Expert Rev Respir Med. 2023 Nov 8. doi: 10.1080/17476348.2023.2281992. Online ahead of print.

ABSTRACT

BACKGROUND: Lately a potential detrimental effect of air pollution to idiopathic pulmonary fibrosis has emerged. We aimed to assess the effects of short-term personal air pollution exposure to the clinical course of IPF.

RESEARCH DESIGN AND METHODS: IPF patients were followed intensively for four nonconsecutive study periods between 13 July 2020 and 5 September 2021. Short-term exposure to O3, NO2 and PM10 concentrations was estimated using spatio-temporal land use regression models. The associations among symptoms, lung function, oxygen saturation and short-term personal air pollutant exposure on the same day, the average of the same and previous day and the average of the same and 2 previous days, were assessed through multiple mixed effects logistic regression models.

RESULTS: Data for up to 24 IPF patients (mean age:72.2 ± 7.6 years) were analyzed. We detected positive significant associations between cough and a 10 μg/m3 increase in same day mean level of NO2 (OR = 1.59, 95%CI:1.00-2.53, p = 0.049), PM10 (OR = 2.42, 95%CI:1.54-3.79, p < 0.001) and O3 (OR = 1.63, 95%CI:1.14-2.32, p = 0.007). A 10 μg/m3 increase in same day mean level of NO2 was also associated with the risk of appearance of wheezing (OR = 3.01, 95%CI:1.00-9.04, p = 0.049), while exposure to O3 was associated with common cold (OR = 6.30, 95%CI:3.59-11.07, p < 0.001). No significant associations were detected in the main study analysis between short-term exposure to air pollutants and forced vital capacity as well as the saturation of oxygen measured by pulse oximeter.

CONCLUSIONS: Short-term exposure to increased concentrations of air pollutants is an independent risk factor for IPF aggravation leading to appearance of cough, expectoration, wheezing and common cold.

PMID:37937867 | DOI:10.1080/17476348.2023.2281992

ERJ Open Res. 2023 Nov 6;9(6):00472-2023. doi: 10.1183/23120541.00472-2023. eCollection 2023 Nov.

ABSTRACT

Even in the absence of liver disease, MARS1 screening should be considered in severe lung fibrosis of young individuals. Interpretation of the genetic variants can evolve with improvement of knowledge (databases, bioinformatic tools) over time. https://bit.ly/45OxF5E.

PMID:37936900 | PMC:PMC10626413 | DOI:10.1183/23120541.00472-2023

Sci Rep. 2023 Nov 7;13(1):19238. doi: 10.1038/s41598-023-46506-0.

ABSTRACT

Chronic kidney disease (CKD) is a comorbidity in idiopathic pulmonary fibrosis (IPF), and managing IPF with CKD is challenging due to limited options for antifibrotic therapy. The aim of this study was to examine the prevalence of CKD and prescription status of pirfenidone in IPF patients and to analyze its impact on mortality. Data from the Korean National Health Insurance Service (NHIS) database between October 2015 and September 2021 were used. IPF and CKD were defined based on both International Classification of Diseases 10th Revision (ICD-10) codes and Rare Intractable Disease (RID) codes. The risk of mortality was assessed based on accompanying CKD with or without antifibrotic therapy. Among 5038 patients with IPF, 8.4% had comorbid CKD and 83.3% with CKD did not receive renal replacement therapy (RRT). Patients with IPF and CKD were older, predominantly male, and had more frequent comorbidities such as cardiovascular disease and diabetes mellitus than subjects without CKD. Pirfenidone was prescribed to 105 (24.6%) of 426 CKD patients, and 89.5% of them did not receive RRT. Pirfenidone was also prescribed to 775 (16.8%) of 4612 IPF patients without CKD. Significant difference was not found in all-cause mortality between the IPF patients with or without CKD regardless of pirfenidone treatment. The use of antifibrotics in IPF patients with CKD is limited due to CKD severity; however, evidence is lacking. Mortality did not increase with accompanying CKD regardless of antifibrotic use. Further research on IPF and CKD is needed.

