B.K.), UTHSCA (AG044271: A.M.N.), and the Translational Geroscience Network.

PMID:35292270 | DOI:10.1016/j.ebiom.2022.103912

Bioengineered. 2022 Mar;13(3):7746-7759. doi: 10.1080/21655979.2022.2044252.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is an idiopathic interstitial lung disease. At present, the pathogenesis of IPF has not been fully elucidated, which has affected the development of effective treatment methods. Here, we explored the function and potential mechanism of long noncoding RNA (lncRNA) CDKN2B antisense RNA 1 (CDKN2B-AS1) in IPF.Transforming growth factor-β (TGF-β) and bleomycin (BLM) were used to induce IPF in cells and animal models. Real Time quantitative Polymerase Chain Reaction (RT-qPCR) showed the expression of CDKN2B-AS1, miR-199a-5p and Sestrin-2 (SESN2) in cells and tissues. The double luciferase reporter gene assay confirmed the targeting relationship among CDKN2B-AS1, miR-199a-5p, and SESN2. Related protein levels were detected by Western blot combined with Cell Counting Kit-8 (CCK-8), wound healing, and flow cytometry to analyze cell proliferation, migration, and apoptosis. The pathological characteristics of mouse lung tissue were determined by Hematoxylin-eosin (HE) and Masson staining. We found that the expression of CDKN2B-AS1 was decreased in TGF-β-treated cells and BLM-treated mice. Overexpression of CDKN2B-AS1 inhibited cell proliferation and migration, promoted apoptosis, decreased the expression of fibrosis-related proteins and promoted autophagy. In addition, overexpression of CDKN2B-AS1 alleviated pulmonary fibrosis in BLM-treated mice. Mechanistically, CDKN2B-AS1 acts as a miR-199a-5p sponge to regulate SESN2 expression. Our results indicate the importance of the CDKN2B-AS1/miR-199a-5p/SESN2 axis.

PMID:35291918 | DOI:10.1080/21655979.2022.2044252

Mol Pharm. 2022 Mar 15. doi: 10.1021/acs.molpharmaceut.2c00052. Online ahead of print.

ABSTRACT

Pirfenidone (PFD) is the first pharmacological agent approved by the US Food and Drug Administration (FDA) in 2014 for the treatment of idiopathic pulmonary fibrosis (IPF). The recommended daily dosage of PFD in patients with IPF is very high (2403 mg/day) and must be mitigated through additives. In the present work, sustained-release (SR) formulations of the PFD-FA cocrystal of two different strengths such as 200 and 600 mg were prepared and its comparative bioavailability in healthy human volunteers was studied against the reference formulation PIRFENEX (200 mg). A single-dose pharmacokinetic study (200 mg IR vs 200 mg SR) demonstrated that the test formulation exhibited lower Cmax and Tmax in comparison to the reference formulation, which showed that the cocrystal behaved like an SR formulation. Further in the multiple-dose comparative bioavailability study (200 mg IR thrice daily vs 600 mg SR once daily), the test formulation was found bioequivalent to the reference formulation. In conclusion, the present study suggests that cocrystallization offers a promising strategy to reduce the solubility of PFD and opens the door for potential new dosage forms of this important pharmaceutical.

PMID:35290064 | DOI:10.1021/acs.molpharmaceut.2c00052

Ann Am Thorac Soc. 2022 Mar 15. doi: 10.1513/AnnalsATS.202203-196LE. Online ahead of print.

NO ABSTRACT

PMID:35289737 | DOI:10.1513/AnnalsATS.202203-196LE

Ann Am Thorac Soc. 2022 Mar 15. doi: 10.1513/AnnalsATS.202202-139LE. Online ahead of print.

NO ABSTRACT

PMID:35289726 | DOI:10.1513/AnnalsATS.202202-139LE

Mediators Inflamm. 2022 Mar 3;2022:6755407. doi: 10.1155/2022/6755407. eCollection 2022.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial pneumonia disease with no cure. Communication between injured cells is triggered and maintained by a complicated network of cytokines and their receptors. IL-19 is supported by increasing evidences for a deleterious role in respiratory diseases. However, its potential role in lung fibrosis has never been explored.

