Int J Nurs Sci. 2021 Mar 4;8(2):175-180. doi: 10.1016/j.ijnss.2021.02.004. eCollection 2021 Apr 10.

ABSTRACT

OBJECTIVE: This study aimed to explore the lived experiences of the disease journey and patients' care needs with idiopathic pulmonary fibrosis (IPF).

METHODS: Face-to-face semi-structured interviews were conducted with a purposive sampling of IPF patients admitted to the department of respiratory medicine in a tertiary hospital in Beijing. Interview data were analyzed using the thematic analysis method. In the end, 16 patients were interviewed.

RESULTS: Four themes emerged from the qualitative data included the long and confusing journey to reach a diagnosis, living with the disease, understanding the disease and treatment and desire for continuity of care. A series of subthemes were also identified, including uncertainty of diagnosis, delaying the process, living with physical symptoms, living with emotional distress, loss of independence, uncertainty with the prognosis, questioning the cause of the disease, concerning the side effects of treatments, lacking continuity of care, and wanting a better quality of healthcare in community hospitals.

CONCLUSIONS: Based on the findings, there is an urgent need to improve the care delivery to this vulnerable population in China. To meet their health needs, it is of paramount importance to develop effective education programs for health professionals and IPF patients and improve care models of healthcare systems, especially in remote areas, to enhance care continuity in the communities.

PMID:33997131 | PMC:PMC8105533 | DOI:10.1016/j.ijnss.2021.02.004

Front Nutr. 2021 Apr 29;8:548076. doi: 10.3389/fnut.2021.548076. eCollection 2021.

ABSTRACT

Ninjin'yoeito, a Kampo prescription, was administered to two patients with idiopathic pulmonary fibrosis (IPF) over a period of 12 weeks to improve loss of appetite and lassitude. In Case 1, improvements were observed in appetite, lassitude, and breathlessness, as well as increases or increasing tendencies in body weight, blood albumin level, and hemoglobin (Hb) level. Case 2 showed no changes in appetite but improvements in lassitude and no deterioration of breathlessness. His body weight and his blood albumin and Hb levels increased or showed increasing trends. In both cases, a trend for improvement of respiratory function was observed. In summary, ninjin'yoeito trended to improve the subjective symptoms and nutritional status of a patient with pulmonary fibrosis.

PMID:33996870 | PMC:PMC8116530 | DOI:10.3389/fnut.2021.548076

Front Immunol. 2021 Apr 30;12:664109. doi: 10.3389/fimmu.2021.664109. eCollection 2021.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is the most devastating progressive interstitial lung disease that remains refractory to treatment. Pathogenesis of IPF relies on the aberrant cross-talk between injured alveolar cells and myofibroblasts, which ultimately leads to an aberrant fibrous reaction. The contribution of the immune system to IPF remains not fully explored. Recent evidence suggests that both innate and adaptive immune responses may participate in the fibrotic process. Dendritic cells (DCs) are the most potent professional antigen-presenting cells that bridge innate and adaptive immunity. Also, they exert a crucial role in the immune surveillance of the lung, where they are strategically placed in the airway epithelium and interstitium. Immature DCs accumulate in the IPF lung close to areas of epithelial hyperplasia and fibrosis. Conversely, mature DCs are concentrated in well-organized lymphoid follicles along with T and B cells and bronchoalveolar lavage of IPF patients. We have recently shown that all sub-types of peripheral blood DCs (including conventional and plasmacytoid DCs) are severely depleted in therapy naïve IPF patients. Also, the low frequency of conventional CD1c+ DCs is predictive of a worse prognosis. The purpose of this mini-review is to focus on the main evidence on DC involvement in IPF pathogenesis. Unanswered questions and opportunities for future research ranging from a better understanding of their contribution to diagnosis and prognosis to personalized DC-based therapies will be explored.

PMID:33995394 | PMC:PMC8121252 | DOI:10.3389/fimmu.2021.664109

Front Immunol. 2021 Apr 22;12:663203. doi: 10.3389/fimmu.2021.663203. eCollection 2021.