PMID:37935732 | DOI:10.1038/s41598-023-46506-0

JCI Insight. 2023 Nov 7:e172977. doi: 10.1172/jci.insight.172977. Online ahead of print.

ABSTRACT

Idiopathic Pulmonary Fibrosis (IPF) is a chronic parenchymal lung disease characterized by repetitive alveolar cell injury, myofibroblast proliferation, and excessive extracellular matrix deposition for which unmet need persists for effective therapeutics. The bioactive eicosanoid, prostaglandin F2a, and its cognate receptor FPr (Ptfgr) are implicated as a TGFβ1 independent signaling hub for IPF. To assess this, we leveraged our published murine PF model (IER-SftpcI73T) expressing a disease-associated missense mutation in the surfactant protein C (Sftpc) gene. Tamoxifen treated IER-SftpcI73T mice develop an early multiphasic alveolitis and transition to spontaneous fibrotic remodeling by 28 days. IER-SftpcI73T mice crossed to a Ptgfr null (FPr-/-) line showed attenuated weight loss and gene dosage dependent rescue of mortality compared to FPr+/+ cohorts. IER-SftpcI73T/FPr-/- mice also showed reductions in multiple fibrotic endpoints for which administration of nintedanib was not additive. Single cell RNA sequencing, pseudotime analysis, and in vitro assays demonstrated Ptgfr expression predominantly within adventitial fibroblasts which were reprogrammed to an "inflammatory/transitional" cell state in a PGF2a/ FPr dependent manner. Collectively, the findings provide evidence for a role for PGF2a signaling in IPF, mechanistically identify a susceptible fibroblast subpopulation, and establish a benchmark effect size for disruption of this pathway in mitigating fibrotic lung remodeling.

PMID:37934604 | DOI:10.1172/jci.insight.172977

Lung. 2023 Nov 7. doi: 10.1007/s00408-023-00653-3. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and fatal disease with an unknown cause. It is characterized by symptoms such as cough and breathlessness, which significantly impact patients' quality of life. Cough, in particular, has emerged as a burdensome symptom for individuals with IPF. The etiology of cough in IPF patients is believed to be complex, involving factors related to the disease itself, such as increased sensitivity of cough nerves, lung structural changes, inflammation, and genetic factors, as well as comorbidities and medication effects. Unfortunately, effective treatment options for cough in IPF remain limited, often relying on empirical approaches based on studies involving chronic cough patients in general and the personal experience of physicians. Medications such as opioids and neuromodulators are commonly prescribed but have shown suboptimal efficacy, imposing significant physical, psychological, and economic burdens on patients. However, there is hope on the horizon, as specific purinergic P2 receptor ligand-gated ion channel (P2X3) inhibitors have demonstrated promising antitussive effects in ongoing clinical trials. This review aims to provide a comprehensive overview of the evaluation and management of cough in IPF patients, as well as highlight emerging pharmacological and non-pharmacological approaches that target the cough reflex and are currently being investigated in clinical settings.

PMID:37934241 | DOI:10.1007/s00408-023-00653-3

ACS Nano. 2023 Nov 7. doi: 10.1021/acsnano.3c06105. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis is a chronic and highly lethal lung disease that largely results from oxidative stress; however, effective antioxidant therapy by targeting oxidative stress pathogenesis is still lacking. The big challenge is to develop an ideal antioxidant material with superior antifibrotic effects. Herein, we report that V4C3 nanosheets (NSs) can serve as a potential antioxidant for treatment of pulmonary fibrosis by scavenging reactive oxygen and nitrogen species. Interestingly, subtle autoxidation can adjust the valence composition of V4C3 NSs and significantly improve their antioxidant behavior. Valence engineering triggers multiple antioxidant mechanisms including electron transfer, H atom transfer, and enzyme-like catalysis, thus endowing V4C3 NSs with broad-spectrum, high-efficiency, and persistent antioxidant capacity. Benefiting from antioxidant properties and good biocompatibility, V4C3 NSs can significantly prevent myofibroblast proliferation and extracellular matrix abnormality, thus alleviating the progression of bleomycin-induced pulmonary fibrosis in vivo by scavenging ROS, anti-inflammation, and rebuilding antioxidant defenses. This study not only provides an important strategy for designing excellent antioxidant nanomaterials, but also proposes a proof-of-concept demonstration for the treatment of pulmonary fibrosis and other oxidative stress-related diseases.

