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

ERJ Open Res. 2021 May 10;7(2):00897-2020. doi: 10.1183/23120541.00897-2020. eCollection 2021 Apr.

ABSTRACT

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) prognosis is heterogeneous despite antifibrotic treatment. Cluster analysis has proven to be a useful tool in identifying interstitial lung disease phenotypes, which has yet to be performed in IPF. The aim of this study is to identify phenotypes of IPF with different prognoses and requirements.

METHODS: Observational retrospective study including 136 IPF patients receiving antifibrotic treatment between 2012 and 2018. Six patients were excluded due to follow-up in other centres. Cluster analysis of 30 variables was performed using approximate singular value-based tensor decomposition method and comparative statistical analysis.

RESULTS: The cluster analysis identified three different groups of patients according to disease behaviour and clinical features, including mortality, lung transplant and progression-free survival time after 3-year follow-up. Cluster 1 (n=60) was significantly associated (p=0.02) with higher mortality. Diagnostic delay was the most relevant characteristic of this cluster, as 48% of patients had ≥2 years from first respiratory symptoms to antifibrotic treatment initiation. Cluster 2 (n=22) had the longest progression-free survival time and was correlated to subclinical patients evaluated in the context of incidental findings or familial screening. Cluster 3 (n=48) showed the highest percentage of disease progression without cluster 1 mortality, with metabolic syndrome and cardiovascular comorbidities as the main characteristics.

CONCLUSION: This cluster analysis of IPF patients suggests that diagnostic and treatment delay are the most significant factors associated with mortality, while IPF progression was more related to metabolic syndrome and cardiovascular comorbidities.

PMID:33981766 | PMC:PMC8107351 | DOI:10.1183/23120541.00897-2020

Am J Physiol Lung Cell Mol Physiol. 2021 May 12. doi: 10.1152/ajplung.00323.2020. Online ahead of print.

ABSTRACT

Extracellular matrix deposition characterizes idiopathic pulmonary fibrosis (IPF) and is orchestrated by myofibroblasts. The lung mesenchyme is an essential source of myofibroblasts in pulmonary fibrosis. While the transcription factor serum response factor (SRF) has shown to be critical in the process of myofibroblast differentiation, its role in development of pulmonary fibrosis has not been determined in vivo. In this study, we observed SRF expression localized to mesenchymal compartments, areas of dense fibrosis, and fibroblastic foci in human (IPF and normal) and bleomycin-treated mouse lungs. To determine the role of mesenchymal SRF in pulmonary fibrosis, we utilized a doxycycline inducible, Tbx4 lung enhancer (Tbx4LE) driven cre-recombinase to disrupt SRF expression in the lung mesenchyme in vivo. Doxycycline-treated Tbx4LE-rtTA/TetO-Cre/tdTom/SRFf,f (and controls) were treated with a single intratracheal dose of bleomycin to induce pulmonary fibrosis and examined for lung mesenchymal expansion, pulmonary fibrosis, and inflammatory response. Bleomycin-treated Tbx4LE-rtTA/TetO-Cre/tdTom/SRFf,f mice showed decreased numbers of Tbx4LE-positive lung mesenchymal cells (LMC) and collagen accumulation (via hydroxyproline assay) compared to controls. This effect was associated with SRF-null LMC losing their proliferative and myofibroblast differentiation potential compared to SRF-positive controls. Together, these data demonstrate that SRF plays a critical role in LMC myofibroblast expansion during bleomycin-induced pulmonary fibrosis. This sets the stage for pharmacologic strategies that specifically target SRF in the lung mesenchyme as a potential means of treating pulmonary fibrosis.

PMID:33978489 | DOI:10.1152/ajplung.00323.2020

J Pathol Clin Res. 2021 May 12. doi: 10.1002/cjp2.224. Online ahead of print.

