Front Med (Lausanne). 2022 Feb 1;9:799912. doi: 10.3389/fmed.2022.799912. eCollection 2022.

ABSTRACT

Despite conventional treatment, a proportion of interstitial lung disease (ILD) patients develop a progressive phenotype known as "fibrosing ILD with a progressive phenotype" (PF-ILD), characterized by worsening respiratory symptoms, decline in lung function, and early mortality. This review describes the epidemiology, and the humanistic and economic burden of PF-ILDs other than idiopathic pulmonary fibrosis (non-IPF PF-ILD). A structured review of the literature was conducted, using predefined search strategies in Ovid MEDLINE and EMBASE, and supplemented with gray literature searches. The search identified 3,002 unique articles and an additional 3 sources were included from the gray literature; 21 publications were included. The estimated prevalence of non-IPF PF-ILD ranges from 6.9 to 70.3/100,000 persons and the estimated incidence from 2.1 to 32.6/100,000 person-years. Limited evidence demonstrates that PF-ILD has a significant impact on patients' quality of life, affecting their daily lives, psychological well-being, careers, and relationships. PF-ILD is also associated with significant economic burden, demonstrating higher healthcare resource use and direct costs compared with the non-progressive phenotype, and indirect costs, which include job losses. This review indicates that PF-ILD places a considerable humanistic burden on both patients and caregivers, and a substantial economic burden on healthcare systems, patients, and society.

PMID:35178411 | PMC:PMC8843847 | DOI:10.3389/fmed.2022.799912

Chest. 2022 Feb 14:S0012-3692(22)00262-8. doi: 10.1016/j.chest.2022.02.012. Online ahead of print.

ABSTRACT

BACKGROUND: Pulmonary hypertension (PH) is a common complication of interstitial lung disease (ILD), and is associated with worse outcomes and increased mortality. Evaluation of PH is recommended in lung transplant candidates but there are currently no standardized screening approaches. Recent trials have identified therapies that are effective in this setting, providing another rationale to routinely screen ILD patients for PH.

RESEARCH QUESTION: What screening strategies for identifying PH in patients with ILD are supported by expert consensus?

STUDY DESIGN AND METHODS: The study convened a panel of 16 pulmonologists with expertise in PH and ILD, and utilized a modified Delphi consensus process with 3 surveys to identify PH screening strategies. Survey 1 consisted primarily of open-ended questions. Surveys 2 and 3 were developed from responses to Survey 1 and contained statements about PH screening that panelists rated from -5 (strongly disagree) to +5 (strongly agree).

RESULTS: Panelists reached consensus on several triggers for suspicion of PH including: symptoms, clinical signs, findings on chest computed tomography or other imaging, abnormalities in pulse oximetry, elevations in brain natriuretic peptide (BNP) or N-terminal propeptide (NT-proBNP), and unexplained worsening in pulmonary function tests or 6-minute walk distance. Echocardiography and BNP/NT-proBNP were identified as screening tools for PH. Right heart catheterization was deemed essential for confirming PH.

INTERPRETATION: Many patients with ILD may benefit from early evaluation of PH now that an approved therapy is available. Protocols to evaluate patients with ILD often overlap with evaluations for PH-ILD and can be used to assess the risk of PH. Since standardized approaches are lacking, this consensus statement is intended to aid clinicians in the identification of patients with ILD and possible PH, and provide guidance for timely right heart catheterization.

PMID:35176276 | DOI:10.1016/j.chest.2022.02.012

ERJ Open Res. 2022 Feb 14;8(1):00481-2021. doi: 10.1183/23120541.00481-2021. eCollection 2022 Jan.

ABSTRACT

BACKGROUND: Fibrotic interstitial lung disease (fILD) has previously been associated with the presence of autoantibody. While studies have focused on systemic autoimmunity, the role of local autoantibodies in the airways remains unknown. We therefore extensively characterised the airway and peripheral autoantibody profiles in patients with fILD, and assessed association with disease severity and outcome.