PMID:37933888 | DOI:10.1021/acsnano.3c06105

Am J Physiol Lung Cell Mol Physiol. 2023 Nov 7. doi: 10.1152/ajplung.00045.2023. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is marked by unremitting matrix deposition and architectural distortion. Multiple pro-fibrotic pathways contribute to the persistent activation of mesenchymal cells (MCs) in fibrosis, highlighting the need to identify and target common signaling pathways. The transcription factor NFAT1 (nuclear factor of activated T cells 1) lies downstream of second messenger calcium signaling and has been recently shown to regulate key pro-fibrotic mediator autotaxin (ATX) in lung MCs. Herein, we investigate the role of NFAT1 in regulating fibroproliferative responses during the development of lung fibrosis. Nfat1-/- deficient mice subjected to bleomycin injury demonstrated improved survival, and protection from lung fibrosis and collagen deposition as compared to bleomycin-injured wildtype (WT) mice. Chimera mice, generated by reconstituting bone marrow cells from WT or Nfat1-/- mice into irradiated WT mice (WTàWT and Nfat1-/-àWT), demonstrated no difference in bleomycin-induced fibrosis, suggesting immune influx-independent fibro-protection in Nfat1-/- mice. Examination of lung tissue and flow sorted lineageneg/PDGFRαpos MCs demonstrated decreased MC numbers, proliferation (cyclin D1 and EdU incorporation), myofibroblast differentiation (αSMA), and survival (Birc5) in Nfat1-/- mice. Nfat1 deficiency abrogated ATX expression in response to bleomycin in vivo and MCs derived from Nfat1-/- mice demonstrated decreased ATX expression and migration in vitro. Human IPF MCs demonstrated constitutive NFAT1 activation, and regulation of ATX in these cells by NFAT1 was confirmed utilizing pharmacologic and genetic inhibition. Our findings identify NFAT1 as a critical mediator of pro-fibrotic processes contributing to dysregulated lung remodeling and suggest its targeting in MCs as a potential therapeutic strategy in IPF.

PMID:37933452 | DOI:10.1152/ajplung.00045.2023

ACS Sens. 2023 Nov 6. doi: 10.1021/acssensors.3c00717. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a disease of unknown etiology that is characterized by excessive deposition and abnormal remodeling of collagen. IPF has a mean survival time of only 2-5 years from diagnosis, creating a need to detect IPF at an earlier stage when treatments might be more effective. We sought to develop a minimally invasive probe that could detect molecular changes in IPF-associated collagen. Here, we describe the design, synthesis, and performance of [68Ga]Ga·DOTA-CMP, which comprises a positron-emitting radioisotope linked to a collagen-mimetic peptide (CMP). This peptide mimics the natural structure of collagen and detects irregular collagen matrices by annealing to damaged collagen triple helices. We assessed the ability of the peptide to detect aberrant lung collagen selectively in a bleomycin-induced mouse model of pulmonary fibrosis using positron emission tomography (PET). [68Ga]Ga·DOTA-CMP PET demonstrated higher and selective uptake in a fibrotic mouse lung compared to controls, minimal background signal in adjacent organs, and rapid clearance via the renal system. These studies suggest that [68Ga]Ga·DOTA-CMP identifies fibrotic lungs and could be useful in the early diagnosis of IPF.

PMID:37930825 | DOI:10.1021/acssensors.3c00717

Front Immunol. 2023 Oct 19;14:1288098. doi: 10.3389/fimmu.2023.1288098. eCollection 2023.

ABSTRACT

BACKGROUND: Dermatomyositis (DM) is an autoimmune and inflammatory disease that can affect the lungs, causing interstitial lung diseases (ILD). However, the exact pathophysiological mechanisms underlying DM-ILD are unknown. Idiopathic pulmonary fibrosis (IPF) belongs to the broader spectrum of ILD and evidence shows that common pathologic pathways might lie between IPF and DM-ILD.

