Am J Respir Crit Care Med. 2022 Aug 23. doi: 10.1164/rccm.202010-3832OC. Online ahead of print.

ABSTRACT

RATIONALE: Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive, and often fatal disorder. Two FDA-approved anti-fibrotic drugs, nintedanib, and pirfenidone, slow the rate of decline in lung function, but responses are variable and side effects are common.

OBJECTIVE: Using an in-silico data-driven approach, we identified a robust connection between the transcriptomic perturbations in IPF disease and those induced by saracatinib, a selective Src kinase inhibitor. Based on these observations, we hypothesized that saracatinib would be effective at attenuating pulmonary fibrosis.

METHODS: We investigated the anti-fibrotic efficacy of saracatinib relative to nintedanib and pirfenidone in three preclinical models: (i) in vitro in normal human lung fibroblasts (NHLFs); (ii) in vivo in bleomycin and recombinant adenovirus transforming growth factor-beta (Ad-TGF-β) murine models of pulmonary fibrosis; and (iii) ex vivo in mice and human precision cut lung slices from these two murine models as well as patients with IPF and healthy donors.

MEASUREMENTS AND MAIN RESULTS: In each model, the effectiveness of saracatinib in blocking fibrogenic responses was equal or superior to nintedanib and pirfenidone. Transcriptomic analyses of TGF-β-stimulated NHLFs identified specific gene sets associated with fibrosis including epithelial mesenchymal transition (EMT), TGF-β, and WNT signaling that was uniquely altered by saracatinib. Transcriptomic analysis of whole lung extracts from the two animal models of pulmonary fibrosis revealed that saracatinib reverted many fibrogenic pathways including EMT, immune responses, and extracellular matrix organization. Amelioration of fibrosis and inflammatory cascades in human precision cut lung slices confirmed the potential therapeutic efficacy of saracatinib in human lung fibrosis.

CONCLUSIONS: These studies identify novel Src-dependent fibrogenic pathways and support the study of the therapeutic effectiveness of saracatinib in IPF treatment.

PMID:35998281 | DOI:10.1164/rccm.202010-3832OC

Cardiovasc Res. 2022 Aug 23:cvac139. doi: 10.1093/cvr/cvac139. Online ahead of print.

ABSTRACT

AIMS: SARS-CoV-2 infection causes COVID-19, which in severe cases evokes life-threatening acute respiratory distress syndrome (ARDS). Transcriptome signatures and the functional relevance of non-vascular cell types (e.g. immune and epithelial cells) in COVID-19 are becoming increasingly evident. However, despite its known contribution to vascular inflammation, recruitment/invasion of immune cells, vascular leakage and perturbed hemostasis in the lungs of severe COVID-19 patients, an in-depth interrogation of the endothelial cell (EC) compartment in lethal COVID-19 is lacking. Moreover, progressive fibrotic lung disease represents one of the complications of COVID-19 pneumonia and ARDS. Analogous features between idiopathic pulmonary fibrosis (IPF) and COVID-19 suggest partial similarities in their pathophysiology, yet, a head-to-head comparison of pulmonary cell transcriptomes between both conditions has not been implemented to date.

METHODS AND RESULTS: We performed single nucleus RNA-seq (snRNA-seq) on frozen lungs from 7 deceased COVID-19 patients, 6 IPF explant lungs and 12 controls. The vascular fraction, comprising 38,794 nuclei, could be subclustered into 14 distinct EC subtypes. Non-vascular cell types, comprising 137,746 nuclei, were subclustered and used for EC-interactome analyses. Pulmonary ECs of deceased COVID-19 patients showed an enrichment of genes involved in cellular stress, as well as signatures suggestive of dampened immunomodulation and impaired vessel wall integrity. In addition, increased abundance of a population of systemic capillary and venous ECs was identified in COVID-19 and IPF. COVID-19 systemic ECs closely resembled their IPF counterparts, and a set of 30 genes was found congruently enriched in systemic ECs across studies. Receptor-ligand interaction analysis of ECs with non-vascular cell types in the pulmonary micro-environment revealed numerous previously unknown interactions specifically enriched/depleted in COVID-19 and/or IPF.