METHODS: Bronchoalveolar lavage (BAL) fluid was collected from a cohort of fILD patients and total BAL antibody concentrations were quantified. An autoantigen microarray was used to measure IgG and IgA autoantibodies against 122 autoantigens in BAL from 40 idiopathic pulmonary fibrosis (IPF), 20 chronic hypersensitivity pneumonitis (CHP), 20 connective tissue disease-associated ILD (CTD-ILD) patients and 20 controls.

RESULTS: A subset of patients with fILD but not healthy controls had a local autoimmune signature in their BAL that was not present systemically, regardless of disease. The proportion of patients with IPF with a local autoantibody signature was comparable to that of CTD-ILD, which has a known autoimmune pathology, identifying a potentially novel subset of patients. The presence of an airway autoimmune signature was not associated with reduced survival probability or changes in lung function in the cohort as a whole. Patients with IPF had increased BAL total IgA and IgG1 while subjects with CHP had increased BAL IgA, IgG1 and IgG4. In patients with CHP, increased BAL total IgA was associated with reduced survival probability.

CONCLUSION: Airway autoantibodies that are not present systemically identify a group of patients with fILD and the mechanisms by which these autoantibodies contribute to disease requires further investigation.

PMID:35174247 | PMC:PMC8841989 | DOI:10.1183/23120541.00481-2021

Front Mol Biosci. 2022 Jan 31;8:800747. doi: 10.3389/fmolb.2021.800747. eCollection 2021.

ABSTRACT

Background and objective: Idiopathic pulmonary fibrosis (IPF) is an aggressive fibrotic pulmonary disease with spatially and temporally heterogeneous alveolar lesions. There are no early diagnostic biomarkers, limiting our understanding of IPF pathogenesis. Methods: Lung tissue from surgical lung biopsy of patients with early-stage IPF (n = 7), transplant-stage IPF (n = 2), and healthy controls (n = 6) were subjected to mRNA sequencing and verified by real-time quantitative PCR (RT-qPCR), immunohistochemistry, Western blot, and single-cell RNA sequencing (scRNA-Seq). Results: Three hundred eighty differentially expressed transcripts (DETs) were identified in IPF that were principally involved in extracellular matrix (ECM) remodeling, lipid metabolism, and immune effect. Of these DETs, 21 (DMD, MMP7, POSTN, ECM2, MMP13, FASN, FADS1, SDR16C5, ACAT2, ACSL1, CYP1A1, UGT1A6, CXCL13, CXCL5, CXCL14, IL5RA, TNFRSF19, CSF3R, S100A9, S100A8, and S100A12) were selected and verified by RT-qPCR. Differences in DMD, FASN, and MMP7 were also confirmed at a protein level. Analysis of scRNA-Seq was used to trace their cellular origin to determine which lung cells regulated them. The principal cell sources of DMD were ciliated cells, alveolar type I/II epithelial cells (AT cells), club cells, and alveolar macrophages (AMs); MMP7 derives from AT cells, club cells, and AMs, while FASN originates from AT cells, ciliated cells, and AMs. Conclusion: Our data revealed a comprehensive transcriptional mRNA profile of IPF and demonstrated that ECM remodeling, lipid metabolism, and immune effect were collaboratively involved in the early development of IPF.