METHODS: We retrieved gene expression profiles of DM and IPF from the Gene Expression Omnibus (GEO) and utilized weighted gene co-expression network analysis (WGCNA) to reveal their co-expression modules. We then performed a differentially expressed gene (DEG) analysis to identify common DEGs. Enrichment analyses were employed to uncover the hidden biological pathways. Additionally, we conducted protein-protein interaction (PPI) networks analysis, cluster analysis, and successfully found the hub genes, whose levels were further validated in DM-ILD patients. We also examined the relationship between hub genes and immune cell abundance in DM and IPF. Finally, we conducted a common transcription factors (TFs)-genes network by NetworkAnalyst.

RESULTS: WGCNA revealed 258 intersecting genes, while DEG analysis identified 66 shared genes in DM and IPF. All of these genes were closely related to extracellular matrix and structure, cell-substrate adhesion, and collagen metabolism. Four hub genes (POSTN, THBS2, COL6A1, and LOXL1) were derived through intersecting the top 30 genes of the WGCNA and DEG sets. They were validated as active transcripts and showed diagnostic values for DM and IPF. However, ssGSEA revealed distinct infiltration patterns in DM and IPF. These four genes all showed a positive correlation with immune cells abundance in DM, but not in IPF. Finally, we identified one possible key transcription factor, MYC, that interact with all four hub genes.

CONCLUSION: Through bioinformatics analysis, we identified common hub genes and shared molecular pathways underlying DM and IPF, which provides valuable insights into the intricate mechanisms of these diseases and offers potential targets for diagnostic and therapeutic interventions.

PMID:37928522 | PMC:PMC10622801 | DOI:10.3389/fimmu.2023.1288098

Mol Biotechnol. 2023 Nov 4. doi: 10.1007/s12033-023-00943-4. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) carries a high mortality rate and has a poor prognosis. The pathogenesis of pulmonary fibrosis (PF) is highly related to dysregulation of multiple RNAs. This study aims to identify and validate dysregulated RNAs that exhibited dynamic alterations in response to bleomycin (BLM)-induced PF. The results will provide therapeutic targets for patients suffering from IPF. Whole transcriptomic profiles of BLM-induced PF were obtained through high-throughput RNA sequencing. miRNA profiling was downloaded from GSE45789 database in the Gene Expression Omnibus (GEO). We identified the differentially expressed RNAs (DERNAs) that exhibited dynamic alterations in response to BLM-induced PF. Subsequently, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genome (KEGG) pathway enrichment analysis were conducted to discovery regulatory processes of PF. Weighted gene co-expression network analysis (WGCNA), protein-protein interaction (PPI) analysis, and co-expression analysis were performed to identify key genes and pathogenic pattern during the progression of PF. MiRanda, miRcode, and TargetScan were utilized to predict target relationships in the potential competing endogenous RNA (ceRNA) network. The results were verified by qRT-PCR analysis. In the context of BLM-induced PF, this study identified a total of 167 differentially expressed messenger RNAs (DEmRNAs), 115 differentially expressed long non-coding RNAs (DElncRNAs), 45 differentially expressed circular RNAs (DEcircRNAs), and 87 differentially expressed microRNAs (DEmiRNAs). These RNA molecules showed dynamic alterations in response to BLM-induced PF. These DEmRNAs exhibited a predominant association with the biological processes pertaining to the organization of extracellular matrix. A regulatory network was built in PF, encompassing 31 DEmRNAs, 18 DE lncRNAs, 13 DEcircRNAs, and 13 DEmiRNAs. Several DERNA molecules were subjected to validate using additional BLM-induced PF model. The outcomes of this validation process shown a strong correlation with the results obtained from RNA sequencing analysis. The GSE213001 dataset was utilized to validate the expression levels and diagnostic efficacy of four specific hub mRNAs (CCDC80, CLU, COL5A1, and COL6A3) in individuals diagnosed with PF. In this study, we identified and validated several RNA molecules that exhibited dynamic alternations in response to BLM-induced PF. These dysregulated RNAs participated in the pathogenesis of PF and can be used as therapeutic targets for early-stage IPF. Although more work must be done to confirm the results, our study may provide directions for future studies.

