Front Genet. 2022 Apr 26;13:865052. doi: 10.3389/fgene.2022.865052. eCollection 2022.

ABSTRACT

Background: Increasing evidence has revealed that epithelial-mesenchymal transition (EMT) and immunity play key roles in idiopathic pulmonary fibrosis (IPF). However, correlation between EMT and immune response and the prognostic significance of EMT in IPF remains unclear. Methods: Two microarray expression profiling datasets (GSE70866 and GSE28221) were downloaded from the Gene Expression Omnibus (GEO) database. EMT- and immune-related genes were identified by gene set variation analysis (GSVA) and the Estimation of STromal and Immune cells in MAlignant Tumors using Expression data (ESTIMATE) algorithm. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to investigate the functions of these EMT- and immune-related genes. Cox and least absolute shrinkage and selection operator (LASSO) regression analyses were used to screen prognostic genes and establish a gene signature. Gene Set Enrichment Analysis (GSEA) and Cell-type Identification By Estimating Relative Subsets Of RNA Transcripts (CIBERSORT) were used to investigate the function of the EMT- and immune-related signatures and correlation between the EMT- and immune-related signatures and immune cell infiltration. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to investigate the mRNA expression of genes in the EMT- and immune-related signatures. Results: Functional enrichment analysis suggested that these genes were mainly involved in immune response. Moreover, the EMT- and immune-related signatures were constructed based on three EMT- and immune-related genes (IL1R2, S100A12, and CCL8), and the K-M and ROC curves presented that the signature could affect the prognosis of IPF patients and could predict the 1-, 2-, and 3-year survival well. Furthermore, a nomogram was developed based on the expression of IL1R2, S100A12, and CCL8, and the calibration curve showed that the nomogram could visually and accurately predict the 1-, 2-, 3-year survival of IPF patients. Finally, we further found that immune-related pathways were activated in the high-risk group of patients, and the EMT- and immune-related signatures were associated with NK cells activated, macrophages M0, dendritic cells resting, mast cells resting, and mast cells activated. qRT-PCR suggested that the mRNA expression of IL1R2, S100A12, and CCL8 was upregulated in whole blood of IPF patients compared with normal samples. Conclusion: IL1R2, S100A12, and CCL8 might play key roles in IPF by regulating immune response and could be used as prognostic biomarkers of IPF.

PMID:35559024 | PMC:PMC9086533 | DOI:10.3389/fgene.2022.865052

Multidiscip Respir Med. 2022 Apr 26;17(1):848. doi: 10.4081/mrm.2022.848. eCollection 2022 Jan 12.

ABSTRACT

BACKGROUND: Interstitial lung diseases (ILDs) comprise a group of multiple entities sharing some clinical, functional, and radiological similarities. In many countries primary care setting has been devoid of pre- and post-graduate educational interventions focused on basic knowledge on ILD. This, along with usual nonspecificity of symptoms at presentation, may contribute to diagnostic delay in this disease setting.

METHODS: We designed a study questionnaire to assess the level of awareness on basic diagnostic and management aspects of core ILDs - idiopathic pulmonary fibrosis (IPF), hypersensitivity pneumonitis, sarcoidosis, connective tissue disease related-ILD, and drug-induced ILD - among primary care physicians (GPs) from five "ACeS Baixo Vouga" health centres and to perceive possible weaknesses. Differences in awareness between GPs under 45 and over 45 yearsold were also assessed.

RESULTS: Globally, 69% of questions were correctly answered but only 21.9% of GPs considered to have a satisfactory self-perceived level of knowledge on ILD. Except sarcoidosis (p=0.017) and some isolated questions on other diseases, no significant differences were found between physicians below 45 years and above. Though, there was a trend to higher awareness in the younger group. The best awareness was seen in sarcoidosis. IPF questions had the worst performance and only 48.5% of GPs recognized the importance of velcro-type crackles in suggesting a possible diagnosis.

CONCLUSION: Specific attention should be devoted to educational interventions directed to GPs on basic notions on the main ILDs. This could improve the usual diagnostic delay in many ILDs, as a timely diagnosis is essential for an early treatment and prolonged patient survival.