METHODS: Bioinformatic, immunohistochemistry and western blot analysis were used to assess the expression of IL-19 in human and mouse fibrosis lung tissues. CCK-8, transwell and flow cytometry assay were utilized to analyze the effect of IL-19 on biological behaviors of lung fibroblasts. Histopathology was used to elucidate profibrotic effect of IL-19 in vivo.

RESULTS: IL-19 was upregulated in fibrosis lung tissues. IL-19 promoted lung fibroblasts proliferation and invasion, inhibited cell apoptosis, and induced differentiation of fibroblasts to the myofibroblast phenotype, which could be revised by LY2109761, a TGF-β/Smad signaling pathway inhibitor. Furthermore, we found that IL-19 aggravated lung fibrosis in murine bleomycin-induced lung fibrosis.

CONCLUSIONS: Our results imply the profibrotic role for IL-19 through direct effects on lung fibroblasts and the potential of targeting IL-19 for therapeutic intervention in pulmonary fibrosis.

PMID:35281428 | PMC:PMC8913154 | DOI:10.1155/2022/6755407

J Thorac Dis. 2022 Feb;14(2):278-294. doi: 10.21037/jtd-21-1418.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis is a fibrotic disease of unknown aetiology and has a poor prognosis. Some patients experience episodes of rapid deterioration known as acute exacerbations (AEs), which are often fatal. This study aimed to clarify whether serum cytokine levels can predict the outcome of idiopathic pulmonary fibrosis.

METHODS: This retrospective study included 69 patients with idiopathic pulmonary fibrosis diagnosed according to the 2018 guideline. AE of idiopathic pulmonary fibrosis was diagnosed using the Japanese Respiratory Society criteria. Serum levels of 27 cytokines were measured using the Bio-Plex method. Cytokine production was estimated per lung volume using the serum cytokine level/percent predicted forced vital capacity (%FVC) value. The ability of the serum cytokine level and serum cytokine level/%FVC value to predict the prognosis and AE was examined in a univariate Cox proportional hazards regression model; significant factors were subjected to multivariate analysis with adjustment for significant clinical parameters, including the modified Medical Research Council score.

RESULTS: The study included 57 men and 12 women (median age, 67 years). The modified Medical Research Council score was ≤1 in 47 patients and ≥2 in 22. None of the serum cytokine levels measured could predict survival or AE; however, the serum platelet-derived growth factor/%FVC and interleukin-9/%FVC values were significant prognostic factors and the serum platelet-derived growth factor/%FVC and interleukin-13/%FVC values were significant predictors of AE. Serum platelet-derived growth factor/%FVC alone was a significant predictor of the prognosis and AE after adjustment for clinical parameters.

CONCLUSIONS: The prognosis of idiopathic pulmonary fibrosis and AEs of the disease could be predicted by the serum platelet-derived growth factor/%FVC value.

PMID:35280478 | PMC:PMC8902107 | DOI:10.21037/jtd-21-1418

Mol Ther. 2022 Mar 9:S1525-0016(22)00159-9. doi: 10.1016/j.ymthe.2022.01.045. Online ahead of print.

ABSTRACT

Increasing circular RNAs (circRNAs) are involved in the progression of idiopathic pulmonary fibrosis (IPF). However, circRNA biogenesis and circRNA-mediated crosstalk between mechanical stiffness and biochemical signals in IPF remain obscure. In this study, a novel circRNA-ANKRD42 from peripheral blood of patients with IPF, which participated in pulmonary fibrosis through the close communication of mechanical stiffness and biochemical signals, was identified. Mechanistic studies revealed that the heterogeneous nuclear ribonucleoprotein L (hnRNP L) activated the circANKRD42 reverse splicing biogenesis. The biogenetic circANKRD42 sponged miR-324-5p to promote the AJUBA expression, which blocked the binding between phosphorylated yes-associated protein 1 (YAP1) and large tumor suppressor kinase 1/2 (LATS1/2), leading to increased YAP1 entering the nucleus. circANKRD42 also sponged miR-136-5p to promote the YAP1 translation. Accumulating YAP1 in nucleus bound to TEAD, which initiated the transcription of genes related to mechanical stiffness. Finally, the therapeutic effect of circANKRD42 was evaluated in mice and the association between circANKRD42 and clinicopathological features was analyzed in IPF patients. Our findings supported that circANKRD42 is a promising biomarker and a potential therapeutic target related to cytoskeleton tension for IPF treatment.