PMID:35174208 | PMC:PMC8841329 | DOI:10.3389/fmolb.2021.800747

Front Cell Dev Biol. 2022 Jan 31;9:810842. doi: 10.3389/fcell.2021.810842. eCollection 2021.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease attributed to the complex interplay of genetic and environmental risks. The muco-ciliary clearance (MCC) system plays a critical role in maintaining the conduit for air to and from the alveoli, but it remains poorly understood whether the MCC abnormalities in conducting airway are involved in IPF pathogenesis. In this study, we obtained the surgically resected bronchi and peripheral lung tissues from 31 IPF patients and 39 control subjects, and we sought to explore the morphologic characteristics of MCC in conducting airway by using immunostaining and scanning and transmission electron microscopy. In the submucosal regions of the bronchi, we found that the areas of mucus glands (MUC5B+) were significantly larger in IPF patients as compared with control subjects (p < 0.05). In the surface epithelium of three airway regions (bronchi, proximal bronchioles, and distal bronchioles), increased MUC5B and MUC5AC expression of secretory cells, decreased number of ciliated cells, and increased ciliary length were observed in IPF patients than control subjects (all p < 0.05). In addition, the mRNA expression levels of MUC5B were up-regulated in both the bronchi and peripheral lung of IPF patients than those of control subjects (p < 0.05), accompanied with 93.55% IPF subjects who had obvious MUC5B+ mucus plugs in alveolar regions. No MUC5B rs35705950 single-nucleotide polymorphism allele was detected in both IPF patients and control subjects. Our study shows that mucus hypersecretion and ciliary impairment in conducting airway are major causes of mucus plugs in alveolar regions and may be closely related to the alveolar injuries in IPF patients.

PMID:35174169 | PMC:PMC8842394 | DOI:10.3389/fcell.2021.810842

Front Pharmacol. 2022 Jan 31;13:823085. doi: 10.3389/fphar.2022.823085. eCollection 2022.

ABSTRACT

Pulmonary fibrosis is a pathologic process associated with scarring of the lung interstitium. Interstitial lung diseases (ILDs) encompass a large and heterogenous group of disorders, a number of which are characterized by progressive pulmonary fibrosis that leads to respiratory failure and death. Idiopathic pulmonary fibrosis (IPF) has been described as an archetype of progressive fibrosing ILD, and the development of pirfenidone and nintedanib has been a major breakthrough in the treatment of patients with this deadly disease. Both drugs principally target scar-forming fibroblasts and have been shown to significantly slow down the accelerated decline of lung function by approximately 50%. In addition, nintedanib has been approved for patients with other progressive fibrosing ILDs and systemic sclerosis-associated ILD. However, there is still no cure for pulmonary fibrosis and no meaningful improvement of symptoms or quality of life has been shown. Advancement in research, such as the advent of single cell sequencing technology, has identified additional pathologic cell populations beyond the fibroblast which could be targeted for therapeutic purposes. The preclinical and clinical development of novel drug candidates is hampered by profound challenges such as a lack of sensitive clinical outcomes or suitable biomarkers that would provide an early indication of patient benefit. With the availability of these anti-fibrotic treatments, it has become even more difficult to demonstrate added efficacy, in particular in short-term clinical studies. Patient heterogeneity and the paucity of biomarkers of disease activity further complicate clinical development. It is conceivable that future treatment of pulmonary fibrosis will need to embrace more precision in treating the right patient at the right time, explore novel measures of efficacy, and likely combine treatment options.

PMID:35173620 | PMC:PMC8841605 | DOI:10.3389/fphar.2022.823085

Respir Res. 2022 Feb 16;23(1):32. doi: 10.1186/s12931-022-01946-6.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a serious interstitial lung disease with a complex pathogenesis and high mortality. The development of new drugs is time-consuming and laborious; therefore, research on the new use of old drugs can save time and clinical costs and even avoid serious side effects. Nifuroxazide (NIF) was originally used to treat diarrhoea, but more recently, it has been found to have additional pharmacological effects, such as anti-tumour effects and inhibition of inflammatory diseases related to diabetic nephropathy. However, there are no reports regarding its role in pulmonary fibrosis.

METHODS: The therapeutic effect of NIF on pulmonary fibrosis in vivo was measured by ELISA, hydroxyproline content, H&E and Masson staining, immunohistochemistry (IHC) and western blot. Immune cell content in lung tissue was also analysed by flow cytometry. NIF cytotoxicity was evaluated in NIH/3T3 cells, human pulmonary fibroblasts (HPFs), A549 cells and rat primary lung fibroblasts (RPLFs) using the MTT assay. Finally, an in vitro cell model created by transforming growth factor-β1 (TGF-β1) stimulation was assessed using different experiments (immunofluorescence, western blot and wound migration assay) to evaluate the effects of NIF on the activation of NIH/3T3 and HPF cells and the epithelial-mesenchymal transition (EMT) and migration of A549 cells.