ABSTRACT

The immune system is receiving increasing attention for interstitial lung diseases, as knowledge on its role in fibrosis development and response to therapies is expanding. Uncontrolled immune responses and unbalanced injury-inflammation-repair processes drive the initiation and progression of idiopathic pulmonary fibrosis. The regulatory immune system plays important roles in controlling pathogenic immune responses, regulating inflammation and modulating the transition of inflammation to fibrosis. This review aims to summarize and critically discuss the current knowledge on the potential role of regulatory immune cells, including mesenchymal stromal/stem cells, regulatory T cells, regulatory B cells, macrophages, dendritic cells and myeloid-derived suppressor cells in idiopathic pulmonary fibrosis. Furthermore, we review the emerging role of regulatory immune cells in anti-fibrotic therapy and lung transplantation. A comprehensive understanding of immune regulation could pave the way towards new therapeutic or preventive approaches in idiopathic pulmonary fibrosis.

PMID:33995390 | PMC:PMC8120991 | DOI:10.3389/fimmu.2021.663203

Front Pharmacol. 2021 Apr 29;12:669227. doi: 10.3389/fphar.2021.669227. eCollection 2021.

ABSTRACT

Idiopathic pulmonary fibrosis is a chronic and progressive fibrotic lung disease, and current treatments are limited by their side effects. Proliferation of human lung fibroblasts in the pulmonary interstitial tissue is a hallmark of this disease and is driven by prolonged ERK signalling in the nucleus in response to growth factors such as platelet-derived growth factor (PDGF). Agents that increase cAMP have been suggested as alternative therapies, as this second messenger can inhibit the ERK cascade. We previously examined a panel of eight Gαs-cAMP-coupled G protein-coupled receptors (GPCRs) endogenously expressed in human lung fibroblasts. Although the cAMP response was important for the anti-fibrotic effects of GPCR agonists, the magnitude of the acute cAMP response was not predictive of anti-fibrotic efficacy. Here we examined the reason for this apparent disconnect by stimulating the Gαs-coupled prostacyclin receptor and measuring downstream signalling at a sub-cellular level. MRE-269 and treprostinil caused sustained cAMP signalling in the nucleus and complete inhibition of PDGF-induced nuclear ERK and fibroblast proliferation. In contrast, iloprost caused a transient increase in nuclear cAMP, there was no effect of iloprost on PDGF-induced ERK in the nucleus, and this agonist was much less effective at reversing PDGF-induced proliferation. This suggests that sustained elevation of cAMP in the nucleus is necessary for efficient inhibition of PDGF-induced nuclear ERK and fibroblast proliferation. This is an important first step towards understanding of the signalling events that drive GPCR inhibition of fibrosis.

PMID:33995100 | PMC:PMC8116805 | DOI:10.3389/fphar.2021.669227

Cancer Genomics Proteomics. 2021 May-Jun;18(3 Suppl):451-459. doi: 10.21873/cgp.20271.

ABSTRACT

BACKGROUND/AIM: The prevalence of idiopathic pulmonary fibrosis (IPF) increases with age and is associated with senescence of alveolar epithelial cells (AECs). AEC senescence in pulmonary cells mediates IPF. We herein aimed to determine if YAP1 gene knockdown, a member of the Hippo/YAP signal pathway, in the bleomycin (BLM)-induced mouse model of IPF, inhibits onset of senescence of AECs and alleviates IPF.

MATERIALS AND METHODS: Adeno-associated viruses (AAVs) expressing Yes-associated protein 1 (YAP1) short hairpin RNA (shRNA) were delivered into the lung of BLM-induced IPF mice via intratracheal injection, to knockdown the YAP1 gene in AECs. The mice were assigned to 4 groups: G1: control (normal mice); G2: IPF mice; G3: IPF + AAV/YAP1; G4: IPF + AAV/scramble. After 28 days, AECs were examined for senescence using H&E staining, Masson's trichrome Staining, senescence-associated ß-galactosidase (SA-β-gal) staining, western blotting and co-immunofluorescence staining, to determine the expression of YAP1, Smad-3 and p21, in order to determine the induction of senescence of ACEs.

RESULTS: The severity of IPF determined by H&E staining, Masson's staining and immunofluorescence (IF) staining was positively correlated with the senescence of AECs. Down-regulation of YAP1 expression of the Hippo-signaling pathway, determined by western blotting in AECs, alleviated pulmonary fibrosis as determined by Masson's staining. Down regulation of YAP1 expression reduced the senescence of AECs as determined by ß-galactosidase (SA-β-gal) staining, which alleviated the clinical symptoms of IPF mice, as determined by body weight and lung index.