PMID:35558644 | PMC:PMC9088858 | DOI:10.4081/mrm.2022.848

FASEB J. 2022 May;36 Suppl 1. doi: 10.1096/fasebj.2022.36.S1.R3541.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease characterized by alveolar type II (AT2) cell dysfunction. Mutations in surfactant protein C (SP-C) are a high effect size, recognized etiological cause of IPF. The SP-C proprotein contains an ~100 KDa Bri2 chondromodulin-1 and prosurfactant protein C (BRICHOS) domain that acts as a molecular chaperone preventing protein aggregation. The presence of misfolded proteins in the ER can be sensed by three transmembrane sentinel proteins - activating transcription factor 6 (ATF6), protein kinase R-like ER kinase (PERK), and inositol-requiring enzyme 1α (IRE1α) - which trigger an intracellular signaling pathway called the unfolded protein response (UPR). Previous characterization of our in-vitro and in-vivo models has demonstrated that BRICHOS mutants activate all 3 arms of the UPR, activate a proinflammatory cascade, and drive AT2 cell death. In-vivo, their expression initiates pathological fibroproliferative lung remodeling, characteristic of human IPF. Using our in-vitro models of BRICHOS-driven ER stress, we explore potential IPF therapeutic intervention targeting two upstream sensors of the UPR, PERK and IRE-1. Mouse lung epithelial (MLE-12) cells were transfected with wildtype (WT) or BRICHOS mutant (C121G) SP-C plasmids in media containing inhibitors of either PERK signaling or IRE-1 RNase activity. Pathway readouts included: quantification of cell death via LDH cytotoxicity and flow cytometry, protein immunoblots to detect UPR activation and apoptotic signaling, QPCR of spliced X-Box Binding Protein 1 (XBP1) and UPR transcriptional targets, and high-resolution microscopy to observe altered SP-C trafficking. Within 48 hours of transfection of MLE-12 cells with SP-CC121G we observed activation of the 3 arms of the UPR, upregulated downstream targets, and initiation of cell death. Inhibition of PERK resulted in down-regulation of PERK pathway proteins and transcriptional targets, increased SP-C protein expression, and promoted increased XBP1 splicing. Inhibition of IRE1 RNase inhibited splicing of XBP1, reduced expression of XBP1 transcriptional targets, and increased JNK phosphorylation. Inhibition of either pathway alone did not reduce cell death, though partial reduction of cell death was noted with either small molecule targeted caspase 3/8 or necroptosis inhibition. Our data suggests that while intervention directed at one arm of the UPR may block proinflammatory signaling or transcriptomic reprogramming, this strategy may not be sufficient to completely inhibit cell death. These findings highlight the interconnectivity and redundancy of the cell quality control machinery and the emerging role of necroptosis due to chronic UPR stress-mediated cell death. Further characterization of this pathway is needed to improve IPF therapeutic outcomes.

PMID:35556347 | DOI:10.1096/fasebj.2022.36.S1.R3541

Eur J Nucl Med Mol Imaging. 2022 May 12. doi: 10.1007/s00259-022-05814-9. Online ahead of print.

ABSTRACT

PURPOSE: The lack of effective molecular biomarkers to monitor idiopathic pulmonary fibrosis (IPF) activity or treatment response remains an unmet clinical need. Herein, we determined the utility of fibroblast activation protein inhibitor for positron emission tomography (FAPI PET) imaging in a mouse model of pulmonary fibrosis.

METHODS: Pulmonary fibrosis was induced by intratracheal administration of bleomycin (1 U/kg) while intratracheal saline was administered to control mice. Subgroups from each cohort (n = 3-5) underwent dynamic 1 h PET/CT after intravenously injecting FAPI-46 radiolabeled with gallium-68 ([68 Ga]Ga-FAPI-46) at 7 days and 14 days following disease induction. Animals were sacrificed following imaging for ex vivo gamma counting and histologic correlation. [68 Ga]Ga-FAPI-46 uptake was quantified and reported as percent injected activity per cc (%IA/cc) or percent injected activity (%IA). Lung CT density in Hounsfield units (HU) was also correlated with histologic examinations of lung fibrosis.

RESULTS: CT only detected differences in the fibrotic response at 14 days post-bleomycin administration. [68 Ga]Ga-FAPI-46 lung uptake was significantly higher in the bleomycin group than in control subjects at 7 days and 14 days. Significantly (P = 0.0012) increased [68 Ga]Ga-FAPI-46 lung uptake in the bleomycin groups at 14 days (1.01 ± 0.12%IA/cc) vs. 7 days (0.33 ± 0.09%IA/cc) at 60 min post-injection of the tracer was observed. These findings were consistent with an increase in both fibrinogenesis and FAP expression as seen in histology.