CONCLUSIONS: This study uncovered novel insights into the abundance, expression patterns and interactomes of EC subtypes in COVID-19 and IPF, relevant for future investigations into the progression and treatment of both lethal conditions.

TRANSLATIONAL PERSPECTIVE: While assessing clinical and molecular characteristics of severe and lethal COVID-19 cases, the vasculature's undeniable role in disease progression has been widely acknowledged. COVID-19 lung pathology moreover shares certain clinical features with late-stage IPF - yet an in-depth interrogation and direct comparison of the endothelium at single-cell level in both conditions is still lacking. By comparing the transcriptomes of ECs from lungs of deceased COVID-19 patients to those from IPF explant and control lungs, we gathered key insights the heterogeneous composition and potential roles of ECs in both lethal diseases, which may serve as a foundation for development of novel therapeutics.

PMID:35998078 | DOI:10.1093/cvr/cvac139

FEBS J. 2022 Aug 23. doi: 10.1111/febs.16600. Online ahead of print.

ABSTRACT

CEMIP (Cell migration-inducing protein), also known as KIAA1199 or HYBID, is a protein involved in the depolymerization of hyaluronic acid (HA), a major glycosaminoglycan component of the extracellular matrix. CEMIP was originally described in patients affected by non-syndromic hearing loss and has subsequently been shown to play a key role in tumor initiation and progression, as well as arthritis, atherosclerosis and idiopathic pulmonary fibrosis. Despite the vast literature associating CEMIP with these diseases, its biology remains elusive. The present review article summarizes all the major scientific evidence regarding its structure, function, role and expression, and attempts to cast light on a protein that modulates EMT, fibrosis and tissue inflammation, an unmet key aspect in several inflammatory disease conditions.

PMID:35997767 | DOI:10.1111/febs.16600

Case Rep Pulmonol. 2022 Aug 13;2022:4054339. doi: 10.1155/2022/4054339. eCollection 2022.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is characterized by uncontrolled progressive lung fibrosis with a median survival of 3 to 5 years. Although currently available pharmacotherapy cannot cure the disease, antifibrotics including pirfenidone and nintedanib were shown to slow disease progression and improve survival in IPF. Nevertheless, there is a knowledge gap on the safety of antifibrotics in patients after liver transplantation receiving concomitant immunosuppressive therapy. This case report of a 68-year-old male patient with IPF illustrates how a complex medical history has led to diagnostic and therapeutic challenges considerably affecting clinical decisions and impacting the patient's journey. The increasing severity of lung function impairment due to the progressive natural history of IPF ultimately led to severe respiratory failure. Double lung transplantation (LTx) was performed as the only therapeutic option in end-stage disease with the potential to improve quality of life and survival. To the best of our knowledge, this is the first case report describing the feasibility and safety of antifibrotic therapy with pirfenidone for IPF in a 68-year-old patient with a history of liver transplantation receiving concomitant immunosuppressive therapy with tacrolimus who underwent successful double lung transplantation when alternative medical interventions had been exhausted.

PMID:35996614 | PMC:PMC9392625 | DOI:10.1155/2022/4054339

Interact Cardiovasc Thorac Surg. 2022 Aug 22:ivac223. doi: 10.1093/icvts/ivac223. Online ahead of print.

ABSTRACT

OBJECTIVES: Pleuroparenchymal fibroelastosis (PPFE) is a rare idiopathic interstitial pneumonia characterized by pleural-parenchymal involvements predominantly in the upper lobes. Unilateral upper lung field pulmonary fibrosis (upper-PF) radiologically consistent with PPFE reportedly develops after lung cancer surgery in the operated side and presents many clinical characteristics in common with PPFE. However, the incidence and perioperative associated factors remain unclear.

METHODS: All consecutive patients with lung cancer completely resected from 2008 to 2016 were retrospectively investigated. Pre-/postoperative characteristics were compared between patients with and without unilateral upper-PF. Cumulative incidence curves were estimated by using competing risk analysis.