CONCLUSION: Down-regulation of YAP1 expression in AECs inhibited AEC senescence which is thought to be the cause of IPF. Therefore, future studies can focus on inhibiting YAP1 to effectively treat IPF.

PMID:33994367 | DOI:10.21873/cgp.20271

Respir Investig. 2021 May 13:S2212-5345(21)00075-7. doi: 10.1016/j.resinv.2021.04.005. Online ahead of print.

ABSTRACT

BACKGROUND: Phase IV clinical trials in Western countries have reported that combined therapy with pirfenidone and nintedanib for idiopathic pulmonary fibrosis (IPF) has a manageable safety profile. However, data on the long-term safety and tolerability of this combination treatment in the real-world setting in Japan are limited.

METHODS: The retrospective data of 46 patients with IPF who received combination therapy with pirfenidone and nintedanib were obtained from 16 institutes in Japan. Adverse events and adverse drug reactions (ADRs) were reported through a retrospective review of medical records.

RESULTS: Nintedanib and pirfenidone were added to preceding treatment with antifibrotic drugs in 32 (69.6%) and 13 (28.3%) patients, respectively. In one patient (2.1%), the two drugs were concurrently initiated. The mean duration of monotherapy before initiating the combination was 26.3 months. In 26 of 38 patients (68.4%), the Gender-Age-Physiology index stage was II or III. Thirty-three patients (71.7%) had some ADRs, and 14 patients (30.4%) permanently discontinued either drug or both drugs owing to the development of ADRs during the observation period (mean: 59 weeks). The percentage of grade III or IV IPF according to the Japanese Respiratory Society severity classification was higher in patients who permanently discontinued either drug or both drugs than in those who continued both drugs (90.9% [10/11; 3 undetermined grade] vs. 61.1% [11/18; 1 undetermined grade]). Decreased appetite (18/46, 39.1%) and diarrhea (16/46, 34.8%) were frequently observed ADRs. Two patients (4.3%) had serious ADRs (liver toxicity and pneumothorax).

CONCLUSIONS: Real-world data imply that combination therapy with pirfenidone and nintedanib for IPF has a manageable safety/tolerability profile.

PMID:33994347 | DOI:10.1016/j.resinv.2021.04.005

Respir Med. 2021 May 4:106432. doi: 10.1016/j.rmed.2021.106432. Online ahead of print.

ABSTRACT

BACKGROUND: Recognition of Anti-tRNA synthetase (ARS) related interstitial lung disease (ILD) is key to ensuring patients have prompt access to immunosuppressive therapies. The purpose of this retrospective cohort study was to identify factors that may delay recognition of ARS-ILD.

METHODS: Patients seen at Vanderbilt University Medical Center between 9/17/2017-10/31/2018 were included in this observational cohort. Clinical and laboratory features were obtained via chart abstraction. Kruskal-Wallis ANOVA, Mann-Whitney U, and Fisher's exact t tests were utilized to determine statistical significance.

RESULTS: Patients with ARS were found to have ILD in 51.9% of cases, which was comparable to the frequency of ILD in systemic sclerosis (59.5%). The severity of FVC reduction in ARS (53.2%) was comparable to diffuse cutaneous systemic sclerosis (56.8%, p = 0.48) and greater than dermatomyositis (66.9%, p = 0.005) or limited cutaneous systemic sclerosis (71.8%, p = 0.005). Frank honeycombing was seen with ARS antibodies but not other myositis autoantibodies. ARS patients were more likely to first present to a pulmonary provider in a tertiary care setting (53.6%), likely due to fewer extrapulmonary manifestations. Only 33% of ARS-ILD were anti-nuclear antibody, rheumatoid factor, or anti-cyclic citrullinated peptide positive. Patients with ARS-ILD had a two-fold longer median time to diagnosis compared to other myositis-ILD patients (11.0 months, IQR 8.5-43 months vs. 5.0 months, IQR 3.0-9.0 months, p = 0.003).

CONCLUSIONS: ARS patients without prominent extra-pulmonary manifestations are at high risk for not being recognized as having a connective tissue disease related ILD and miscategorized as usual interstitial pneumonia/idiopathic pulmonary fibrosis without comprehensive serologies.

PMID:33994288 | DOI:10.1016/j.rmed.2021.106432

Rheumatology (Oxford). 2021 May 16:keab441. doi: 10.1093/rheumatology/keab441. Online ahead of print.