CONCLUSION: CT was unable to assess disease activity in a murine model of IPF. Conversely, FAPI PET detected both the presence and activity of lung fibrogenesis, making it a promising tool for assessing early disease activity and evaluating the efficacy of therapeutic interventions in lung fibrosis patients.

PMID:35556159 | DOI:10.1007/s00259-022-05814-9

FASEB J. 2022 May;36 Suppl 1. doi: 10.1096/fasebj.2022.36.S1.R5020.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing interstitial pneumonia of unknown origin. Fibrosis, a wound healing process, occurs when fibroblasts increase proliferation, convert to myofibroblasts, and secrete extracellular matrix (ECM) proteins. As a result, tissue becomes scarred, reducing lung compliance and ultimately leads to organ dysfunction and death. IFP is characterized by profibrotic agonists and alpha-smooth muscle actin (α-SMA) expression. TGF-β, IL-1β, LPA, 5-HT are agonists involved in cell migration regulation, proliferation, and cytokine production. Chronic agonists exposure causes α-SMA expression which stiffens fibrotic tissue alongside ECM proteins. Prior studies have shown that the sodium hydrogen exchanger isoform 1 (NHE1) is a key regulator in cell migration and pathophysiological development of cancer. The characteristics of IFP are similar to that of cancer (i.e., response to growth signals, myofibroblast origin and behavior, altered cellular communications, and intercellular signaling pathways). Due to these similarities, we hypothesize that NHE1 plays a key role in IFP progression. Results show fibroblast to myofibroblast differentiation is induced in the presence of NHE1 and can also be blocked by the NHE1 inhibitor (EIPA) in mammalian hamster cells. Cells treated with agonists showed some to high α-SMA expression. Cells treated with agonist and EIPA had no expression of α-SMA (TGF-β/EIPA: 35.67 ± 1.76; IL-1β/EIPA: 11.67 ± 2.03, LPA/EIPA: 33.33 ± 2.19, 5HT/EIPA: 30.00 ± 1.15), and is comparable to the untreated control (20.83 ± 3.12). This improves our understanding of NHE1's role in IPF, and how NHE1 can be a target to impede or hopefully reverse myofibroblast differentiation in IPF patients.

PMID:35555717 | DOI:10.1096/fasebj.2022.36.S1.R5020

FASEB J. 2022 May;36 Suppl 1. doi: 10.1096/fasebj.2022.36.S1.R5278.

ABSTRACT

Idiopathic Pulmonary Fibrosis (IPF) is a progressive lung disease characterized by the deregulation of the wound healing process leaving an accumulation of fibroblasts and scarring tissue. Fibroblasts, under normal conditions, support growth and health of connective tissues and maintain the extracellular matrix (ECM). However, as the disease progresses, increases in profibrotic agonists lead to activation of fibroblasts causing stiffening of the cells, increasing in secretion of ECM proteins in the bronchial. The chronic nature of the disease leads fibroblast differentiating into myofibroblast cells making the tissue less compliant. The affected patient's alveolar architecture becomes damaged which then leads to lung inflexibility, disruption of gas exchange, respiratory failure, and death. Sodium Hydrogen Exchanger Isoform 1 (NHE1) is an ion transporter protein found in the membrane that mediates cellular pH, cell migration, and cytoskeletal anchoring. NHE1 has also been found to impact the pathophysiological development of cancer and other diseases. Interestingly, a number of signaling pathways which contribute to the activation of tumor cells are also involved in profibrotic behavior in fibroblasts and myofibroblast, the purpose of this study was to investigate if NHE1 worsened IPF and if inhibiting NHE1 would decrease the profibrotic activity of fibrosis. We measured two of the indicators of progressing fibrosis: the remodeling of skeletal proteins through formation of actin stress fibers, and the production and secretion of ECM proteins such as collagen and fibronectin. Actin stress fibers have an important role in cell migration and contractility. To stimulate this formation, cells were treated with three agonists that have all been found to increase fibrotic activity: Transforming Growth Factor-β (TGF-β), Serotonin (5HT), and Lysophosphatidic Acid (LPA) in the presence and absence of Ethyl-Isopropyl Amiloride (EIPA), a NHE1 inhibitor. LPA induced stress fibers 43.94 +/- 4.4 % over the control, and both TGF-β and 5HT also stimulated the formation of stress fibers by 32.08 +/- 2.1 and 39.1 +/- 4.2 %, respectively, over the control non-treated cells. In each case, the addition of EIPA blocked stress fibers indicating that all three profibrotic factors required NHE1 activity for cytoskeletal remodeling. Additionally, when any combination of agonists were added in combination or a mixture of all three, it was observed that these combinations seemed to block stress fiber formation in comparison to the control. An initial interpretation hints at a competitive or feed-back loop to controlling fibrosis. The role of NHE1 in TGF- β induced fibroblast-myofibroblast differentiation is also determined and is identified with expression of alpha smooth muscle actin (α-SMA) with and without EIPA. Finally, the role of NHE1 in production and secretion of ECM proteins, such as collagen and fibronectin, were investigated to detect changes in these proteins in the presence and absence of agonists and EIPA. This work highlights that NHE1 has a role in supporting profibrotic behavior and may be a novel target to fight IPF.