RESULTS: In vivo, intraperitoneal injection of NIF relieved and reversed pulmonary fibrosis caused by bleomycin (BLM) bronchial instillation. In addition, NIF inhibited the expression of a variety of cellular inflammatory factors and immune cells. Furthermore, NIF suppressed the activation of fibroblasts and EMT of epithelial cells induced by TGF-β1. Most importantly, we used an analytical docking experiment and thermal shift assay to further verify that NIF functions in conjunction with signal transducer and activator of transcription 3 (Stat3). Moreover, NIF inhibited the TGF-β/Smad pathway in vitro and decreased the expression of phosphorylated Stat3 in vitro and in vivo.

CONCLUSION: Taken together, we conclude that NIF inhibits and reverses pulmonary fibrosis, and these results support NIF as a viable therapeutic option for IPF treatment.

PMID:35172837 | DOI:10.1186/s12931-022-01946-6

Am J Physiol Lung Cell Mol Physiol. 2022 Feb 16. doi: 10.1152/ajplung.00408.2021. Online ahead of print.

ABSTRACT

After lung injury, "damage-associated transient progenitors" (DATPs) emerge, representing a transitional state between injured epithelial cells and newly regenerated alveoli. DATPs express profibrotic genes, suggesting that they might promote idiopathic pulmonary fibrosis (IPF). However, the molecular pathways that induce and/or maintain DATPs are incompletely understood. Here we show that the bifunctional kinase/RNase-IRE1α-a central mediator of the unfolded protein response (UPR) to endoplasmic reticulum (ER) stress is a critical promoter of DATP abundance and function. Administration of a nanomolar-potent, mono-selective kinase inhibitor of IRE1α (KIRA8)-or conditional epithelial IRE1α gene knockout-both reduce DATP cell number and fibrosis in the bleomycin model, indicating that IRE1α cell-autonomously promotes transition into the DATP state. IRE1α enhances the profibrotic phenotype of DATPs, since KIRA8 decreases expression of integrin αvβ6, a key activator of TGFβ in pulmonary fibrosis, corresponding to decreased TGFβ-induced gene expression in the epithelium and decreased collagen accumulation around DATPs. Furthermore, IRE1α regulates DNA damage response (DDR) signaling, previously shown to promote the DATP phenotype, as IRE1α loss-of-function decreases H2AX phosphorylation, Cdkn1a (p21) expression, and DDR-associated secretory gene expression. Finally, KIRA8 treatment increases the differentiation of Krt19CreERT2-lineage-traced DATPs into type 1 alveolar epithelial cells after bleomycin injury, indicating that relief from IRE1α signaling enables DATPs to exit the transitional state. Thus, IRE1α coordinates a network of stress pathways that conspire to entrap injured cells in the DATP state. Pharmacologic blockade of IRE1α signaling helps resolve the DATP state, thereby ameliorating fibrosis and promoting salutary lung regeneration.

PMID:35170357 | DOI:10.1152/ajplung.00408.2021

Clin Oncol (R Coll Radiol). 2022 Feb 12:S0936-6555(22)00080-2. doi: 10.1016/j.clon.2022.01.043. Online ahead of print.