ABSTRACT

OBJECTIVES: Pulmonary manifestations in rheumatoid arthritis (RA) are common comorbidities. Interstitial lung disease (ILD), both idiopathic and in RA has been associated with several genetic variants. We assessed pulmonary fibrosis (PF) in an inception cohort of RA patients in relation to genetic variants and disease-related factors.

METHODS: 1466 early RA patients were consecutively included and followed prospectively from index date until death or December 31, 2016. Clinical, and laboratory data and treatment were continuously registered according to Swedish Rheumatology quality register. DNA was available from 1184 patients and 571 151 genome-wide-single-nucleotide polymorphism were analysed (GSA, Illumina, deCode, Island). Thirteen identified genetic variants were extracted. At follow-up the patients answered a questionnaire regarding disease progression and lung involvement, which was validated by reviewing medical records and analysing radiological examinations.

RESULTS: The prevalence of PF was 5.6%, and the annualized incidence rate was 5.0/1000 (95%CI 3.80, 6.54). Four SNPs were associated with PF in RA; rs35705950 (MUC5B), OR = 2.5 (95%CI 1.5, 4.0), adjusted p-value = 0.00016 and q-value = 0.0021, rs111521887 (TOLLIP) OR = 1.9 (95%CI 1.3, 2.8), adjusted p-value = 0.0014 and q-value = 0.0092; rs2609255 (FAM13A) (OR = 1.7 (95%CI 1.1, 2.5), adjusted p-value = 0.013 and q-value = 0.055) and rs2736100 (TERT) OR = 1.5 (1.0, 2.2), adjusted p-value = 0.046, q-value was 0.15. Older age and rheumatoid factor-positivity were associated with increased risk, whilst methotrexate treatment was associated with a lower risk of PF.

CONCLUSIONS: Development of PF in an inception cohort of RA patients was associated with four of 12 ILD risk genes. RA-related factors except for age at diagnosis and RF-positivity were of limited importance in PF development.

PMID:33993221 | DOI:10.1093/rheumatology/keab441

Transplant Rev (Orlando). 2021 May 4;35(3):100626. doi: 10.1016/j.trre.2021.100626. Online ahead of print.

ABSTRACT

Chronic lung allograft dysfunction (CLAD) is the major long-term cause of morbidity and mortality after lung transplantation. Both bronchiolitis obliterans syndrome and restrictive lung allograft syndrome, two main types of CLAD, lead to fibrosis in either the small airways or alveoli and pleura. Pathological pathways in CLAD and other types of fibrosis, for example idiopathic pulmonary fibrosis, are assumed to overlap and therefore fibrosis biomarkers could aid in the early detection of CLAD. These biomarkers could help to differentiate between different phenotypes of CLAD and could, in comparison to biomarkers of inflammation, possibly distinguish an infectious event from CLAD when a decline in lung function is present. This review gives an overview of known CLAD specific biomarkers, describes new promising fibrosis biomarkers currently investigated in other types of fibrosis, and discusses the possible use of these fibrosis biomarkers for CLAD.

PMID:33992914 | DOI:10.1016/j.trre.2021.100626

Respir Med. 2021 May 4:106437. doi: 10.1016/j.rmed.2021.106437. Online ahead of print.

ABSTRACT

Pleuroparenchymal fibroelastosis (PPFE) is a rare, generally idiopathic form of interstitial pneumonia with unique clinical, radiological and histopathological features. It is named after the presence of upper lobe pleural and subjacent parenchymal fibrosis, with accompanying elastic fibers. Although it is usually an idiopathic disease, it has been linked to other co-existent diseases. Diagnostic suspicion of PPFE is based on the identification of typical abnormalities on chest CT scan, which are prevailingly located in the upper lobes, adjacent to the apex of the lungs. Diagnosis can be confirmed by histological analysis, although biopsy is not always feasible. The disease is generally progressive, but not uniformly. The course of the disease is frequently slow and involves a progressive loss of upper lobe volume, which results in platythorax, associated with a significant reduction of body mass. PPFE concomitant to other interstitial lung diseases is associated with a poorer prognosis. The disease occasionally progresses rapidly causing irreversible respiratory insufficiency, which leads to death. Currently, there is no effective pharmacological therapy available, and lung transplantation is the best therapeutic option. The purpose of this review is to draw the attention to PPFE, describe its clinical, radiological and histopathological features, analyze its diagnostic criteria, and provide an update on the management of the disease.