PMID:35555705 | DOI:10.1096/fasebj.2022.36.S1.R5278

FASEB J. 2022 May;36 Suppl 1. doi: 10.1096/fasebj.2022.36.S1.L7685.

ABSTRACT

Age is a risk factor for many diseases including idiopathic pulmonary fibrosis (IPF) by affecting wound healing through abnormal fibrogenesis. Common cellular and molecular traits associated with aging can be found in senescent cells, which may occur throughout the lifespan playing physiological roles during normal development or limiting the proliferation of damaged and aged cells. In this study we investigated in smoking mice whether the senescence of lung cells, triggered by the oxidative stress response, is associated with molecular pathways that can influence lung fibrogenesis and contribute to the remodeling of the fibrotic tissue characterizing some phenotypes of COPD in humans. Among the complex mixture of hundreds senescence secreted factors that include proinflammatory cytokines, chemokines, growth factors, and proteases, we selected important factors involved in differentiation of myofibroblasts, their dedifferentiation and apoptosis, as well as in their metabolic function. The expression of these factors and the amount of matrix deposition was analyzed after chronic cigarette smoke (CS) exposure of C57 Bl/6 and DBA/2 mice sensitive to oxidative, in different lung compartmentscharacterized by a fibrotic remodeling using histochemistry or immunohistochemistry. Unlike C57 Bl/6, DBA/2 mice at 4 months of exposure show marked positivity for 8-OHdG, a marker of oxidative damage, in subpleural areas, in central parts of the lung parenchyma, on airways and on cells of the fibro-muscular layer. In these areas, a marked positivity is observed for fibrogenic cytokines such as TGF-β, PDGF-b and CTGF, and for other factors such as the p16ink4A senescence marker, and proliferation markers PCNA and Ki67. In DBA/2 mice, these compartments are characterized by a progressive fibrous remodeling at various experimental time points from 5 months of CS exposure onwards as demonstrated by Masson's trichrome staining. Fibroproliferative foci are present in sub-pleural areas, in peripheral areas of airways, and in central parts of the lung parenchyma. They are characterized by increasing number of α-SMA positive myofibroblasts, which express the senescence marker p16ink4A and the transcription factor MyoD that plays a crucial role in myoblast proliferation and differentiation. MyoD induces cell cycle arrest, promotes cellular terminal differentiation of fibroblasts into myofibroblasts, and in senescent myofibroblasts it has been reported to determine resistance to apoptosis and opposes their dedifferentiation. All these factors contribute to the development in smoking DBA/2 mice of lung lesions, which are like those seen in patients with "Combined Fibrosis/Emphysema Syndrome." Despite consistent levels of TGF-β, PDGF-b and CTGF, C57 Bl/6 mice develop after chronic CS exposure fibrotic remodeling at lower extent. Of interest, a very low expression of factors indicative of senescence (p16ink4A and MyoD) and cell proliferation (PCNA and Ki67) is observed. Our results suggest that apoptosis, senescence, and proliferation induced at different rate by fibrotic cytokines and senescence associated secretory factors play important role in early or late appearance of fibrotic remodeling of lung and airways exposed to CS.