PMID:35278674 | DOI:10.1016/j.ymthe.2022.01.045

Respir Res. 2022 Mar 11;23(1):57. doi: 10.1186/s12931-022-01978-y.

ABSTRACT

BACKGROUND: Patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD), like those with idiopathic pulmonary fibrosis (IPF), might develop an unexpected acute exacerbation (AE)-a rapidly progressing and deadly respiratory decline. Although AE incidence and risk factors in RA-ILD patients are known, their post-AE clinical course remains unknown owing to the rarity of AE-RA-ILD. This multicentre retrospective study evaluated post-AE mortality and prognostic variables in AE-RA-ILD patients and created a mortality prediction model for AE-RA-ILD.

METHODS: This research comprised 58 patients with AE-RA-ILD and 96 with AE-IPF (a control disease). Multivariate Cox regression analysis was performed to identify prognostic variables. A prediction model was created with recursive partitioning (decision tree).

RESULTS: The post-AE 90-day mortality rate in the overall AE-RA-ILD group was 48.3%; percent predicted forced vital capacity within 12 months before AE onset (baseline %FVC) and PaO2/FiO2 ratio at AE onset (P/F at AE) were independent predictors of mortality. Post-AE 90-day mortality rates were 40.6% and 43.8%, respectively, in AE-RA-ILD and AE-IPF patients propensity score-matched for age, sex, baseline %FVC and P/F at AE (P = 1.0000). In AE-RA-ILD patients, C-indices of baseline %FVC and P/F at AE to predict post-AE 90-day mortality were 0.604 and 0.623, respectively. A decision tree model based on these prognostic factors classified AE-RA-ILD patients into mild, moderate and severe groups (post-AE 90-day mortality rates: 20.8%, 64.0% and 88.9%, respectively; P = 0.0002); the C-index improved to 0.775.

CONCLUSIONS: Post-AE mortality was high in AE-RA-ILD patients similar to AE-IPF patients. The discovered prognostic factors and our mortality prediction model may aid in the management of AE-RA-ILD patients.

PMID:35277175 | DOI:10.1186/s12931-022-01978-y

Physiol Res. 2022 Apr 11. Online ahead of print.

ABSTRACT

Exercise tolerance in patients with idiopathic pulmonary fibrosis IPF is mainly limited by mechanical constrain of ventilation and high physiologic dead space. Oxygen enriched gas inhalation seems to increase ventilatory efficiency by reduction of dead space to tidal volume ratio (VD/VT) which probably mirrors improved pulmonary capillary flow and leads to longer physical tolerance at lower level of minute ventilation. The effect is noticeable at FIO2 that can be delivered in rehabilitation purposes or daily living activities.

PMID:35275694

Eur Respir J. 2022 Mar 10:2102058. doi: 10.1183/13993003.02058-2021. Online ahead of print.

ABSTRACT

OBJECTIVES: The objective of this work was to apply quantitative and semi-quantitative dynamic contrast enhanced MRI (DCE-MRI) methods to evaluate lung perfusion in idiopathic pulmonary fibrosis (IPF).