RESULTS: Among 587 included patients, 25 patients (4.3%) were diagnosed as unilateral upper-PF. The 3-, 5- and 10-year cumulative incidence of unilateral upper-PF was 2.3%, 3.3% and 5.3%, respectively. In multivariable analysis, male sex, presence of pulmonary apical cap, lobar resection and low % vital capacity (%VC < 80%) were independent perioperative associated factors. The 10-year cumulative incidence was 6.3% in patients treated with lobar resection, 8.0% in male patients, 10.3% in patients with pulmonary apical cap and 14.5% in patients with low %VC. Postoperative pleural effusion at 6 months after surgery was much more common in the patients who later developed unilateral upper-PF (96.0% vs 24.2%). This pleural effusion persisted and was accompanied by pleural thickening and subpleural pulmonary fibrosis thereafter. During the clinical courses of 25 patients with unilateral upper-PF, 18 patients presented symptoms related upper-PF and 6 patients died.

CONCLUSION: Unilateral upper-PF is not a rare but under-recognized late complication after lung cancer surgery.

PMID:35993903 | DOI:10.1093/icvts/ivac223

JCI Insight. 2022 Aug 22;7(16):e153058. doi: 10.1172/jci.insight.153058.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic disease of unmet medical need. It is characterized by formation of scar tissue leading to a progressive and irreversible decline in lung function. IPF is associated with repeated injury, which may alter the composition of the extracellular matrix (ECM). Here, we demonstrate that IPF patient-derived pulmonary ECM drives profibrotic response in normal human lung fibroblasts (NHLF) in a 3D spheroid assay. Next, we reveal distinct alterations in composition of the diseased ECM, identifying potentially novel associations with IPF. Growth differentiation factor 15 (GDF15) was identified among the most significantly upregulated proteins in the IPF lung-derived ECM. In vivo, GDF15 neutralization in a bleomycin-induced lung fibrosis model led to significantly less fibrosis. In vitro, recombinant GDF15 (rGDF15) stimulated α smooth muscle actin (αSMA) expression in NHLF, and this was mediated by the activin receptor-like kinase 5 (ALK5) receptor. Furthermore, in the presence of rGDF15, the migration of NHLF in collagen gel was reduced. In addition, we observed a cell type-dependent effect of GDF15 on the expression of cell senescence markers. Our data suggest that GDF15 mediates lung fibrosis through fibroblast activation and differentiation, implicating a potential direct role of this matrix-associated cytokine in promoting aberrant cell responses in disease.

PMID:35993367 | DOI:10.1172/jci.insight.153058

Cureus. 2022 Jul 18;14(7):e26979. doi: 10.7759/cureus.26979. eCollection 2022 Jul.

ABSTRACT

Interstitial lung disease is occasionally reported in patients with psoriasis as drug-induced pneumonitis secondary to concomitant use of immunosuppressants in most cases. Although few cases have been reported describing the simultaneous existence of psoriasis and interstitial pneumonia, there are no reports that clearly show their direct association. A 55-year-old male known case of psoriasis and hypertension presented to the emergency department with complaints of pain and weakness of bilateral upper limbs following an episode of seizure and shortness of breath on exertion for one year. Following workup, the patient was diagnosed to have interstitial lung disease. There was no history of any immunosuppressant or use of biologics. So, immune dysfunction triggered by psoriasis might have caused the lung fibrotic changes. Careful monitoring of lung and skin lesions is vital for diagnosing psoriasis-associated pneumonia.