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a serious threat to healthcare systems worldwide. Binding of the virus to angiotensin-converting enzyme 2 (ACE2) is an important step in the infection mechanism. However, it is unknown if ACE2 expression in patients with chronic lung diseases (CLDs), such as chronic obstructive pulmonary disease (COPD), idiopathic pulmonary arterial hypertension (IPAH), or pulmonary fibrosis (PF), is changed as compared to controls. We used lung samples from patients with COPD (n = 28), IPAH (n = 10), and PF (n = 10) as well as healthy control donor (n = 10) tissue samples to investigate the expression of ACE2 and related cofactors that might influence the course of SARS-CoV-2 infection. Expression levels of the ACE2 receptor, the putative receptor CD147/BSG, and the viral entry cofactors TMPRSS2 (transmembrane serine protease 2), EZR, and FURIN were determined by quantitative PCR and in open-access RNA sequencing datasets. Immunohistochemical and single-cell RNA sequencing (scRNAseq) analyses were used for localization and coexpression, respectively. Soluble ACE2 (sACE2) plasma levels were analyzed by enzyme-linked immunosorbent assay. In COPD as compared to donor, IPAH, and PF lung tissue, gene expression of ACE2, TMPRSS2, and EZR was significantly elevated, but circulating sACE2 levels were significantly reduced in COPD and PF plasma compared to healthy control and IPAH plasma samples. Lung tissue expressions of FURIN and CD147/BSG were downregulated in COPD. None of these changes were associated with changes in pulmonary hemodynamics. Histological analysis revealed coexpression of ACE2, TMPRSS2, and Ezrin in bronchial regions and epithelial cells. This was confirmed by scRNAseq analysis. There were no significant expression changes of the analyzed molecules in the lung tissue of IPAH and idiopathic PF as compared to control. In conclusion, we reveal increased ACE2 and TMPRSS2 expression in lung tissue with a concomitant decrease of protective sACE2 in COPD patients. These changes represent the possible risk factors for an increased susceptibility of COPD patients to SARS-CoV-2 infection.

PMID:33978304 | DOI:10.1002/cjp2.224

Health Soc Care Community. 2021 May 12. doi: 10.1111/hsc.13426. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis is a progressive fibrotic lung disease that is on the rise globally. The disease is associated with significant morbidity and hence poses significant challenges for their informal carers, particularly daughters in mid-adulthood, who struggle with their own personal demands and that of their ill parents. Yet there is a dearth of literature on the experiences of these specific carers. Hence, the purpose of this study is to explore the lived experiences of daughters caring for a parent with pulmonary fibrosis within a community setting. This was explored using a phenomenological qualitative framework that was conducted between January and April 2017. Semi-structured audio-recorded interviews were conducted with six adult daughters who provided care to a parent having pulmonary fibrosis. Purposive sampling was used to recruit study participants. Transcribed data were analysed using Interpretative Phenomenological Analysis. Three main themes were extracted which communicate the essence of the daughters' lived experiences: "Walking on tiptoes", "Flooded by emotions" and "Shifts in family dynamics." Participants described experiencing the toll of being constantly vigilant for symptoms. They also expressed a range of emotions that included guilt, helplessness and worry related to their care experience. However, these emotional struggles were suppressed in order to present an external facade of strength and control. A shift in roles was also described where the daughters became the informal carers/support for both their ill and well parent, albeit in different ways. Caring for a person with pulmonary fibrosis is an emotional and life changing experience and hence, there is the need for individualised interventions that target the unique perceptions of these informal carers.

PMID:33978275 | DOI:10.1111/hsc.13426

Pulm Ther. 2021 May 11. doi: 10.1007/s41030-021-00155-8. Online ahead of print.

ABSTRACT

INTRODUCTION: Timely and accurate diagnosis of idiopathic pulmonary fibrosis (IPF) is challenging, requiring specific tests including chest high-resolution computed tomography (HRCT), and limited by access to specialist centres with a multidisciplinary team (MDT). Here we describe PerFECT 2.0, an Italian web-based platform designed to create a network between tertiary centres with an MDT (hubs) and secondary centres (spokes), aiming to facilitate the diagnosis of IPF.

METHODS: PerFECT 2.0 went live on 1 November 2016. Spoke centres submit anonymised documentation (HRCT images, pathological samples, clinical data) for a second opinion on the potential diagnosis of IPF from a hub centre. HRCT images are quickly uploaded, with patient-identifying information automatically removed. The hub centre views documentation online (no downloads allowed), makes any further information requests, then returns their second opinion as free text. An e-learning area contains educational material and simulated training clinical cases. Metrics were collected for 2017-2019; a user survey was conducted from 30 June-31 July 2020.