MATERIALS AND METHODS: In this prospective trial 41 subjects, including healthy control (control) and IPF subjects, were studied using DCE-MRI at baseline. IPF subjects were then followed for 1 year, progressive IPF (IPFprog) were distinguished from stable IPF (IPFstable) subjects based on a decline in percent predicted FVC (FVC%p) or DLCO (DLCO%p) measured during followup visits. 35/41 subjects were retained for final baseline analysis at (control: N=15; IPFstable: N=14; IPFprog: N=6). Seven measures and their coefficients of variation (CV) were derived using temporally resolved DCE-MRI. Two sets of global and regional comparisons were made: control versus IPF groups, and control versus IPFstable versus IPFprog groups, using linear regression analysis. Each measure was compared to FVC%p, DLCO%p, and the lung clearance index (LCI%p) using a Spearman rank correlation.

RESULTS: DCE-MRI identified regional perfusion differences between control and IPF subjects using first moment transit time (FMTT), contrast uptake slope (SLOPE), and pulmonary blood flow (PBF) (p≤0.05), while global averages did not. FMTT was shorter for IPFprog compared to both IPFstable (p=0.004) and control groups (p=0.023). Correlations were observed between PBF CV and DLCO%p (rs=-0.48, p=0.022) and %LCI (rs=+0.47, p=0.015). Significant group differences were detected in age (p<0.001), DLCO%p (p<0.001), FVC%p (p=0.001), and LCI%p (p=0.007).

CONCLUSIONS: Global analysis obscures regional changes in pulmonary hemodynamics in IPF using DCE-MRI in IPF. Decreased FMTT may be a candidate marker for IPF progression.

PMID:35273033 | DOI:10.1183/13993003.02058-2021

Eur Respir J. 2022 Mar 10:2102571. doi: 10.1183/13993003.02571-2021. Online ahead of print.

ABSTRACT

RATIONALE: Progressive fibrosing interstitial lung disease (PF-ILD) is characterised by progressive physiologic, symptomatic, and/or radiographic worsening. The real-world prevalence and characteristics of PF-ILD remain uncertain.

METHODS: Patients were enrolled from the Canadian Registry for Pulmonary Fibrosis between 2015-2020. PF-ILD was defined as a relative forced vital capacity (FVC) decline ≥10%, death, lung transplantation, or any 2 of: relative FVC decline ≥5 and <10%, worsening respiratory symptoms, or worsening fibrosis on computed tomography of the chest, all within 24 months of diagnosis. Time-to-event analysis compared progression between key diagnostic subgroups. Characteristics associated with progression were determined by multivariable regression.

RESULTS: Of 2746 patients with fibrotic ILD (mean age 65±12 years, 51% female), 1376 (50%) met PF-ILD criteria in the first 24 months of follow-up. PF-ILD occurred in 427 (59%) patients with idiopathic pulmonary fibrosis (IPF), 125 (58%) with fibrotic hypersensitivity pneumonitis (HP), 281 (51%) with unclassifiable ILD (U-ILD), and 402 (45%) with connective tissue disease-associated ILD (CTD-ILD). Compared to IPF, time to progression was similar in patients with HP (hazard ratio [HR] 0.96, 95% confidence interval, CI 0.79-1.17), but was delayed in patients with U-ILD (HR 0.82, 95% CI 0.71-0.96) and CTD-ILD (HR 0.65, 95% CI 0.56-0.74). Background treatment varied across diagnostic subtypes with 66% of IPF patients receiving antifibrotic therapy, while immunomodulatory therapy was utilised in 49%, 61%, and 37% of patients with CHP, CTD-ILD, and U-ILD respectively. Increasing age, male sex, gastroesophageal reflux disease, and lower baseline pulmonary function were independently associated with progression.

INTERPRETATION: Progression is common in patients with fibrotic ILD, and is similarly prevalent in HP and IPF. Routinely collected variables help identify patients at risk for progression and may guide therapeutic strategies.