ABSTRACT

Thoracic radiotherapy decisions in patients with interstitial lung disease (ILD) are complex due to concerns about severe or even fatal radiation pneumonitis. This systematic review analysed the published evidence regarding the incidence of radiation pneumonitis and mortality after thoracic radiotherapy and investigated clinical and dosimetric predictors of radiation pneumonitis in lung cancer patients with ILD. A systematic search was carried out in PubMed, Medline, Embase and the Cochrane database for articles published between January 2000 and April 2021. Two authors independently screened eligible studies that met our predefined criteria. Studies were assessed for design and quality and a qualitative data synthesis was carried out. The search strategy resulted in 1750 articles. After two rounds of screening, 24 publications were included. The median overall incidence of grade ≥3 radiation pneumonitis was 19.7% (range 8-46%). The incidence was greater in conventional radical radiotherapy-treated patients (median 31.8%) compared with particle beam therapy- or stereotactic ablative radiotherapy-treated patients (median 12.5%). The median rate of grade 5 radiation pneumonitis was 11.9% (range 0-60%). The presence of ILD was an independent predictor of severe radiation pneumonitis. Severe radiation pneumonitis was more common in the presence of usual interstitial pneumonia (UIP) pattern or idiopathic pulmonary fibrosis (IPF) than non-UIP or non-IPF subtype. Several other clinical predictors were reported in the literature. V5, V10, V20 and mean lung dose were the most common dosimetric predictors for severe radiation pneumonitis, often with stricter dose constraints than conventionally used. Patients with lung cancer associated with ILD had a poorer overall survival compared with patients without ILD. In conclusion, patients with lung cancer associated with ILD have a poor prognosis. They are at high risk of severe and even fatal radiation pneumonitis. Careful patient selection is necessary, appropriate high-risk consenting and strict lung dose-volume constraints should be used, if these patients are to be treated with thoracic radiotherapy.

PMID:35168842 | DOI:10.1016/j.clon.2022.01.043

JCI Insight. 2022 Feb 15:e153672. doi: 10.1172/jci.insight.153672. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is an aging-associated disease characterized by the accumulation of myofibroblasts and progressive lung scarring. To identify transcriptional gene programs driving persistent lung fibrosis in aging, we performed RNA-seq on lung fibroblasts isolated from young and aged mice during the early resolution phase post-bleomycin injury. We discovered that relative to injured young fibroblasts, injured aged fibroblasts exhibited a pro-fibrotic state characterized by elevated expression of genes implicated in inflammation, matrix remodeling, and cell survival. We identified pro-viral integration site of Moloney murine leukemia virus 1 (PIM1) and its target Nuclear Factor of Activated T Cells-1 (NFATc1) as putative drivers of the sustained pro-fibrotic gene signatures in injured aged fibroblasts. PIM1 and NFATc1 transcripts were enriched in a pathogenic fibroblast population recently discovered in IPF lungs, and their protein expression was abundant in fibroblastic foci. Overexpression of PIM1 in normal human lung fibroblasts in vitro potentiated their fibrogenic activation in a NFATc1-dependent manner. Pharmacological inhibition of PIM1 attenuated IPF fibroblast activation and sensitized them to apoptotic stimuli. Inhibition of PIM1 signaling in IPF lung explants ex vivo inhibited pro-survival gene expression and collagen secretion, suggesting that targeting this pathway may represent a therapeutic strategy to block IPF progression.

PMID:35167499 | DOI:10.1172/jci.insight.153672

Lung. 2022 Feb 15. doi: 10.1007/s00408-022-00516-3. Online ahead of print.

NO ABSTRACT

PMID:35166906 | DOI:10.1007/s00408-022-00516-3

Arkh Patol. 2022;84(1):59-66. doi: 10.17116/patol20228401159.

ABSTRACT

The paper presents an X-ray morphological differential diagnosis of idiopathic pulmonary fibrosis (IPF) and fibrotic hypersensitivity pneumonitis (FHP). It describes the etiology, pathogenesis, radiological signs, and pathoanatomy of IPF and FHP. For differential diagnosis, radiological and morphological signs were studied in 105 patients with IPF and in 111 patients with FHP. The mean ages of patients with IPF or FHP were 65.0±8.9 and 48.9±12.3 years, respectively. The history of IPF to the moment of its diagnosis ranged from 1 to 18 months, while that of FHP was 35 to 79 days. The authors describe the additional morphological signs of FHP: delicate collagen fibrosis; smooth muscle metaplasia in the interalveolar septa and fibrotic areas; fibroblastic foci mainly in the walls of bronchioles; plasma cell infiltration of interalveolar septa with a touch of neutrophils and eosinophils. A table has been compiled for differential diagnosis according to the morphological signs of IPF and FHP.

PMID:35166480 | DOI:10.17116/patol20228401159

J Clin Med. 2022 Jan 31;11(3):777. doi: 10.3390/jcm11030777.