PMID:35555197 | DOI:10.1096/fasebj.2022.36.S1.L7685

FASEB J. 2022 May;36 Suppl 1. doi: 10.1096/fasebj.2022.36.S1.R6252.

ABSTRACT

INTRODUCTION: Microvascular stability is highly dependent on endothelial cell-pericyte coupling. In fibrotic diseases, such as idiopathic pulmonary fibrosis (IPF), extracellular matrix stiffening and elevated concentrations of profibrotic factors, such as TGF-β, can disrupt this cell-cell communication. Treatment of IPF with the antifibrotic drug Nintedanib, which targets PDGF-βR, FGF-R, and VEGF-R signaling, may counteract these effects to strengthen endothelial cell-pericyte coupling and promote microvessel stability1,2 . We have developed a multi-scale computational model that simulates intracellular signaling in endothelial cells and pericytes, heterotypic cell-cell communication, and the dynamic lung microenvironment to study how Nintedanib2 and other drugs affect microvascular network remodeling in IPF. We hypothesize that blocking PDGF-βR and FGF-R signaling with Nintedanib is sufficient to rescue TGF-β-induced endothelial cell-pericyte decoupling.

MATERIALS AND METHODS: The multi-scale model is comprised of logic-based ordinary differential equations representing intracellular signaling networks in both endothelial cells and pericytes integrated into an agent-based model representing the lung environment wherein the simulated cells interact with one another, sensing and dynamically altering their microenvironment (Figure 1). The logic-based network signaling models were developed using the Netflux3 toolkit in MATLAB. The agent-based model of the spatiotemporal 2D lung environment was constructed in NetLogo4 . The multi-scale model was created by linking the logic-based network models with the agent-based model using the NL4Py5 package in Python.

RESULTS AND DISCUSSION: Endothelial cell-pericyte decoupling was signified by decreased N-cadherin expression in pericytes, increased αSMA and Col1mRNA (indicating possible pericyte-to-myofibroblast transition), and increased physical separation and distances between endothelial cells and pericytes. The multi-scale model predicted that increasing TGF-β concentrations significantly elevated αSMA and Col1mRNA expression in simulated pericytes. N-cadherin levels did not change in response to TGF-β or Nintedanib treatment in the network model of the pericyte alone but were affected by the presence of endothelial cells in the agent-based model, highlighting the importance of endothelial cell-pericyte interactions in determining pericyte behaviors.

CONCLUSIONS: Our multi-scale model demonstrates the importance of considering endothelial cell-pericyte communication in predicting cellular responses to pro-fibrotic environments. By representing intracellular biochemical signaling networks, heterotypic cell interactions, and the dynamic multi-cell microenvironment, we were able to demonstrate a potential mechanism through which Nintedanib treatment affects endothelial cell-pericyte coupling in IPF.

REFERENCES: 1) Hanumegowda, C., et al.; Chest. 2012 2) Wollin, L., et al.; Eur Respir J. 2015 3) Kraeutler, MJ., et al.; BMC Syst Biol. 2010 4) Sklar, E., Artif. Life 2007 5) Gunaratne, C.; 2018. NL4Py.

PMID:35554306 | DOI:10.1096/fasebj.2022.36.S1.R6252

Mil Med Res. 2022 May 12;9(1):21. doi: 10.1186/s40779-022-00382-3.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a fatal chronic interstitial lung disease with no established treatment and is characterized by progressive scarring of the lung tissue and an irreversible decline in lung function. Chronic inflammation has been demonstrated to be the pathological basis of fibrosis. Emerging studies have revealed that most interleukin-17 (IL-17) isoforms are essential for the mediation of acute and chronic inflammation via innate and adaptive immunity. Overexpression or aberrant expression of IL-17 cytokines contributes to various pathological outcomes, including the initiation and exacerbation of IPF. Here, we aim to provide an overview of IL-17 family members in the pathogenesis of IPF.

PMID:35550651 | DOI:10.1186/s40779-022-00382-3

BMC Pulm Med. 2022 May 12;22(1):190. doi: 10.1186/s12890-022-01973-5.