PMID:35273032 | DOI:10.1183/13993003.02571-2021

Toxicol Appl Pharmacol. 2022 Mar 9;441:115972. doi: 10.1016/j.taap.2022.115972. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic and fatal interstitial lung disease. Currently, no treatment can block or reverse the development of lung fibrosis in patients suffering from IPF. Recent studies indicate that arsenic trioxide (ATO), a safe, effective anti-cancer pro-oxidant drug, prevents the differentiation of normal human lung fibroblasts (NHLFs) in vitro and reduces experimental pulmonary fibrosis in vivo. In this context, we investigated the anti-fibrotic effects of ATO on the main fibrosis functions of human lung fibroblasts (HLFs) isolated from patients with IPF. IPF and non-IPF (control) HLFs were incubated with 0.01-1 μM ATO and stimulated with pro-fibrotic factors (PDGF-BB or TGF-β1). We measured their rates of proliferation, migration and differentiation and the cell stress response triggered by ATO. ATO did not affect cell viability but strongly inhibited the proliferation and migration of PDGF-BB-stimulated IPF and control HLFs. ATO also prevented myofibroblastic differentiation, as assessed by the expression of α-smooth muscle actin (α-SMA) and collagen-1, and the phosphorylation of SMAD2/3 in TGF-β1-stimulated HLFs. These antifibrotic effects were associated with increased expression of the transcription factor NRF2 and its target genes NQO1 and HMOX1. Genetic silencing of NRF2 inhibited the ATO-induced cell stress response but did not prevent the ATO-dependent inhibition of α-SMA expression in TGF-β1-stimulated HLFs. The results demonstrate that ATO, at concentrations similar to exposure in blood plasma of ATO-treated cancer patients, counteracted pro-fibrotic activities of HLFs from IPF patients. We propose to consider ATO for clinical exploration to define the therapeutic potential in patients with IPF.

PMID:35276128 | DOI:10.1016/j.taap.2022.115972

Int J Environ Res Public Health. 2022 Feb 22;19(5):2510. doi: 10.3390/ijerph19052510.

ABSTRACT

The aim of the study was to evaluate the trend in the incidence of idiopathic pulmonary fibrosis (IPF) in a real-world setting of the Marche region, a region of Central Italy, between 2014 and 2019. This observational prospective study was based on administrative databases of hospital discharges and drug prescriptions. All adult residents in the Marche Region with a first prescription of antifibrotic drugs, or a first hospitalization with a diagnosis of IPF during the study period, were identified as incident cases of IPF. A multiple Poisson regression analysis was used to estimate the IPF incidence trend, adjusted for age, sex, and health conditions. The mean incidence rate was 9.8 cases per 100,000 person-years. A significant increasing trend of 6% per year was observed. The incidence rates were significantly higher in males than females, older subjects, and those with poorer health conditions. To our knowledge, this is the first study evaluating incidences of IPF over a 6-year period in Italy, combining hospital discharge and drug prescription databases. The study highlights that the combined use of two secondary sources is a reliable strategy to accurately identify new cases of IPF when the appropriate disease registry is lacking.

PMID:35270205 | DOI:10.3390/ijerph19052510

Cells. 2022 Mar 3;11(5):877. doi: 10.3390/cells11050877.

ABSTRACT

Pulmonary senescence is accelerated by unresolved DNA damage response, underpinning susceptibility to pulmonary fibrosis. Recently it was reported that the SARS-Cov-2 viral infection induces acute pulmonary epithelial senescence followed by fibrosis, although the mechanism remains unclear. Here, we examine roles of alveolar epithelial stem cell senescence and senescence-associated differentiation disorders in pulmonary fibrosis, exploring the mechanisms mediating and preventing pulmonary fibrogenic crisis. Notably, the TGF-β signalling pathway mediates alveolar epithelial stem cell senescence by mechanisms involving suppression of the telomerase reverse transcriptase gene in pulmonary fibrosis. Alternatively, telomere uncapping caused by stress-induced telomeric shelterin protein TPP1 degradation mediates DNA damage response, pulmonary senescence and fibrosis. However, targeted intervention of cellular senescence disrupts pulmonary remodelling and fibrosis by clearing senescent cells using senolytics or preventing senescence using telomere dysfunction inhibitor (TELODIN). Studies indicate that the development of senescence-associated differentiation disorders is reprogrammable and reversible by inhibiting stem cell replicative senescence in pulmonary fibrosis, providing a framework for targeted intervention of the molecular mechanisms of alveolar stem cell senescence and pulmonary fibrosis. Abbreviations: DPS, developmental programmed senescence; IPF, idiopathic pulmonary fibrosis; OIS, oncogene-induced replicative senescence; SADD, senescence-associated differentiation disorder; SALI, senescence-associated low-grade inflammation; SIPS, stress-induced premature senescence; TERC, telomerase RNA component; TERT, telomerase reverse transcriptase; TIFs, telomere dysfunction-induced foci; TIS, therapy-induced senescence; VIS, virus-induced senescence.