ABSTRACT

We previously reported higher ACE2 levels in smokers and patients with COPD. The current study investigates if patients with interstitial lung diseases (ILDs) such as IPF and LAM have elevated ACE2, TMPRSS2, and Furin levels, increasing their risk for SARS-CoV-2 infection and development of COVID-19. Surgically resected lung tissue from IPF, LAM patients, and healthy controls (HC) was immunostained for ACE2, TMPRSS2, and Furin. Percentage ACE2, TMPRSS2, and Furin expression was measured in small airway epithelium (SAE) and alveolar areas using computer-assisted Image-Pro Plus 7.0 software. IPF and LAM tissue was also immunostained for myofibroblast marker α-smooth muscle actin (α-SMA) and growth factor transforming growth factor beta1 (TGF-β1). Compared to HC, ACE2, TMPRSS2 and Furin expression were significantly upregulated in the SAE of IPF (p < 0.01) and LAM (p < 0.001) patients, and in the alveolar areas of IPF (p < 0.001) and LAM (p < 0.01). There was a significant positive correlation between smoking history and ACE2 expression in the IPF cohort for SAE (r = 0.812, p < 0.05) and alveolar areas (r = 0.941, p < 0.01). This, to our knowledge, is the first study to compare ACE2, TMPRSS2, and Furin expression in patients with IPF and LAM compared to HC. Descriptive images show that α-SMA and TGF-β1 increase in the IPF and LAM tissue. Our data suggests that patients with ILDs are at a higher risk of developing severe COVID-19 infection and post-COVID-19 interstitial pulmonary fibrosis. Growth factors secreted by the myofibroblasts, and surrounding tissue could further affect COVID-19 adhesion proteins/cofactors and post-COVID-19 interstitial pulmonary fibrosis. Smoking seems to be the major driving factor in patients with IPF.

PMID:35160229 | DOI:10.3390/jcm11030777

Cells. 2022 Jan 22;11(3):372. doi: 10.3390/cells11030372.

ABSTRACT

Recent studies have suggested that causative variants in telomerase complex genes (TCGs) are present in around 10% of individuals with idiopathic pulmonary fibrosis (IPF) regardless of family history of the disease. However, the studies used a case-control rare variant enrichment study design which is not directly translatable to routine practice. To validate the prevalence results and to establish the individual level, routine clinical practice, and utility of those results we performed next generation sequencing of TCGs on a cohort of well-characterized consecutive individuals with IPF (diagnosis established according to ATS/ERS/JRS/ALAT guidelines). Of 27 IPF patients, three had a family history of idiopathic interstitial pneumonia (familial IPF) and 24 did not (sporadic IPF). Pathogenic/likely-pathogenic variants (according to American College of Medical Genetics criteria) in TCG were found in three individuals (11.1%) of the whole cohort; specifically, they were present in 2 out of 24 (8.3%) of the sporadic and in 1 out of 3 (33.3%) of the patients with familial IPF. Our results, which were established on an individual-patient level study design and in routine clinical practice (as opposed to the case-control study design), are roughly in line with the around 10% prevalence of causative TCG variants in patients with IPF.