PMID:33992495 | DOI:10.1016/j.rmed.2021.106437

Rev Mal Respir. 2021 May 12:S0761-8425(21)00236-9. doi: 10.1016/j.rmr.2021.04.015. Online ahead of print.

ABSTRACT

We present data on prognostic factors in a Tunisian cohort of people with Idiopathic pulmonary fibrosis.

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) has a poor prognosis, with a median survival in patients with the condition of only 3 to 5 years. Previous studies have identified a number of prognostic factors in this chronic pulmonary disease.

METHODS: We conducted a retrospective study, including patients with idiopathic pulmonary fibrosis (IPF) who were diagnosed at the Pneumology Department of the University Hospital Fattouma-Bourguiba, Monastir, between 1991 and 2014. The aim of this study was to compare clinical, radiological, pulmonary functional predictors of survival in IPF in a Tunisian cohort with those of previous studies.

RESULTS: This study included 126 patients. Their mean age was 66 years, with a male predominance (68.3%). Respiratory function tests revealed a restrictive ventilatory deficit in 72.6% of cases. The median survival of our study population was 22.5 months [6.7-49.5]. In univariate analysis, factors associated with a poor prognosis were: lower baseline values of TLC, FCV and DLco, level of dyspnea assessed by mMRC scale, hypoxemia at diagnosis, the degree of desaturation during exercise, a higher annual decline of FVC and DLco, acute respiratory distress and also the GAP score. In multivariate analysis, independent prognostic factors were: baseline DLco, level of dyspnea, desaturation at exertion and the annual decline of the DLco.

CONCLUSION: Lower baseline DLco, the level of dyspnea, desaturation on exercise, and annual decline in DLco are all associated with a poor prognosis in IPF.

PMID:33992493 | DOI:10.1016/j.rmr.2021.04.015

BMC Pulm Med. 2021 May 15;21(1):165. doi: 10.1186/s12890-021-01530-6.

ABSTRACT

BACKGROUND: Nintedanib is effective for treating idiopathic pulmonary fibrosis (IPF), but some patients may exhibit a suboptimal response and develop on-treatment acute exacerbation (AE-IPF), hepatic injury, or mortality. It remains unclear which patients are at risk for these adverse outcomes.

METHODS: We analysed the demographic and clinical data, baseline plasma levels of Krebs von den Lungen-6 (KL-6) and surfactant protein A (SPA), and longitudinal clinical courses of a real-world cohort of IPF patients who received nintedanib ≥ 14 days between March 2017 and December 2020. Cox proportional-hazards regression, subdistribution hazards regression, and sensitivity analyses were performed to investigate the association between baseline predictors and AE-IPF, mortality, and nintedanib-related hepatic injury. The relationship between baseline predictors and pulmonary function decline was determined.

RESULTS: Fifty-seven patients were included, of whom 24 (42%) developed hepatic injury, 20 (35%) had AE-IPF, and 16 (28%) died on-treatment. A baseline plasma KL-6 level ≥ 2.5 ng/mL, and diffusion capacity for carbon monoxide (DLCO) < 55% predicted, were associated with increased risk of hepatic injury (adjusted hazard ratio [aHR] was 3.46; 95% CI 1.13-10.60; p = 0.029 for KL-6, and 6.05; 95% CI 1.89-19.32; p = 0.002 for DLCO). Both factors also predicted severe and recurrent hepatic injury. Patients with baseline KL-6 ≥ 2.5 ng/mL also had a higher risk of AE-IPF (aHR 4.52; 95% CI 1.63-12.55; p = 0.004). For on-treatment mortality, baseline KL-6 ≥ 3.5 ng/mL and SPA ≥ 600 pg/mL were significant predictors (aHR 5.39; 95% CI 1.16-24.97; p = 0.031 for KL-6, and aHR 12.28; 95% CI 2.06-73.05; p = 0.006 for SPA). Results from subdistribution hazard regression and sensitivity analyses supported these findings. Patients with elevated baseline plasma KL-6 levels also exhibited a trend towards faster pulmonary function decline.

CONCLUSIONS: For patients with IPF who are receiving nintedanib, we have identified baseline predictors, in particular plasma KL-6 levels, for the risk of adverse outcomes. Patients with these predictors may require close monitoring for unfavourable responses during treatment. Our findings also support the prognostic role of molecular markers like KL-6 and may contribute to future formulation of more individualized therapeutic strategies for IPF.