PMID:35989802 | PMC:PMC9385169 | DOI:10.7759/cureus.26979

J Mol Med (Berl). 2022 Aug 19. doi: 10.1007/s00109-022-02242-y. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrosing interstitial pneumonia of unknown etiology. The role of genetic risk factors has been the focus of numerous studies probing for associations of genetic variants with IPF. We aimed to determine whether single-nucleotide polymorphisms (SNPs) of four candidate genes are associated with IPF susceptibility and survival in a Portuguese population. A retrospective case-control study was performed with 64 IPF patients and 74 healthy controls. Ten single-nucleotide variants residing in the MUC5B, TOLLIP, SERPINB1, and PLAU genes were analyzed. Single- and multi-locus analyses were performed to investigate the predictive potential of specific variants in IPF susceptibility and survival. Multifactor dimensionality reduction (MDR) was employed to uncover predictive multi-locus interactions underlying IPF susceptibility. The MUC5B rs35705950 SNP was significantly associated with IPF: T allele carriers were significantly more frequent among IPF patients (75.0% vs 20.3%, P < 1.0 × 10-6). Genotypic and allelic distributions of TOLLIP, PLAU, and SERPINB1 SNPs did not differ significantly between groups. However, the MUC5B-TOLLIP T-C-T-C haplotype, defined by the rs35705950-rs111521887-rs5743894-rs5743854 block, emerged as an independent protective factor in IPF survival (HR = 0.37, 95% CI 0.17-0.78, P = 0.009, after adjustment for FVC). No significant multi-locus interactions correlating with disease susceptibility were detected. MUC5B rs35705950 was linked to an increased risk for IPF, as reported for other populations, but not to disease survival. A haplotype incorporating SNPs of the MUC5B-TOLLIP locus at 11p15.5 seems to predict better survival and could prove useful for prognostic purposes and IPF patient stratification. KEY MESSAGES : The MUC5B rs35705950 minor allele is associated with IPF risk in the Portuguese. No predictive multi-locus interactions of IPF susceptibility were identified by MDR. A haplotype defined by MUC5B and TOLLIP SNPs is a protective factor in IPF survival. The haplotype may be used as a prognostic tool for IPF patient stratification.

PMID:35986225 | DOI:10.1007/s00109-022-02242-y

Lancet Respir Med. 2022 Aug 16:S2213-2600(22)00251-X. doi: 10.1016/S2213-2600(22)00251-X. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is an incurable lung disease characterised by progressive scarring leading to alveolar stiffness, reduced lung capacity, and impeded gas transfer. We aimed to identify genetic variants associated with declining lung capacity or declining gas transfer after diagnosis of IPF.

METHODS: We did a genome-wide meta-analysis of longitudinal measures of forced vital capacity (FVC) and diffusing capacity of the lung for carbon monoxide (DLCO) in individuals diagnosed with IPF. Individuals were recruited to three studies between June, 1996, and August, 2017, from across centres in the US, UK, and Spain. Suggestively significant variants were investigated further in an additional independent study (CleanUP-IPF). All four studies diagnosed cases following American Thoracic Society/European Respiratory Society guidelines. Variants were defined as significantly associated if they had a meta-analysis p<5 × 10-8 when meta-analysing across all discovery and follow-up studies, had consistent direction of effects across all four studies, and were nominally significant (p<0·05) in each study.

FINDINGS: 1329 individuals with a total of 5216 measures were included in the FVC analysis. 975 individuals with a total of 3361 measures were included in the DLCO analysis. For the discovery genome-wide analyses, 7 611 174 genetic variants were included in the FVC analysis and 7 536 843 in the DLCO analysis. One variant (rs115982800) located in an antisense RNA gene for protein kinase N2 (PKN2) showed a genome-wide significant association with FVC decline (-140 mL/year per risk allele [95% CI -180 to -100]; p=9·14 × 10-12).

INTERPRETATION: Our analysis identifies a genetic variant associated with disease progression, which might highlight a new biological mechanism for IPF. We found that PKN2, a Rho and Rac effector protein, is the most likely gene of interest from this analysis. PKN2 inhibitors are currently in development and signify a potential novel therapeutic approach for IPF.

FUNDING: Action for Pulmonary Fibrosis, Medical Research Council, Wellcome Trust, and National Institutes of Health National Heart, Lung, and Blood Institute.

PMID:35985358 | DOI:10.1016/S2213-2600(22)00251-X

Expert Opin Ther Targets. 2022 Aug 19. doi: 10.1080/14728222.2022.2114897. Online ahead of print.