PMID:35159182 | DOI:10.3390/cells11030372

Cells. 2022 Jan 20;11(3):346. doi: 10.3390/cells11030346.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is an interstitial pneumonia characterized by chronic progressive fibrosis, ultimately leading to respiratory failure and early mortality. Although not fully explored, the major causative factors in IPF pathogenesis are dysregulated fibroblast proliferation and excessive accumulation of extracellular matrix (ECM) deposited by myofibroblasts differentiated from pulmonary fibroblasts. More signalling pathways, including the PI3K-Akt-mTOR and autophagy pathways, are involved in IPF pathogenesis. Niclosamide ethanolamine salt (NEN) is a highly effective multitarget small-molecule inhibitor reported in antitumor studies. Here, we reported that in an IPF animal model treated with NEN for 14 days, attractive relief of pulmonary function and hydroxyproline content were observed. To further explore, the therapeutic effect of NEN in IPF and pathological changes in bleomycin-challenged mouse lung sections were assessed. Additionally, the effects of NEN on abnormal proliferation and ECM production in IPF cell models established with TGF-β1-stimulated A549 cells or DHLF-IPF cells were studied. In nonclinical studies, NEN ameliorated lung function and histopathological changes in bleomycin-challenged mice, and the lung hydroxyproline content was significantly diminished with NEN treatment. In vitro, NEN inhibited PI3K-mTORC1 signalling and arrested the cell cycle to prevent uncontrolled fibroblast proliferation. Additionally, NEN inhibited TGF-β1-induced epithelial-mesenchymal transition (EMT) and ECM accumulation via the mTORC1-4EBP1 axis. Furthermore, NEN-activated noncanonical autophagy resensitized fibroblasts to apoptosis. The above findings demonstrated the potential antifibrotic effect of NEN mediated via modulation of the PI3K-mTORC1 and autophagy pathways. These data provide strong evidence for a therapeutic role for NEN in IPF.

PMID:35159160 | DOI:10.3390/cells11030346

Cancers (Basel). 2022 Jan 22;14(3):552. doi: 10.3390/cancers14030552.

ABSTRACT

Uncontrolled inflammation is a salient factor in multiple chronic inflammatory diseases and cancers. In this review, we provided an in-depth analysis of the relationships and distinctions between uncontrolled inflammation, fibrosis and cancers, while emphasizing the challenges and opportunities of developing novel therapies for the treatment and/or management of these diseases. We described how drug delivery systems, combination therapy and the integration of tissue-targeted and/or pathways selective strategies could overcome the challenges of current agents for managing and/or treating chronic inflammatory diseases and cancers. We also recognized the value of the re-evaluation of the disease-specific roles of multiple pathways implicated in the pathophysiology of chronic inflammatory diseases and cancers-as well as the application of data from single-cell RNA sequencing in the success of future drug discovery endeavors.

PMID:35158821 | DOI:10.3390/cancers14030552

Eur J Rheumatol. 2022 Feb 14. doi: 10.5152/eurjrheum.2021.21102. Online ahead of print.

ABSTRACT

Interstitial lung disease (ILD) is one of the common extra-articular manifestations of rheumatoid arthritis (RA) and it is associated with high mortality rate. The usual interstitial pneumonia (UIP) pattern of RA associated ILD (RA-ILD) shows some similarities to idiopathic pulmonary fibrosis, suggesting that antifibrotic therapies may have potential positive affects. In this review, we discuss the effectiveness of antifibrotic therapy for RA-ILD.

PMID:35156636 | DOI:10.5152/eurjrheum.2021.21102

Pulmonology. 2022 Feb 10:S2531-0437(22)00002-2. doi: 10.1016/j.pulmoe.2021.12.001. Online ahead of print.

ABSTRACT

BACKGROUND: Human telomerase reverse transcriptase (hTERT) is the catalytic subunit of telomerase enzyme, which adds nucleotides to telomeres and counteracts their length shortening. The development of a telomere maintenance mechanism represents a hallmark of cancer. On the other hand, idiopathic pulmonary fibrosis (IPF) is associated with mutations in telomerase genes and shorter telomeres. IPF is frequently complicated with lung cancer.

AIM: To investigate the expression of hTERT in lung cancer with co-existing IPF and to compare with lung cancer without fibrosis.

METHODS: Diagnostic lung cancerous biopsies were retrieved from 18 patients with lung cancer and concomitant IPF, as well as 18 age and gender matched controls with lung cancer without pulmonary fibrosis. The expression of hTERT was studied with immunohistochemistry. ImajeJ software was used to quantitate subcellular stain intensity. Immunohistochemical investigation of two senescence-associated markers, p16 and p21, was also performed in all 36 cases.