PMID:33992083 | DOI:10.1186/s12890-021-01530-6

Exp Mol Med. 2021 May 14. doi: 10.1038/s12276-021-00618-7. Online ahead of print.

ABSTRACT

Epoxyeicosatrienoic acids (EETs) are metabolites of arachidonic acid that are rapidly metabolized into diols by soluble epoxide hydrolase (sEH). sEH inhibition has been shown to increase the biological activity of EETs, which are known to have anti-inflammatory properties. However, the role of EETs in pulmonary fibrosis remains unexplored. Liquid chromatography with tandem mass spectrometry (LC-MS/MS) was used to analyze EETs in the lung tissues of patients with idiopathic pulmonary fibrosis (IPF, n = 29) and controls (n = 15), and the function of 11,12-EET was evaluated in in vitro and in vivo in pulmonary fibrosis models. EET levels in IPF lung tissues, including those of 8,9-EET, 11,12-EET, and 14,15-EET, were significantly lower than those in control tissues. The 11,12-EET/11,12-DHET ratio in human lung tissues also differentiated IPF from control tissues. 11,12-EET significantly decreased transforming growth factor (TGF)-β1-induced expression of α-smooth muscle actin (SMA) and collagen type-I in MRC-5 cells and primary fibroblasts from IPF patients. sEH-specific siRNA and 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU; sEH inhibitor) also decreased TGF-β1-induced expression of α-SMA and collagen type-I in fibroblasts. Moreover, 11,12-EET and TPPU decreased TGF-β1-induced p-Smad2/3 and extracellular-signal-regulated kinase (ERK) expression in primary fibroblasts from patients with IPF and fibronectin expression in Beas-2B cells. TPPU decreased the levels of hydroxyproline in the lungs of bleomycin-induced mice. 11,12-EET or sEH inhibitors could inhibit pulmonary fibrosis by regulating TGF-β1-induced profibrotic signaling, suggesting that 11,12-EET and the regulation of EETs could serve as potential therapeutic targets for IPF treatment.

PMID:33990688 | DOI:10.1038/s12276-021-00618-7

Free Radic Biol Med. 2021 May 11:S0891-5849(21)00291-4. doi: 10.1016/j.freeradbiomed.2021.05.010. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease with a poor prognosis and limited treatment options. Oxidative and nitrosative stress is implicated as one of the main pathogenic pathways in IPF. Hence, the rationale for testing antioxidants as potential therapeutics for lung fibrosis is appealing, which has not demonstrated, so far, a consistent benefit. We have recently demonstrated that nitroxides, particularly 3-carbamoyl-proxyl (3-CP), markedly reduce airway inflammation, airway hyper-responsiveness, and protein nitration of the lung tissue in a mouse model of ovalbumin-induced acute asthma, thus prompting its use for the treatment of IPF. The present study investigates the effect of 3-CP on the development of lung fibrosis using the murine intratracheal bleomycin model. 3-CP was administered either intranasally or orally during the entire experiment or starting 7 days after induction of the lung injury. 3-CP was found to be both a preventive and a therapeutic drug reducing the lung fibrosis (histological score), the increase in collagen content, protein nitration, TGF-β levels, the degree of weight loss as well as inhibiting the impairment of lung function. Nitroxides are catalytic antioxidants that preferentially detoxify radicals, and therefore the effect of 3-CP on the severity of the disease supports the involvement of reactive oxygen and nitrogen species in the disease pathology.

PMID:33989760 | DOI:10.1016/j.freeradbiomed.2021.05.010

Free Radic Biol Med. 2021 May 11:S0891-5849(21)00284-7. doi: 10.1016/j.freeradbiomed.2021.05.003. Online ahead of print.