PMID:37924392 | DOI:10.1007/s12033-023-00943-4

Cell Death Discov. 2023 Nov 4;9(1):407. doi: 10.1038/s41420-023-01702-9.

ABSTRACT

Idiopathic pulmonary fibrosis is a progressive and fatal interstitial lung disease with a poor prognosis and limited therapeutic options, which is characterized by aberrant myofibroblast activation and pathological remodeling of the extracellular matrix, while the mechanism remains elusive. In the present investigation, we observed a reduction in ADRB2 expression within both IPF and bleomycin-induced fibrotic lung samples, as well as in fibroblasts treated with TGF-β1. ADRB2 inhibition blunted bleomycin-induced lung fibrosis. Blockage of the ADRB2 suppressed proliferation, migration, and invasion and attenuated TGF-β1-induced fibroblast activation. Conversely, the enhancement of ADRB2 expression or functionality proved capable of inducing fibroblast-to-myofibroblast differentiation. Subsequent mechanistic investigation revealed that inhibition of ADRB2 suppressed the activation of SMAD2/3 in lung fibroblasts and increased phos-SMAD2/3 proteasome degradation, and vice versa. Finally, ADRB2 inhibition combined with antioxidants showed increased efficacy in the therapy of bleomycin-induced lung fibrosis. In short, these data indicate that ADRB2 is involved in lung fibroblast differentiation, and targeting ADRB2 could emerge as a promising and innovative therapeutic approach for pulmonary fibrosis.

PMID:37923730 | DOI:10.1038/s41420-023-01702-9

Matrix Biol. 2023 Nov 1:S0945-053X(23)00106-3. doi: 10.1016/j.matbio.2023.10.003. Online ahead of print.

ABSTRACT

Elastin is a long-lived fibrous protein that is abundant in the extracellular matrix of the lung. Elastic fibers provide the lung the characteristic elasticity during inhalation with recoil during exhalation thereby ensuring efficient gas exchange. Excessive deposition of elastin and other extracellular matrix proteins reduces lung compliance by impairing ventilation and compromising gas exchange. Notably, the degree of elastosis is associated with the progressive decline in lung function and survival in patients with interstitial lung diseases. Currently there are no proven therapies which effectively reduce the elastin burden in the lung nor prevent dysregulated elastosis. This review describes elastin's role in the healthy lung, summarizes elastosis in pulmonary diseases, and evaluates the current understanding of elastin regulation and dysregulation with the goal of guiding future research efforts to develop novel and effective therapies.

PMID:37922998 | DOI:10.1016/j.matbio.2023.10.003

Pathol Res Pract. 2023 Oct 20;251:154901. doi: 10.1016/j.prp.2023.154901. Online ahead of print.

ABSTRACT

The long pentraxin 3 (PTX3) is protective in different pathologies but was not analyzed in-depth in Idiopathic Pulmonary Fibrosis (IPF). Here, we have explored the influence of PTX3 in the bleomycin (BLM)-induced murine model of IPF by looking at immune cells (macrophages, mast cells, T cells) and stemness/regenerative markers of lung epithelium (SOX2) and fibro-blasts/myofibroblasts (CD44) at different time points that retrace the progression of the disease from onset at day 14, to full-blown disease at day 21, to incomplete regression at day 28. We took advantage of transgenic PTX3 overexpressing mice (Tie2-PTX3) and Ptx3 null ones (PTX3-KO) in which pulmonary fibrosis was induced. Our data have shown that PTX3 overexpression in Tie2-PTX3 compared to WT or PTX3-KO: reduced CD68+ and CD163+ macrophages and the Tryptase+ mast cells during the whole experimental time; on the contrary, CD4+ T cells are consistently present on day 14 and dramatically decreased on day 21; CD8+ T cells do not show significant differences on day 14, but are significantly reduced on day 21; SOX2 is reduced on days 14 and 21; CD44 is reduced on day 21. Therefore, PTX3 could act on the proimmune and fibrogenic microenvironment to prevent fibrosis in BLM-treated mice.

PMID:37922722 | DOI:10.1016/j.prp.2023.154901

Mayo Clin Proc. 2023 Nov;98(11):1685-1696. doi: 10.1016/j.mayocp.2023.05.002.