RESULTS: Both groups highly expressed hTERT, without significant difference (100% vs 95%, p = 0.521). Evaluation of p16 and p21 immunostaining revealed negative to minimal immunoreactivity in both groups. hTERT localization exhibited higher median nuclear intensity in the group of lung cancer with IPF (0.62 vs 0.45, p = 0.016), while cytoplasmic intensity did not differ significantly (0.17 vs 0.15, p = 0.463). Higher median nuclear intensity was also correlated with small cell lung cancer subtype in the whole study sample (0.69 vs 0.45, p = 0.09).

CONCLUSION: hTERT is highly expressed in lung cancer with concomitant IPF, but with differential localization compared to lung cancer without IPF, implying differences in pathogenicity and requiring further investigation.

PMID:35153179 | DOI:10.1016/j.pulmoe.2021.12.001

Physiother Theory Pract. 2022 Feb 12:1-9. doi: 10.1080/09593985.2022.2032510. Online ahead of print.

ABSTRACT

BACKGROUND: Patients with idiopathic pulmonary fibrosis (IPF) often present with dyspnea, fatigue, and desaturation. These symptoms can be highly limiting, as they lead to a decrease in performing activities of daily living (ADL). Therefore, it is essential to evaluate the degree of functional limitation of these individuals.

OBJECTIVE: The present study aimed to evaluate the validity and reliability of the Glittre-ADL test (TGlittre) and its association with self-reported limitation in ADL and health-related quality of life (HRQoL) in patients with IPF.

METHODS: Twenty-seven individuals with IPF (60.5 ± 10.6 years), with forced vital capacity 2.26 ± 1.03 L (51.09 ± 20.62% of predicted) were assessed for the time spent in TGlittre, 6-minute walking distance (6MWD), limitation in ADL and HRQoL.

RESULTS: TGlittre was reliable (intraclass correlation coefficient3,1 = 0.96; P < .001); however, a learning effect of 10.6% was observed between the first and second execution of TGlittre. The time spent in TGlittre correlated with 6MWD, limitation in ADL, and disease-specific HRQoL (P < .05).

CONCLUSION: TGlittre is valid and reliable for assessing functional capacity in patients with IPF. Still, it presents a learning effect and should be performed twice when assessing functional capacity in clinical practice.

PMID:35152825 | DOI:10.1080/09593985.2022.2032510

J Biol Chem. 2022 Feb 9:101709. doi: 10.1016/j.jbc.2022.101709. Online ahead of print.

ABSTRACT

Pulmonary surfactant is a lipoprotein complex essential for lung function, and insufficiency or altered surfactant composition is associated with major lung diseases such as acute respiratory distress syndromes, idiopathic pulmonary fibrosis, and chronic obstructive pulmonary disease. Pulmonary surfactant is primarily composed of phosphatidylcholine (PC) in complex with specialized surfactant proteins and secreted by Alveolar Type 2 cells (AT2). Surfactant homeostasis on the alveolar surface is balanced by the rates of synthesis and secretion with re-uptake and recycling by AT2 cells, with some degradation by pulmonary macrophages and loss up the bronchial tree. However, whether phospholipid transporters exist in AT2 cells to mediate re-uptake of surfactant phospholipid remains to be identified. Here, we demonstrate that Major Facilitator Superfamily Domain containing 2a (Mfsd2a), a sodium-dependent lysophosphatidylcholine (LPC) transporter, is expressed at the apical surface of AT2 cells. A mouse model with inducible AT2 cell-specific deficiency of Mfsd2a exhibited AT2 cell hypertrophy with reduced total surfactant phospholipid levels due to reductions in the most abundant surfactants, phosphatidylcholine containing di-palmitic acid and phosphatidylcholine species containing the omega-3 fatty acid docosahexaenoic acid. These changes in surfactant levels and composition were mirrored by similar changes in the AT2 cell lipidome. Mechanistically, direct tracheal instillation of fluorescent LPC and PC probes indicated that Mfsd2a mediates the uptake of LPC generated by pulmonary phospholipase activity in the alveolar space. These studies reveal that Mfsd2a-mediated LPC uptake is quantitatively important in maintaining surfactant homeostasis and identify this lipid transporter as a physiological component of surfactant recycling.

PMID:35150739 | DOI:10.1016/j.jbc.2022.101709