ABSTRACT

BACKGROUND: Cardiovascular disease is prevalent in idiopathic pulmonary fibrosis (IPF), yet the extent of left-sided heart failure (HF) burden, whether this has changed with time and whether HF impacts mortality risk in these patients are unknown. The aims of this study were therefore to determine the temporal trends in incidence and prevalence of left-sided HF in patients with IPF in England and compare these to published estimates in the general population and those with comparable chronic respiratory conditions such as chronic obstructive pulmonary disease (COPD), as well as determine the risk of all-cause and cause-specific mortality in patients with comorbid left-sided HF and IPF at population-level using electronic healthcare data.

METHODS: Clinical Practice Research Datalink (CPRD) Aurum primary-care data linked to mortality and secondary-care data was used to identify IPF patients in England. Left-sided HF prevalence and incidence rates were calculated for each calendar year between 2010 and 2019, stratified by age and sex. Risk of all-cause, cardiovascular and IPF-specific mortality was calculated using multivariate Cox regression.

RESULTS: From 40,577patients with an IPF code in CPRD Aurum, 25, 341 IPF patients met inclusion criteria. Left-sided HF prevalence decreased from 33.4% (95% CI 32.2-34.6) in 2010 to 20.9% (20.0-21.7) in 2019. Left-sided HF incidence rate per 100 person-years (95% CI) remained stable between 2010 and 2017 but decreased from 4.3 (3.9-4.8) in 2017 to 3.4 (3.0-3.9) in 2019. Throughout follow-up, prevalence and incidence were higher in men and with increasing age. Comorbid HF was associated with poorer survival (adjusted HR (95%CI) 1.08 (1.03-1.14) for all-cause mortality; 1.32 (1.09-1.59) for cardiovascular mortality).

CONCLUSION: Left-sided HF burden in IPF patients in England remains high, with incidence almost 4 times higher than in COPD, a comparable lung disease with similar cardiovascular risk factors. Comorbid left-sided HF is also a poor prognostic marker. More substantial reduction in left-sided HF prevalence than incidence suggests persistently high IPF mortality. Given rising IPF incidence in the UK, this calls for better management of comorbidities such as left-sided HF to help optimise IPF survival.

PMID:35549901 | DOI:10.1186/s12890-022-01973-5

Am J Respir Cell Mol Biol. 2022 May 12. doi: 10.1165/rcmb.2021-0246OC. Online ahead of print.

ABSTRACT

IPF is a devastating lung disease with limited therapeutic possibilities. FGF19, an endocrine FGF, was recently shown to decrease liver fibrosis. To ask whether FGF19 had anti-fibrotic properties in the lung and decipher its effects on common features associated with lung fibrogenesis. We assessed, by Elisa, FGF19 levels in plasma and bronchoalveolar lavage fluids (BALF)obtained from controls and IPF patients. In vivo, using an intravenously administered adeno11 associated virus (AAV), we overexpressed FGF19 at the fibrotic phase of two experimental models of murine lung fibrosis and assessed its effect on lung morphology, lung collagen content, fibrosis markers and pro fibrotic mediator expression, at mRNA and protein levels. In vitro, we investigated whether FGF19 could modulate the TGFβ-induced differentiation of primary human lung fibroblast into myofibroblast and the apoptosis of murine alveolar type II cell. While FGF19 was not detected in BALF, FGF19 concentration was decreased in the plasma of IPF patients compared to controls. In vivo, the overexpression of FGF19 was associated with a marked decrease of lung fibrosis and fibrosis markers, with a decrease of pro fibrotic mediator expression and lung collagen content. In vitro, FGF19 decreased alveolar type 2 epithelial cell apoptosis through the decrease of the proapoptotic BIM protein expression and prevented TGF-ß induced myofibroblast differentiation through the inhibition of JNK phosphorylation. Altogether these data identify FGF19 as an anti-fibrotic molecule with a potential therapeutic interest in fibrotic lung disorders.

PMID:35549849 | DOI:10.1165/rcmb.2021-0246OC

Am J Respir Crit Care Med. 2022 May 12. doi: 10.1164/rccm.202202-0350LE. Online ahead of print.

NO ABSTRACT

PMID:35549841 | DOI:10.1164/rccm.202202-0350LE

Am J Respir Crit Care Med. 2022 May 12. doi: 10.1164/rccm.202203-0502LE. Online ahead of print.