ABSTRACT

Combined pulmonary fibrosis and emphysema (CPFE) syndrome refers to co-occurrence of two disease processes in the lung that can be difficult to diagnose but is associated with high morbidity and mortality burden. Diagnosis of CPFE is challenging because the two diseases can counterbalance respective impairments resulting in deceivingly normal-appearing chest radiography and spirometry in a dyspneic patient. Although an international committee published the terminology and definitions of CPFE in 2022, consensus on exact diagnostic criteria and optimal management strategy is yet to be determined. Herein, we provide a narrative review summarizing the literature on CPFE from 1990 to 2022, including historical background, epidemiology, pathogenesis, clinical features, imaging and pulmonary function findings, diagnosis, prognosis, complications, and treatment. Although CPFE was initially conceived as a variant presentation of idiopathic pulmonary fibrosis, it has been recognized to occur in patients with a wide variety of interstitial lung diseases, including connective tissue disease-associated interstitial lung diseases, and hypersensitivity pneumonitis. The affected patients have a heightened risk for pulmonary hypertension and lung cancer. Clinicians need to recognize the characteristic presenting features of CPFE along with prognostic implications of this entity.

PMID:37923525 | DOI:10.1016/j.mayocp.2023.05.002

Respirology. 2023 Nov 3. doi: 10.1111/resp.14621. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: The lung immune prognostic index (LIPI), a simple index calculated from the blood lactate dehydrogenase level and derived neutrophil-to-lymphocyte ratio, is thought to be associated with host immune status. However, the utility of LIPI in patients with idiopathic interstitial pneumonias (IIPs) is unknown.

METHODS: In this multicentre, retrospective, observational study, an association between LIPI and the survival of patients with IIPs was evaluated.

RESULTS: Exploratory and validation cohorts consisting of 460 and 414 patients with IIPs, respectively, were included (159 and 159 patients had idiopathic pulmonary fibrosis [IPF], and 301 and 255 had non-IPF, respectively). In the exploratory cohort, patients with IPF and a low LIPI had significantly better survival than those with a high LIPI (median of 5.6 years vs. 3.9 years, p = 0.016). The predictive ability of LIPI for the survival of patients with IPF was validated in the validation cohort (median of 8.5 years vs. 4.4 years, p = 0.003). In a multivariate Cox proportional hazard analysis, LIPI was selected as an independent predictive factor for the survival of IPF patients. There was no significant association between LIPI and survival of non-IPF patients in the exploratory and validation cohorts.

CONCLUSION: The LIPI was a predictive factor for the survival of patients with IPF and could aid the management of IPF.

PMID:37921012 | DOI:10.1111/resp.14621

Tanaffos. 2023 Jan;22(1):129-135.

ABSTRACT

BACKGROUND: The effect of the combination of prednisolone, azathioprine, and acetylcysteine for the treatment of Idiopathic pulmonary fibrosis (IPF) is minimal. We aimed to investigate the effect of these drugs in case of intolerance to new anti-fibrotic drugs.

MATERIALS AND METHODS: This historical prospective study was performed on 91 patients with idiopathic pulmonary fibrosis who were referred to a pulmonologist in Mashhad during 2016-2020. Patients were divided into two groups, Pirfenidone which was prescribed for 46 subjects, and a combination of prednisolone, azathioprine, and acetylcysteine which was prescribed for 45 subjects. Patients were selected by convenience sampling and a life expectancy comparison between the two groups was performed by Cox regression.

RESULTS: There were no statistically significant differences between age, gender, and drug type in the two groups at the beginning of treatment. The death rate per year in the triple-drug treatment group was 44.44% (n = 20) and in the Pirfenidone treatment group was 11.08% (n=2). Of the 65 recovered population, 49% (22 patients) were in the triple-drug treatment group, and 78% (36 patients) were in the Pirfenidone treatment group which indicated that Pirfenidone has a significant impact on reducing death rate compared to triple-drug treatment (pvalue=0.003 <0.05). Pirfenidone decreased the risk of death, compared to triple therapy (0.23 when death was set up as one in the triple-therapy group).