RESULTS: Ten hub centres and 137 spoke centres have registered. The requests for a second opinion numbered 251 in 2017, 270 in 2018 and 265 in 2019 (overall mean 19.9 requests per month). The proportion of requests answered was 100.0% (251) in 2017, 100.0% (270) in 2018 and 97.7% (259) in 2019. The mean response time was 15.7 days. In the user survey, of nine hub responders and 19 spoke responders, 78% and 74%, respectively, reported that the platform is easy to use, and 100% and 89%, respectively, would recommend the platform to colleagues.

CONCLUSION: The PerFECT 2.0 web-based platform has created a network that enables secondary centres to gain quick and easy access to a second opinion from a tertiary centre with an MDT through online evaluation of anonymised documentation, thereby facilitating and supporting the timely and accurate diagnosis of IPF.

PMID:33974238 | DOI:10.1007/s41030-021-00155-8

JAMA. 2021 May 11;325(18):1841-1851. doi: 10.1001/jama.2021.4956.

ABSTRACT

IMPORTANCE: Alteration in lung microbes is associated with disease progression in idiopathic pulmonary fibrosis.

OBJECTIVE: To assess the effect of antimicrobial therapy on clinical outcomes.

DESIGN, SETTING, AND PARTICIPANTS: Pragmatic, randomized, unblinded clinical trial conducted across 35 US sites. A total of 513 patients older than 40 years were randomized from August 2017 to June 2019 (final follow-up was January 2020).

INTERVENTIONS: Patients were randomized in a 1:1 allocation ratio to receive antimicrobials (n = 254) or usual care alone (n = 259). Antimicrobials included co-trimoxazole (trimethoprim 160 mg/sulfamethoxazole 800 mg twice daily plus folic acid 5 mg daily, n = 128) or doxycycline (100 mg once daily if body weight <50 kg or 100 mg twice daily if ≥50 kg, n = 126). No placebo was administered in the usual care alone group.

MAIN OUTCOMES AND MEASURES: The primary end point was time to first nonelective respiratory hospitalization or all-cause mortality.

RESULTS: Among the 513 patients who were randomized (mean age, 71 years; 23.6% women), all (100%) were included in the analysis. The study was terminated for futility on December 18, 2019. After a mean follow-up time of 13.1 months (median, 12.7 months), a total of 108 primary end point events occurred: 52 events (20.4 events per 100 patient-years [95% CI, 14.8-25.9]) in the usual care plus antimicrobial therapy group and 56 events (18.4 events per 100 patient-years [95% CI, 13.2-23.6]) in the usual care group, with no significant difference between groups (adjusted HR, 1.04 [95% CI, 0.71-1.53; P = .83]. There was no statistically significant interaction between the effect of the prespecified antimicrobial agent (co-trimoxazole vs doxycycline) on the primary end point (adjusted HR, 1.15 [95% CI 0.68-1.95] in the co-trimoxazole group vs 0.82 [95% CI, 0.46-1.47] in the doxycycline group; P = .66). Serious adverse events occurring at 5% or greater among those treated with usual care plus antimicrobials vs usual care alone included respiratory events (16.5% vs 10.0%) and infections (2.8% vs 6.6%); adverse events of special interest included diarrhea (10.2% vs 3.1%) and rash (6.7% vs 0%).

CONCLUSIONS AND RELEVANCE: Among adults with idiopathic pulmonary fibrosis, the addition of co-trimoxazole or doxycycline to usual care, compared with usual care alone, did not significantly improve time to nonelective respiratory hospitalization or death. These findings do not support treatment with these antibiotics for the underlying disease.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02759120.

PMID:33974018 | DOI:10.1001/jama.2021.4956

Front Cardiovasc Med. 2021 Apr 22;8:678530. doi: 10.3389/fcvm.2021.678530. eCollection 2021.