NO ABSTRACT

PMID:35549837 | DOI:10.1164/rccm.202203-0502LE

Front Pharmacol. 2022 Apr 25;13:882678. doi: 10.3389/fphar.2022.882678. eCollection 2022.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease characterized by progressive and irreversible loss of lung function. Clinically safe and efficacious drug treatments for IPF are lacking. Pirfenidone (an anti-inflammatory, antioxidant and anti-fibrotic small-molecule drug) is considered a promising treatment for IPF. Unfortunately, several disadvantages of pirfenidone caused by traditional administration (e.g., gastrointestinal reactions, short elimination half-life) hinder its implementation. We designed pirfenidone pH-sensitive liposomes (PSLs) to target the acidic microenvironment of IPF and act directly at the disease site through pulmonary administration. Pirfenidone was encapsulated in liposomes to extend its half-life, and modified with polyethylene glycol on the surface of liposomes to improve the permeability of the mucus layer in airways. In vitro, the cytotoxicity of pirfenidone PSLs to pulmonary fibroblasts was increased significantly at 48 h compared with that using pirfenidone. In a murine and rat model of bleomycin-induced pulmonary fibrosis, pirfenidone PSLs inhibited IPF development and increased PSL accumulation in the lungs compared with that using pirfenidone solution or phosphate-buffered saline. Pirfenidone PSLs had potentially fewer side effects and stronger lung targeting. These results suggest that pirfenidone PSLs are promising preparations for IPF treatment.

PMID:35548360 | PMC:PMC9081653 | DOI:10.3389/fphar.2022.882678

Zhonghua Jie He He Hu Xi Za Zhi. 2022 May 12;45(5):453-459. doi: 10.3760/cma.j.cn112147-20210917-00655.

ABSTRACT

Objective: To raise the awareness of idiopathic pleuroparenehymal fibroelastosis (iPPFE) through investigating the clinical, radiographic and pathological features. Methods: Five cases of iPPFE proved by pathology. The clinical data were studied respectively, and the relevant literature was reviewed. Results: All the cases of iPPFE were manifested by cough and dyspnea. The patients including 3 males and 2 females, aged from 30 to 70 years Chest CT scan showed pleural thickening, subpleural consolidation in both upper lungs complicated with tractive bronchiectasis.Computed tomography-guided percutaneous lung biopsy or surgical lung were performed and the same pathological showed pleura and subpleural dense elastic and collagen fibers. The elastic fibers stain was also positive,which was consistent with PPFE. One patient received low-dose corticosteroid, two received pirfenidone therapy, the others received no treatment. Three patients were stable during the follow-up. Conclusions: iPPFE has characteristic pathological features. However, the number of clinically reported cases is low due to missed diagnosis or misdiagnosed. Improving the understanding of features of iPPFE is helpful for the dianosis, therapy, and prognosis of this disease.

PMID:35527460 | DOI:10.3760/cma.j.cn112147-20210917-00655

Thorax. 2022 May 9:thoraxjnl-2021-218563. doi: 10.1136/thoraxjnl-2021-218563. Online ahead of print.

ABSTRACT

BACKGROUND: Considerable clinical heterogeneity in idiopathic pulmonary fibrosis (IPF) suggests the existence of multiple disease endotypes. Identifying these endotypes would improve our understanding of the pathogenesis of IPF and could allow for a biomarker-driven personalised medicine approach. We aimed to identify clinically distinct groups of patients with IPF that could represent distinct disease endotypes.

METHODS: We co-normalised, pooled and clustered three publicly available blood transcriptomic datasets (total 220 IPF cases). We compared clinical traits across clusters and used gene enrichment analysis to identify biological pathways and processes that were over-represented among the genes that were differentially expressed across clusters. A gene-based classifier was developed and validated using three additional independent datasets (total 194 IPF cases).

FINDINGS: We identified three clusters of patients with IPF with statistically significant differences in lung function (p=0.009) and mortality (p=0.009) between groups. Gene enrichment analysis implicated mitochondrial homeostasis, apoptosis, cell cycle and innate and adaptive immunity in the pathogenesis underlying these groups. We developed and validated a 13-gene cluster classifier that predicted mortality in IPF (high-risk clusters vs low-risk cluster: HR 4.25, 95% CI 2.14 to 8.46, p=3.7×10-5).

INTERPRETATION: We have identified blood gene expression signatures capable of discerning groups of patients with IPF with significant differences in survival. These clusters could be representative of distinct pathophysiological states, which would support the theory of multiple endotypes of IPF. Although more work must be done to confirm the existence of these endotypes, our classifier could be a useful tool in patient stratification and outcome prediction in IPF.