ABSTRACT

INTRODUCTION: . Idiopathic pulmonary fibrosis (IPF) is a chronic disease of unknown origin characterized by progressive scarring of the lung leading to irreversible loss of function. Despite the availability of two drugs that are able to slow down disease progression, IPF remains a deadly disease. The pathogenesis of IPF is poorly understood, but a dysregulated wound healing response following recurrent alveolar epithelial injury is thought to be crucial. Areas covered. In the last few years, the role of the immune system in IPF pathobiology has been reconsidered; indeed, recent data suggest that a dysfunctional immune system may promote and unfavorable interplay with pro-fibrotic pathways thus acting as a cofactor in disease development and progression. In this article, we review and critically discuss the role of T cells in the pathogenesis and progression of IPF in the attempt to highlight ways in which further research in this area may enable the development of targeted immunomodulatory therapies for this dreadful disease.

EXPERT OPINION: A better understanding of T cells interactions has the potential to facilitate the development of immune modulators targeting multiple T cell-mediated pathways thus halting disease initiation and progression.

PMID:35983984 | DOI:10.1080/14728222.2022.2114897

ACS Pharmacol Transl Sci. 2022 Jul 18;5(8):548-554. doi: 10.1021/acsptsci.2c00050. eCollection 2022 Aug 12.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF), a fatal disease characterized by excessive matrix degradation and fibrosis, destroys the lung architecture and results in the inability of the lungs to absorb oxygen. The cause(s) of IPF is unknown and current treatments are palliative. Matrix metalloproteinases (MMPs) and A Disintegrin And Metalloproteinases (ADAMs) likely play roles in IPF progression. However, specific MMPs and ADAMs in IPF have not been identified due to challenges in MMP/ADAM profiling. We employed a designer affinity resin that binds exclusively to the active forms of MMPs and ADAMs and found by mass spectrometry higher levels of active MMP-1, ADAM9, ADAM10, and ADAM17 in lung tissues of IPF patients. Inhibition of MMP-1 and ADAM10 with the small-molecule inhibitor GI254023X in an in vitro lung fibrosis assay decreased the profibrotic protein α-smooth muscle actin (α-SMA). Our results indicate that inhibition of MMP-1 and ADAM10 may hold promise in treatment of IPF.

PMID:35983283 | PMC:PMC9380212 | DOI:10.1021/acsptsci.2c00050

Front Immunol. 2022 Aug 2;13:924244. doi: 10.3389/fimmu.2022.924244. eCollection 2022.

ABSTRACT

BACKGROUND: The mast cell-specific metalloprotease CPA3 has been given important roles in lung tissue homeostasis and disease pathogenesis. However, the dynamics and spatial distribution of mast cell CPA3 expression in lung diseases remain unknown.

METHODS: Using a histology-based approach for quantitative spatial decoding of mRNA and protein single cell, this study investigates the dynamics of CPA3 expression across mast cells residing in lungs from control subjects and patients with severe chronic obstructive pulmonary disease (COPD) or idiopathic lung fibrosis (IPF).

RESULTS: Mast cells in COPD lungs had an anatomically widespread increase of CPA3 mRNA (bronchioles p < 0.001, pulmonary vessels p < 0.01, and alveolar parenchyma p < 0.01) compared to controls, while granule-stored CPA3 protein was unaltered. IPF lungs had a significant upregulation of both mast cell density, CPA3 mRNA (p < 0.001) and protein (p < 0.05), in the fibrotic alveolar tissue. Spatial expression maps revealed altered mast cell mRNA/protein quotients in lung areas subjected to disease-relevant histopathological alterations. Elevated CPA3 mRNA also correlated to lung tissue eosinophils, CD3 T cells, and declined lung function. Single-cell RNA sequencing of bronchial mast cells confirmed CPA3 as a top expressed gene with potential links to both inflammatory and protective markers.