CONCLUSION: Pirfenidone has a favorable effect on increasing life expectancy and triple therapy should be considered as short-term only in subjects intolerant to anti-fibrotic.

PMID:37920315 | PMC:PMC10618587

BMC Pulm Med. 2023 Nov 1;23(1):420. doi: 10.1186/s12890-023-02735-7.

ABSTRACT

BACKGROUND: Clustering is helpful in identifying subtypes in complex fibrosing interstitial lung disease (F-ILD) and associating them with prognosis at an early stage of the disease to improve treatment management. We aimed to identify associations between clinical characteristics and outcomes in patients with F-ILD.

METHODS: Retrospectively, 575 out of 926 patients with F-ILD were eligible for analysis. Four clusters were identified based on baseline data using cluster analysis. The clinical characteristics and outcomes were compared among the groups.

RESULTS: Cluster 1 was characterized by a high prevalence of comorbidities and hypoxemia at rest, with the worst lung function at baseline; Cluster 2 by young female patients with less or no smoking history; Cluster 3 by male patients with highest smoking history, the most noticeable signs of velcro crackles and clubbing of fingers, and the severe lung involvement on chest image; Cluster 4 by male patients with a high percentage of occupational or environmental exposure. Clusters 1 (median overall survival [OS] = 7.0 years) and 3 (OS = 5.9 years) had shorter OS than Clusters 2 (OS = not reached, Cluster 1: p < 0.001, Cluster 3: p < 0.001) and 4 (OS = not reached, Cluster 1: p = 0.004, Cluster 3: p < 0.001). Clusters 1 and 3 had a higher cumulative incidence of acute exacerbation than Clusters 2 (Cluster 1: p < 0.001, Cluster 3: p = 0.014) and 4 (Cluster 1: p < 0.001, Cluster 3: p = 0.006). Stratification by using clusters also independently predicted acute exacerbation (p < 0.001) and overall survival (p < 0.001).

CONCLUSIONS: The high degree of disease heterogeneity of F-ILD can be underscored by four clusters based on clinical characteristics, which may be helpful in predicting the risk of fibrosis progression, acute exacerbation and overall survival.

PMID:37914987 | PMC:PMC10621076 | DOI:10.1186/s12890-023-02735-7

Eur Respir J. 2023 Nov 2:2300088. doi: 10.1183/13993003.00088-2023. Online ahead of print.

ABSTRACT

RATIONALE: Recent data suggest that the localization of airway epithelial cells in the distal lung in idiopathic pulmonary fibrosis (IPF) may drive pathology. We set out to discover if chemokines expressed in these ectopic airway epithelial cells may contribute to the pathogenesis of IPF.

METHODS: We analyzed whole lung and single-cell transcriptomic data obtained from patients with IPF. We also measured chemokine levels in blood, bronchoalveolar lavage (BAL) of IPF patients and air-liquid interface (ALI) cultures. We employed ex vivo donor and IPF lung fibroblasts and an animal model of pulmonary fibrosis to test the effects of chemokine signaling on fibroblast function.

RESULTS: By analysis of both whole lung transcriptomics, protein, and BAL, we discovered that CXCL6-a member of the IL-8 family-was increased in patients with IPF. Elevated CXCL6 levels in the BAL of two cohorts of patients with IPF were associated with poor survival (Hazard ratio of death or progression=1.89 (95%CI 1.16-3.08, N=179, p=0.01). By immunostaining and single-cell RNA sequencing, CXCL6 was detected in secretory cells. Administration of mCXCL5 (LIX, murine CXCL6 homolog) to mice increased collagen synthesis with and without bleomycin. CXCL6 increased collagen I levels in donor and IPF fibroblasts 4.4-fold and 1.7-fold, respectively. Both silencing of and chemical inhibition of CXCR1/2 blocked the effects of CXCL6 on collagen, while over-expression of CXCR2 increased collagen I levels 4.5-fold in IPF fibroblasts.

CONCLUSIONS: CXCL6 is expressed in ectopic airway epithelial cells. Elevated levels of CXCL6 are associated with IPF mortality. CXCL6-driven collagen synthesis represents a functional consequence of ectopic localization of airway epithelial cells in IPF.