PMID:35534152 | DOI:10.1136/thoraxjnl-2021-218563

Semin Respir Crit Care Med. 2022 May 9. doi: 10.1055/s-0042-1747966. Online ahead of print.

ABSTRACT

The administration of exogenous oxygen to support adequate gas exchange is the cornerstone of respiratory care. In the past few years, other gaseous molecules have been introduced in clinical practice to treat the wide variety of physiological derangement seen in critical care patients.Inhaled nitric oxide (NO) is used for its unique selective pulmonary vasodilator effect. Recent studies showed that NO plays a pivotal role in regulating ischemia-reperfusion injury and it has antibacterial and antiviral activity.Helium, due to its low density, is used in patients with upper airway obstruction and lower airway obstruction to facilitate gas flow and to reduce work of breathing.Carbon monoxide (CO) is a poisonous gas that acts as a signaling molecule involved in many biologic pathways. CO's anti-inflammatory and antiproliferative effects are under investigation in the setting of acute respiratory distress and idiopathic pulmonary fibrosis.Inhaled anesthetics are widely used in the operative room setting and, with the development of anesthetic reflectors, are now a valid option for sedation management in the intensive care unit.Many other gases such as xenon, argon, and hydrogen sulfide are under investigation for their neuroprotective and cardioprotective effects in post-cardiac arrest syndrome.With all these therapeutic options available, the clinician must have a clear understanding of the physiologic basis, therapeutic potential, and possible adverse events of these therapeutic gases. In this review, we will present the therapeutic gases other than oxygen used in clinical practice and we will describe other promising therapeutic gases that are in the early phases of investigation.

PMID:35533689 | DOI:10.1055/s-0042-1747966

Physiol Rev. 2022 May 9. doi: 10.1152/physrev.00046.2021. Online ahead of print.

ABSTRACT

Parenchymal lung disease is the fourth leading cause of death in the United States; among the top causes, it continues on the rise. Telomeres and telomerase have historically been linked to cellular processes related to aging and cancer, but surprisingly in the recent decade, genetic discoveries have linked the most apparent manifestations of telomere and telomerase dysfunction in humans to the etiology of lung disease: both idiopathic pulmonary fibrosis and emphysema. The short telomere defect is pervasive in a subset of idiopathic pulmonary fibrosis (IPF) patients, and human IPF is the phenotype most intimately tied to germline defects in telomere maintenance. One-third of families with pulmonary fibrosis carries germline mutations in telomerase or other telomere maintenance genes, and one half of patients with apparently sporadic IPF have short telomere length. Beyond explaining genetic susceptibility, short telomere length uncovers clinically relevant syndromic extrapulmonary disease including a T cell immunodeficiency and a propensity to myeloid malignancies. Recognizing this subset of patients who shares a unifying molecular defect has provided a precision medicine paradigm wherein the telomere-mediated lung disease diagnosis provides more prognostic value than histopathology or multi-disciplinary evaluation. Here, we critically evaluate this progress emphasizing how the genetic findings puts forth a new pathogenesis paradigm of age-related lung disease that links telomere abnormalities to alveolar stem senescence, remodeling and defective gas exchange.

PMID:35532056 | DOI:10.1152/physrev.00046.2021

Zhonghua Jie He He Hu Xi Za Zhi. 2022 May 12;45(5):493-497. doi: 10.3760/cma.j.cn112147-20211031-00754.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease of unknown etiology, which was characterized by irreversible lung function decrease and high mortality. Up till now, only two drugs, i.e. Pirfenidone and Nintedanib,have been approved by Food and Drug Administration (FDA) for therapy of IPF, and the treatment is less effective. Therefore, it is urgent to develop new therapeutic drugs. In recent years, studies had paid attention to lipid metabolism in IPF. In this review, we discussed recent major advances of lipid metabolism, biomarkers and clinical trials in IPF.

PMID:35527464 | DOI:10.3760/cma.j.cn112147-20211031-00754

Chest. 2022 May;161(5):e330-e331. doi: 10.1016/j.chest.2021.12.660.

NO ABSTRACT

PMID:35526912 | DOI:10.1016/j.chest.2021.12.660