CONCLUSION: This study shows that lung tissue mast cell populations in COPD and IPF lungs have spatially complex and markedly upregulated CPA3 expression profiles that correlate with immunopathological alterations and lung function. Given the proposed roles of CPA3 in tissue homeostasis, remodeling, and inflammation, these alterations are likely to have clinical consequences.

PMID:35983043 | PMC:PMC9378779 | DOI:10.3389/fimmu.2022.924244

Thorax. 2022 Aug 18:thorax-2022-219354. doi: 10.1136/thorax-2022-219354. Online ahead of print.

NO ABSTRACT

PMID:35981882 | DOI:10.1136/thorax-2022-219354

J Exp Med. 2022 Oct 3;219(10):e20220126. doi: 10.1084/jem.20220126. Epub 2022 Aug 18.

ABSTRACT

Progressive tissue fibrosis, including idiopathic pulmonary fibrosis (IPF), is characterized by excessive recruitment of fibroblasts to sites of tissue injury and unremitting extracellular matrix deposition associated with severe morbidity and mortality. However, the molecular mechanisms that control progressive IPF have yet to be fully determined. Previous studies suggested that invasive fibroblasts drive disease progression in IPF. Here, we report profiling of invasive and noninvasive fibroblasts from IPF patients and healthy donors. Pathway analysis revealed that the activated signatures of the invasive fibroblasts, the top of which was ERBB2 (HER2), showed great similarities to those of metastatic lung adenocarcinoma cancer cells. Activation of HER2 in normal lung fibroblasts led to a more invasive genetic program and worsened fibroblast invasion and lung fibrosis, while antagonizing HER2 signaling blunted fibroblast invasion and ameliorated lung fibrosis. These findings suggest that HER2 signaling may be a key driver of fibroblast invasion and serve as an attractive target for therapeutic intervention in IPF.

PMID:35980387 | DOI:10.1084/jem.20220126

Biomaterials. 2022 Aug 10:121731. doi: 10.1016/j.biomaterials.2022.121731. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) therapy has always been a big and long-standing challenge in clinical practice due to the lack of miraculous medicine. Mesenchymal stem cells (MSCs)-based therapy has recently emerged as a promising candidate for redefining IPF therapy. Enhancing the therapeutic efficacy of MSCs and understanding of their growth, migration and differentiation in harsh lung microenviroments are two keys to improving the stem cell-based IPF treatment. Herein, a non-viral dual-functional nanocarrier is fabricated by a one-pot approach, using protamine sulfate stabilized Au nanoparticles (AuPS), to genetically engineer MSCs for simultaneous IPF treatment and monitoring the biological behavior of the MSCs. AuPS exhibits superior cellular uptake ability, which results in efficient genetic engineering of MSCs to overexpress hepatocyte growth factor for enhanced IPF therapy. In parallel, the intracellular accumulation of AuPS improves the CT imaging contrast of MSCs, allowing visual tracking of the therapeutic engineered MSCs up to 48 days. Overall, this work has described for the first time a novel strategy for enhanced therapeutic efficacy and long-term CT imaging tracking of transplanted MSCs in IPF therapy, providing great prospect for stem cell therapy of lung disease.

PMID:35970616 | DOI:10.1016/j.biomaterials.2022.121731

Cureus. 2022 Jul 12;14(7):e26777. doi: 10.7759/cureus.26777. eCollection 2022 Jul.

ABSTRACT

Partial anomalous pulmonary venous return (PAPVR) is a spectrum of congenital cardiovascular abnormalities. It is most commonly found as an incidental finding. However, it can lead to severe pulmonary hypertension depending on the magnitude of the shunt involved. We report a case of a 60-year-old female patient with PAPVR detected incidentally on imaging. We aim to highlight the incidence of PAPVR in adults and to elaborate on its unique association with a duplicated superior vena cava.

PMID:35967179 | PMC:PMC9366027 | DOI:10.7759/cureus.26777

Front Med (Lausanne). 2022 Jul 28;9:917973. doi: 10.3389/fmed.2022.917973. eCollection 2022.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive, chronic disease of the lungs which is characterized by heavy symptom burden, especially in the last year of life. Despite recently established anti-fibrotic treatment IPF prognosis is one of the worst among interstitial lung diseases. In this review available evidence regarding pharmacological and non-pharmacological management of the main IPF symptoms, dyspnea and cough, is presented.