PMID:35269498 | DOI:10.3390/cells11050877

Molecules. 2022 Feb 22;27(5):1481. doi: 10.3390/molecules27051481.

ABSTRACT

Pulmonary fibrosis (PF) is a disease-refractive lung condition with an increased rate of mortality. The potential factors causing PF include viral infections, radiation exposure, and toxic airborne chemicals. Idiopathic PF (IPF) is related to pneumonia affecting the elderly and is characterized by recurring scar formation in the lungs. An impaired wound healing process, defined by the dysregulated aggregation of extracellular matrix components, triggers fibrotic scar formation in the lungs. The potential pathogenesis includes oxidative stress, altered cell signaling, inflammation, etc. Nintedanib and pirfenidone have been approved with a conditional endorsement for the management of IPF. In addition, natural product-based treatment strategies have shown promising results in treating PF. In this study, we reviewed the recently published literature and discussed the potential uses of natural products, classified into three types-isolated active compounds, crude extracts of plants, and traditional medicine, consisting of mixtures of different plant products-in treating PF. These natural products are promising in the treatment of PF via inhibiting inflammation, oxidative stress, and endothelial mesenchymal transition, as well as affecting TGF-β-mediated cell signaling, etc. Based on the current review, we have revealed the signaling mechanisms of PF pathogenesis and the potential opportunities offered by natural product-based medicine in treating PF.

PMID:35268581 | DOI:10.3390/molecules27051481

ERJ Open Res. 2022 Mar 7;8(1):00443-2021. doi: 10.1183/23120541.00443-2021. eCollection 2022 Jan.

ABSTRACT

BACKGROUND: Nutritional status impacts quality of life and prognosis of patients with respiratory diseases, including idiopathic pulmonary fibrosis (IPF). However, there is a lack of studies performing an extensive nutritional assessment of IPF patients. This study aimed to investigate the nutritional status and to identify nutritional phenotypes in a cohort of IPF patients at diagnosis.

METHODS: Patients underwent a thorough pulmonary and nutritional evaluation including questionnaires on nutritional status, and physical activity, anthropometry, body impedance, dynamometry, 4-m gait speed and blood tests.

RESULTS: 90 IPF patients (78.9% males, mean age 72.7 years) were enrolled. The majority of patients were classified as Gender-Age-Physiology Index stage 2 (47, 52.2%) with an inactive lifestyle according to International Physical Activity Questionnaire score (39, 43.3%), and had mean forced vital capacity and diffusing capacity for carbon monoxide 86.5% and 54.2%, respectively. In regards to nutritional phenotypes, the majority of patients were normally nourished (67.8%, 95% CI 58.6-77.7%), followed by non-sarcopenic obese (25.3%, 95% CI 16.1-35.2%), sarcopenic (4.6%, 95% CI 0.0-14.5%) and sarcopenic obese (2.3%, 95% CI 0.0-12.2%). Among the normally nourished, 49.2% showed early signs of nutritional and physical performance alterations, including body mass index ≥30 kg·m-2 in 4.3%, history of weight loss ≥5% in 11.9%, and reduction of gait speed and hand grip strength in 11.9% and 35.6%, respectively. Low vitamin D values were observed in 56.3% of cases.

CONCLUSIONS: IPF patients at diagnosis are mainly normally nourished and obese, but early signs of nutritional and physical performance impairment can already be identified at this stage.

PMID:35265706 | PMC:PMC8899499 | DOI:10.1183/23120541.00443-2021