PMID:37918852 | DOI:10.1183/13993003.00088-2023

Life Sci. 2023 Oct 31:122218. doi: 10.1016/j.lfs.2023.122218. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive chronic inflammatory disease with poor clinical outcomes and ineffective drug treatment options. Eupatilin is a major component extracted from the traditional herbal medicine Artemisia asiatica Nakai. Notably, it was demonstrated to have an anti-fibrosis effect in endometrial fibrosis, vocal fold, and hepatic fibrosis. Its role and mechanism in IPF remain unclear.

METHODS: This study used the TGF-β1-induced human embryonic lung fibroblasts (MRC-5) activation, IPF lung fibroblasts, and bleomycin-induced lung fibrosis mice model. Western blot, immunofluorescence staining, quantitative real time-PCR, hematoxylin and eosin staining, Masson's trichrome staining, and immunohistochemistry were used to evaluate the effect of eupatilin on fibroblast activation, pulmonary fibrosis, and autophagy. The autophagosomes were observed with a transmission electron microscope (TEM). RNA sequencing was used to determine the signaling pathway and key regulator related to autophagy.

RESULTS: Eupatilin significantly decreased the expression of Col1A1, fibronectin, α-SMA, and SQSTM1/p62. In contrast, it increased the expression of LC3B II/I and the number of autophagosomes in TGF-β1 treated MRC-5, IPF lung fibroblasts, and bleomycin-induced lung fibrosis mice model; it also alleviated bleomycin-induced lung fibrosis. The KEGG pathway mapping displayed that PI3K/Akt and Sestrin2 were associated with the enhanced fibrogenic process. Eupatilin suppressed the phosphorylation of PI3K/Akt/mTOR. Autophagy inhibitor 3-methyladenine (3-MA) and Akt activator SC-79 abrogated the anti-fibrotic effect of eupatilin. Sestrin2 expression was also downregulated in TGF-β1 treated lung fibroblasts and lung tissues of the bleomycin-induced pulmonary fibrosis mice model. Furthermore, eupatilin promoted Sestrin2 expression, and the knockdown of Sestrin2 significantly aggravated the degree of fibrosis, increased the phosphorylation of PI3K/Akt/mTOR, and decreased autophagy.

CONCLUSION: These findings indicate that eupatilin ameliorates pulmonary fibrosis through Sestrin2/PI3K/Akt/mTOR-dependent autophagy pathway.

PMID:37918625 | DOI:10.1016/j.lfs.2023.122218

Palliat Med Rep. 2023 Oct 30;4(1):292-299. doi: 10.1089/pmr.2023.0038. eCollection 2023.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a serious illness with an unpredictable disease course and survival rates comparable with some cancers. Patients with IPF suffer considerable symptom burden, declining quality of life, and high health care resource utilization. Patients and caregivers report many unmet needs, including a desire for more education regarding diagnosis and assistance with navigating disease trajectory. Compelling evidence suggests that palliative care (PC) provides an extra layer of support for patients with serious illness.

RESEARCH QUESTION: The purpose of this survey was to gain perspectives regarding PC for patients with IPF by board-certified pulmonologists in South Carolina (SC).

STUDY DESIGN AND METHODS: A 24-item survey was adapted (with permission) from the Pulmonary Fibrosis Foundation PC Survey instrument. Data were analyzed and results are presented.

RESULTS: Pulmonologists (n = 32, 44%) completed the survey; 97% practice in urbanized settings. The majority agreed that PC and hospice do not provide the same service. There were varying views about comfort in discussing prognosis, disease trajectory, and addressing advance directives. Options for ambulatory and inpatient PC are limited and early PC referral does not occur. None reported initiating a PC referral at time of initial IPF diagnosis.

INTERPRETATION: Pulmonologists in SC who participated in this survey are aware of the principles of PC in providing comprehensive care to patients with IPF and have limited options for PC referral. PC educational materials provided early in the diagnosis can help facilitate and guide end-of-life planning and discussions. Minimal resources exist for patients in underserved communities.

PMID:37915951 | PMC:PMC10616941 | DOI:10.1089/pmr.2023.0038