ABSTRACT

Heart failure with preserved ejection fraction (HFpEF) is a major public health problem with growing prevalence and poor outcomes, mainly due to the lack of an effective treatment. HFpEF pathophysiology is heterogeneous and complex. Recently a "new paradigm" has been proposed, suggesting that cardiovascular and non-cardiovascular coexisting comorbidities lead to a systemic inflammatory state, perturbing the physiology of the endothelium and the perivascular environment and engaging molecular pathways that ultimately converge to myocardial fibrosis. If inflammation and fibrosis are the "fil rouge" in the heterogeneous spectrum of HFpEF, anti-fibrotic and anti-inflammatory drugs may have a role in its treatment. Pirfenidone is an orally bioavailable drug with antifibrotic and anti-inflammatory properties already approved for the treatment of idiopathic pulmonary fibrosis. Pirfenidone has been recently tested in animal models of myocardial fibrosis with promising results. Here we will review the rationale underlying the potential therapeutic effect of Pirfenidone in HFpEF.

PMID:33969025 | PMC:PMC8100203 | DOI:10.3389/fcvm.2021.678530

Front Immunol. 2021 Apr 22;12:665818. doi: 10.3389/fimmu.2021.665818. eCollection 2021.

ABSTRACT

Acute inflammatory exacerbations (AIE) represent precipitous deteriorations of a number of chronic lung conditions, including pulmonary fibrosis (PF), chronic obstructive pulmonary disease and asthma. AIEs are marked by diffuse and persistent polycellular alveolitis that profoundly accelerate lung function decline and mortality. In particular, excess monocyte mobilization during AIE and their persistence in the lung have been linked to poor disease outcome. The etiology of AIEs remains quite uncertain, but environmental exposure and genetic predisposition/mutations have been identified as two contributing factors. Guided by clinical evidence, we have developed a mutant model of pulmonary fibrosis leveraging the PF-linked missense isoleucine to threonine substitution at position 73 [I73T] in the alveolar type-2 cell-restricted Surfactant Protein-C [SP-C] gene [SFTPC]. With this toolbox at hand, the present work investigates the role of peripheral monocytes during the initiation and progression of AIE-PF. Genetic ablation of CCR2+ monocytes (SP-CI73TCCR2KO) resulted in improved lung histology, mouse survival, and reduced inflammation compared to SP-CI73TCCR2WT cohorts. FACS analysis of CD11b+CD64-Ly6Chi monocytes isolated 3 d and 14 d after SP-CI73T induced injury reveals dynamic transcriptional changes associated with "Innate Immunity' and 'Extracellular Matrix Organization' signaling. While immunohistochemical and in situ hybridization analysis revealed comparable levels of tgfb1 mRNA expression localized primarily in parenchymal cells found nearby foci of injury we found reduced effector cell activation (C1q, iNOS, Arg1) in SP-CI73TCCR2KO lungs as well as partial colocalization of tgfb1 mRNA expression in Arg1+ cells. These results provide a detailed picture of the role of resident macrophages and recruited monocytes in the context of AIE-PF driven by alveolar epithelial dysfunction.

PMID:33968067 | PMC:PMC8101410 | DOI:10.3389/fimmu.2021.665818

Front Immunol. 2021 Apr 23;12:642855. doi: 10.3389/fimmu.2021.642855. eCollection 2021.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a relentlessly progressive disease harboring significant morbidity and mortality despite recent advances in therapy. Regardless of disease severity acute exacerbations (IPF-AEs) may occur leading to considerable loss of function and are the leading cause of death in IPF. Histologic features of IPF-AE are very similar to acute respiratory distress syndrome (ARDS), but the underlying mechanisms are incompletely understood. We investigated the role of the NLRP3 inflammasome in IPF and IPF-AE. Bronchoalveolar lavage (BAL) cells were sampled from patients with IPF (n = 32), IPF-AE (n = 10), ARDS (n = 7) and healthy volunteers (HV, n = 37) and the NLRP3-inflammasome was stimulated in-vitro. We found the NLRP3 inflammasome to be hyper-inducible in IPF compared to HV with increased IL-1ß and pro-IL-1ß levels on ELISA upon stimulation as well as increased caspase-1 activity measured by caspase-1p20 immunoblotting. In IPF-AE, IL-1ß was massively elevated to an extent similar to ARDS. To evaluate potential mechanisms, we co-cultured BAL cells with radiated A549 cells (a model to simulate apoptotic alveolar epithelial cells), which led to increased NLRP3 mRNA expression and increased caspase-1 dependent IL-1ß production. In the presence of a reactive oxygen species (ROS) inhibitor (diphenyleneiodonium) and a cathepsin B inhibitor (E64D), NLRP3 expression was suppressed indicating that induction of NLRP3 activation following efferocytosis of apoptotic A549 cells is mediated via ROS and cathepsin-B. In summary, we present evidence of involvement of the NLRP3 inflammasome-caspase pathway in the pathogenesis of IPF-AE, similarly to ARDS, which may be mediated by efferocytosis of apoptotic alveolar epithelial cells in IPF.