ABSTRACT

Cellular senescence is a heterogeneous process guided by genetic, epigenetic and environmental factors, characterizing many types of somatic cells. It has been suggested as an aging hallmark that is believed to contribute to aging and chronic diseases. Senescent cells (SC) exhibit a specific senescence-associated secretory phenotype (SASP), mainly characterized by the production of proinflammatory and matrix-degrading molecules. When SC accumulate, a chronic, systemic, low-grade inflammation, known as inflammaging, is induced. In turn, this chronic immune system activation results in reduced SC clearance thus establishing a vicious circle that fuels inflammaging. SC accumulation represents a causal factor for various age-related pathologies. Targeting of several aging hallmarks has been suggested as a strategy to ameliorate healthspan and possibly lifespan. Consequently, SC and SASP are viewed as potential therapeutic targets either through the selective killing of SC or the selective SASP blockage, through natural or synthetic compounds. These compounds are members of a family of agents called senotherapeutics divided into senolytics and senomorphics. Few of them are already in clinical trials, possibly representing a future treatment of age-related pathologies including diseases such as atherosclerosis, osteoarthritis, osteoporosis, cancer, diabetes, neurodegenerative diseases such as Alzheimer's disease, cardiovascular diseases, hepatic steatosis, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis and age-related macular degeneration. In this review, we present the already identified senolytics and senomorphics focusing on their redox-sensitive properties. We describe the studies that revealed their effects on cellular senescence and enabled their nomination as novel anti-aging agents. We refer to the senolytics that are already in clinical trials and we present various adverse effects exhibited by senotherapeutics so far. Finally, we discuss aspects of the senotherapeutics that need improvement and we suggest the design of future senotherapeutics to target specific redox-regulated signaling pathways implicated either in the regulation of SASP or in the elimination of SC.

PMID:33989756 | DOI:10.1016/j.freeradbiomed.2021.05.003

PLoS One. 2021 May 14;16(5):e0251636. doi: 10.1371/journal.pone.0251636. eCollection 2021.

ABSTRACT

INTRODUCTION: Nintedanib can inhibit processes involved in the progression of fibrosis and can reduce the decline in forced vital capacity in patients with idiopathic pulmonary fibrosis (IPF) and fibrotic-interstitial lung disease (fibrotic-ILDs). Although the adverse events associated with nintedanib in IPF patients are well known, its safety in other fibrotic-ILD patients remained unclear.

METHODS: We searched PubMed, EMBASE, Cochrane CENTRAL and Cochrane CDSR for randomized controlled studies which compared nintedanib with a placebo in ILD patients. We estimated pooled odds ratios (ORs) and 95% confidence intervals (CIs) for adverse events using the DerSimonian-Laird random-effects model.

RESULTS: Six studies with a total of 2,583 patients were included in the meta-analysis. The pooled estimates showed that patients treated with nintedanib had a significantly higher likelihood of having any adverse events (OR = 2.39; 95% CI = 1.71-3.36) or adverse events leading to treatment discontinuation (OR = 1.73; 95% CI = 1.34-2.25). However, they had trend to lower likelihood of having fatal adverse events (OR = 0.69; 95% CI = 0.41-1.14) compared with the placebo group. Use of nintedanib was positively associated with diarrhea (OR = 5.96; 95% CI = 4.35-8.16), nausea (OR = 3.00; 95% CI = 1.93-4.66), vomiting (OR = 3.22; 95% CI = 2.17-4.76) and weight loss (OR = 3.38; 95% CI = 1.1.76-6.47). Whereas, patients treated with nintedanib were less likely to have a cough (OR = 0.73; 95% CI = 0.56-0.96) and dyspnea (OR = 0.70; 95% CI = 0.53-0.94).

CONCLUSIONS: Compared to a placebo, nintedanib was associated with a higher risk of adverse events, especially for diarrhea, nausea, vomiting and weight loss, but it was also associated with a lower risk of cough and dyspnea in IPF and fibrotic-ILD patients.

PMID:33989328 | DOI:10.1371/journal.pone.0251636

Ann Transl Med. 2021 Apr;9(7):563. doi: 10.21037/atm-20-6143.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a fatal chronic pulmonary fibrosis disease and pathological mechanisms of fibrogenesis in IPF are still to be elucidated. Here, we investigated the potential role of Nogo-B in pulmonary fibrogenesis.

METHODS: A mouse model of pulmonary fibrosis was established by intratracheal injection of bleomycin (BLM). Lung epithelial cells MLE-12 and TC-1 JHU-1 were cultured for TGF-β treatment. The extent of lung fibrosis was evaluated using hematoxylin and eosin (HE) staining and Masson staining in model mice and Nogo-B knockout mice. The protein levels of Nogo-B, endoplasmic reticulum stress (ERS) sensors including PERK, IRE1α, ATF6 and epithelial-mesenchymal transition (EMT) markers including E-cadherin and N-cadherin, vimentin were assayed by Western blotting respectively after Nogo-B knockdown or overexpression with lentivirus. Enzyme-linked immunosorbent assay (ELISA) was used to evaluate cytokine levels of TGF-β, TNF-α, IL-1β, IL-6 and IL-10 in bronchoalveolar lavage fluid (BALF).

RESULTS: Nogo-B expression was up-regulated in lung tissues of fibrosis model mice and alveolar epithelial cells. Nogo-B knockdown significantly attenuated lung fibrogenesis, downregulated the levels of inflammatory cytokines, inhibited EMT as well as decreased the level of phosphor-PERK/PERK but not the levels of phosphor-IRE1α/IRE1α and c-ATF6. Additionally, a potential efficacy of PERK blockade was demonstrated in improving the extent of lung fibrosis in model mice.

CONCLUSIONS: This study discovered that involvement of Nogo-B in pulmonary fibrogenesis was associated with the PERK branch of ERS pathway and EMT. Nogo-B could be considered as a potential therapeutic target for the treatment of IPF.

PMID:33987261 | PMC:PMC8105797 | DOI:10.21037/atm-20-6143

Front Med (Lausanne). 2021 Apr 27;8:616200. doi: 10.3389/fmed.2021.616200. eCollection 2021.

ABSTRACT

Chronic inflammatory pulmonary diseases are characterized by recurrent and persistent inflammation of the airways, commonly associated with poor clinical outcomes. Although their etiologies vary tremendously, airway neutrophilia is a common feature of these diseases. Neutrophils, as vital regulators linking innate and adaptive immune systems, are a double-edged sword in the immune response of the lung involving mechanisms such as phagocytosis, degranulation, neutrophil extracellular trap formation, exosome secretion, release of cytokines and chemokines, and autophagy. Although neutrophils serve as strong defenders against extracellular pathogens, neutrophils and their components can trigger various cascades leading to inflammation and fibrogenesis. Here, we review current studies to elucidate the versatile roles of neutrophils in chronic pulmonary inflammatory diseases and describe the common pathogenesis of these diseases. This may provide new insights into therapeutic strategies for chronic lung diseases.

PMID:33987189 | PMC:PMC8110706 | DOI:10.3389/fmed.2021.616200

Eur Respir J. 2021 May 13:2004196. doi: 10.1183/13993003.04196-2020. Online ahead of print.

ABSTRACT

Defective angiogenesis, incomplete thrombus revascularisation and fibrosis are considered critical pathomechanisms of chronic thromboembolic pulmonary hypertension (CTEPH) after pulmonary embolism (PE). Angiopoietin-2 (ANGPT2) has been shown to regulate angiogenesis, but its importance for thrombus resolution and remodelling is unknown.ANGPT2 plasma concentrations were measured in patients with CTEPH (n=68) and acute PE (n=84). Tissue removed during pulmonary endarterectomy (PEA) for CTEPH was analysed (immuno)histologically. A mouse model of inferior vena cava ligation was used to study the kinetics of venous thrombus resolution in wild-type mice receiving recombinant ANGPT2 via osmotic pumps, and in transgenic mice overexpressing ANGPT2 in endothelial cells.Circulating ANGPT2 levels were higher in CTEPH patients compared to patients with idiopathic pulmonary arterial hypertension and healthy controls, and decreased after PEA. Plasma ANGPT2 levels were also elevated in patients with PE and diagnosis of CTEPH during follow-up. Histological analysis of PEA specimens confirmed increased ANGPT2 expression, and low levels of phosphorylated TIE2 were observed in regions with early-organised pulmonary thrombi, myofibroblasts and fibrosis. Microarray and high-resolution microscopy analysis could localise ANGPT2 overexpression to endothelial cells, and hypoxia and TGF-β1 were identified as potential stimuli. Gain-of-function experiments in mice demonstrated that exogenous ANGPT2 administration and transgenic endothelial ANGPT2 overexpression resulted in delayed venous thrombus resolution, and thrombi were characterised by lower TIE2 phosphorylation and fewer microvessels.Our findings suggest that ANGPT2 delays venous thrombus resolution and that overexpression of ANGPT2 contributes to thrombofibrosis and may thus support the transition from PE to CTEPH.

PMID:33986029 | DOI:10.1183/13993003.04196-2020