PMID:33968032 | PMC:PMC8104027 | DOI:10.3389/fimmu.2021.642855

Adv Respir Med. 2021;89(2):231-233. doi: 10.5603/ARM.a2021.0023.

ABSTRACT

Coronavirus Disease-2019 (COVID-19), caused by the novel coronavirus, remains a largely unsolved mystery for researchers around the world as its global onslaught upon mankind continues unabated. To make matters worse, an upcoming and alarming trend that is increasingly being noticed as a post-COVID sequel is that of pulmonary fibrosis. Given the scale of the pandemic, the magnitude of this problem is likely to be high. Extrapolated conclusions from previous studies discussing the beneficial role of antifibrotics in progressive fibrosing interstitial lung diseases provide some hope that these medicines might have a potentially useful role in COVID-19 related lung fibrosis as well. Increased serum levels of inflammatory and pro-fibrotic mediators in COVID-19 patients, similar cytokine profiles in idiopathic pulmonary fibrosis and COVID-19, and broad anti-fibrotic activity of approved antifibrotics irrespective of the underlying etiology, are some of the proposed mechanisms favoring the argument. However, no studies currently support or refute the use of antifibrotics in patients developing post-COVID-19 pulmonary fibrosis. In view of such uncertainties, it is critically important for lung fibrosis networks to conduct well-designed prospective clinical trials addressing this issue to find conclusive answers.

PMID:33966265 | DOI:10.5603/ARM.a2021.0023

EBioMedicine. 2021 May 6;67:103373. doi: 10.1016/j.ebiom.2021.103373. Online ahead of print.

NO ABSTRACT

PMID:33965873 | DOI:10.1016/j.ebiom.2021.103373

Respir Med. 2021 Apr 27;183:106415. doi: 10.1016/j.rmed.2021.106415. Online ahead of print.

ABSTRACT

BACKGROUND: Low income, a known prognostic indicator of various chronic respiratory diseases, has not been properly studied in idiopathic pulmonary fibrosis (IPF). We hypothesize that a low income has an adverse prognostic impact on IPF.

METHODS: Patients were selected from the French national prospective cohort COFI. Patients' income was assessed through the median city-level income provided by the French National Institute of Statistics and Economic Studies according to their residential address. Patients were classified in two groups as "low income" vs. "higher income" depending on whether their annual income was estimated to be < or ≥18 170 €/year (the first quartile of the income distribution in the study population). The survival and progression-free survival (PFS) of the groups were compared by a log-rank test and a Cox model in multivariate analysis.

RESULTS: 200 patients were included. The average follow-up was 33.8 ± 22.7 months. Patients in the low income group were significantly more likely to be of non-European origin (p < 0.006), and to have at least one occupational exposure (p < 0.0001), and they tended to have a higher cumulative exposure to fine particles PM2.5 (p = 0.057). After adjusting for age, gender, forced vital capacity at inclusion, geographical origin, and occupational exposure having a low-income level was a factor associated with a worse PFS (HR: 1.81; CI95%: 1.24-2.62, p = 0.001) and overall survival (HR: 1.49; CI95%: 1.0006-2.23, p = 0.049).

CONCLUSIONS: Low income appears to be a prognostic factor in IPF. IPF patients with low incomes may also be exposed more frequently to occupational exposures.

PMID:33965849 | DOI:10.1016/j.rmed.2021.106415

Pulm Pharmacol Ther. 2021 May 6:102038. doi: 10.1016/j.pupt.2021.102038. Online ahead of print.

ABSTRACT

BACKGROUND: The SARS-CoV-2 pandemic has changed the health-care systems around the world in a remarkable way. We describe the strategies adopted to cope with the limitations imposed by the pandemic to the access to health care by patients diagnosed with idiopathic Pulmonary Fibrosis (IPF).

MATERIAL AND METHODS: We conducted a retrospective observational analysis including IPF patients under antifibrotic drugs (nintedanib and pirfenidone) that accessed to the Outpatient clinic of the University of Palermo, Italy. Patients received a phone number and an email address in case of any urgency and a virtual meeting was settled up monthly.

RESULTS: 40 patients (M/F: 30/10) were followed up, 33 under nintedanib treatment, 7 under pirfenidone. Among patients under nintedanib, 1 patient reported high fever (T max 39°C) and purulent sputum with no sign of infections, 1 had hemoptysis that was spontaneously resolved. 2 patients accessed to the emergency department for the worsening of dyspnea; 5 patients had diarrhea that resolved with symptomatic drugs in few days. 3 patients had an increase of alkaline phosphatase levels, leading to the withdrawal of the antifibrotic drug for 15 days, and subsequent normalization of the plasmatic levels. Among patients under pirfenidone, one subject had an increase of ferritin serum levels with no symptoms. The remaining subjects were in stable clinical conditions. None of the patients reported hospitalization or exacerbations, and did not experience antifibrotic withdrawal.

CONCLUSIONS: We were able to demonstrate that by implementing alternative ways to monitor the disease, patients did not incur in increased rates of acute exacerbations or higher frequency of side effects and antifibrotic treatment withdrawal.

PMID:33965569 | DOI:10.1016/j.pupt.2021.102038

Pharmacol Res. 2021 May 6:105605. doi: 10.1016/j.phrs.2021.105605. Online ahead of print.

ABSTRACT

Heart Failure (HF) is the leading cause of death worldwide. Myocardial fibrosis, one of the clinical manifestations implicated in almost every form of heart disease, contributes significantly to HF development. However, there is no approved drug specifically designed to target cardiac fibrosis. Nintedanib (NTB) is an FDA approved tyrosine kinase inhibitor for idiopathic pulmonary fibrosis (IPF) and chronic fibrosing interstitial lung diseases (ILD). The favorable clinical outcome of NTB in IPF patients is well established. Furthermore, NTB is well tolerated in IPF patients irrespective of cardiovascular comorbidities. However, there is a lack of direct evidence to support the therapeutic efficacy and safety of NTB in cardiac diseases. In this study we examined the effects of NTB treatment on cardiac fibrosis and dysfunction using a murine model of HF. Specifically, 10 weeks old C57BL/6J male mice were subjected to Transverse Aortic Constriction (TAC) surgery. NTB was administered once daily by oral gavage (50mg/kg) till 16 weeks post-TAC. Cardiac function was monitored by serial echocardiography. Histological analysis and morphometric studies were performed at 16 weeks post-TAC. In the control group, systolic dysfunction started developing from 4 weeks post-surgery and progressed till 16 weeks. However, NTB treatment prevented TAC-induced cardiac functional decline. In another experiment, NTB treatment was stopped at 8 weeks, and animals were followed till 16 weeks post-TAC. Surprisingly, NTB's beneficial effect on cardiac function was maintained even after treatment interruption. NTB treatment remarkably reduced cardiac fibrosis as confirmed by Masson's trichrome staining and decreased expression of collagen genes (COL1A1, COL3A1). Compared to the TAC group, NTB treated mice showed a lower HW/TL ratio and cardiomyocyte cross-sectional area. NTB treatment reduced myocardial and systemic inflammation by inhibiting pro-inflammatory subsets and promoting regulatory T cells (Tregs). Our in vitro studies demonstrated that NTB prevents myofibroblast transformation, TGFβ1-induced SMAD3 phosphorylation, and the production of fibrogenic proteins (Fibronectin-1, α-SMA). However, NTB promoted immunosuppressive phenotype in Tregs, and altered vital signaling pathways in isolated cardiac fibroblast and cardiomyocytes, suggesting that its biological effect and underlying cardiac protection mechanisms are not limited to fibroblast and fibrosis alone. Our findings provide a proof of concept for repurposing NTB to combat adverse myocardial fibrosis and encourage the need for further validation in large animal models and subsequent clinical development for HF patients.

PMID:33965510 | DOI:10.1016/j.phrs.2021.105605