PMID:35966835 | PMC:PMC9368785 | DOI:10.3389/fmed.2022.917973

Ann Transl Med. 2022 Jul;10(14):797. doi: 10.21037/atm-22-3215.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a heterogeneous and progressive fibrosing interstitial lung disease with a poor prognosis. However, there are currently no effective biomarker that can reliably predict the prognosis for IPF in clinic. The serum level of soluble suppression of tumorigenicity-2 (sST2), which is involved in the immune response, has proven to be a prognostic predictor for various diseases. Previous studies have confirmed that the immune dysfunction plays an important role in the pathogenesis of IPF and the serum sST2 concentrations in patients with IPF are elevated. However, the relationship between sST2 and the prognosis of IPF remains unknown.

METHODS: A total of 83 patients with IPF and 20 healthy controls from 2016 to 2021 were enrolled and demographic variables, indices of lung function testing as well as the biomarkers including the sST2 were obtained at baseline. During follow-up, the primary endpoint was defined as all-cause death and clinical deterioration. Cox hazard models and Kaplan-Meier method were used to assess the prognostic value of various indices including sST2.

RESULTS: Mean duration of follow-up was 29 months, during which 49 patients had an event, and of them, 35 patients died. The sST2 level was higher in the IPF patients compared with the healthy controls. Although the sST2 level did not directly predict all-cause death in the present study, it was proved to be an independent predictor of event-free survival. Multivariate forward stepwise model which was adjusted by age, sex, and body surface area (BSA) showed that the overexpression of sST2 increased the hazard ratio [1.005, 95% confidence interval (CI): 1.001-1.010]. A higher sST2 serum level heralded more deterioration and the poor outcomes. Moreover, the effect of sST2 on the prognosis of IPF may not necessarily involve the development of IPF-related pulmonary hypertension (PH).

CONCLUSIONS: In our study, the sST2 serum level was significantly elevated and a higher serum level of sST2 predicted more deterioration and poor outcomes in patients with IPF. Thus, sST2 can serve as a valuable prognostic biomarker for the outcome of IPF. However, further multicenter clinical trials of larger sample size are needed in the future.

PMID:35965810 | PMC:PMC9372699 | DOI:10.21037/atm-22-3215

BMC Pulm Med. 2022 Aug 14;22(1):313. doi: 10.1186/s12890-022-02105-9.

ABSTRACT

BACKGROUND: The disease course of idiopathic pulmonary fibrosis (IPF) is progressive and occasionally, other types of interstitial lung disease (ILD) may progress similarly to IPF. This study aimed to evaluate risk factors for disease progression within 24 months in patients with various ILDs.

METHODS: This prospective study obtained 97 patients with a suspected ILD who underwent a transbronchial lung cryobiopsy. The extent of several high-resolution computed tomography (HRCT) patterns was assessed. Due to the inclusion criteria the study population presented a low extent of honeycombing and definite usual interstitial pneumonia (UIP) pattern on HRCT suggesting an early stage of ILD. Disease progression within 24 months despite treatment was defined as a relative decline of ≥ 10% in forced vital capacity (FVC), or a relative decline in FVC of ≥ 5% and one of the three additional criteria: (1) a decline in diffusion capacity to carbon monoxide (DLCO) ≥ 15%; (2) increased fibrosis on HRCT; (3) progressive symptoms, or progressive symptoms and increased fibrosis on HRCT. The same definition was utilized in patients with IPF and other ILDs. Risk factors for disease progression were evaluated in a multivariable logistic regression model.

RESULTS: Disease progression was revealed in 52% of the patients with ILD, 51% of the patients with IPF, and 53% of the patients with other types of ILD. A high extent of reticulation on HRCT (Odds ratio [OR] 3.11, 95% Confidence interval [CI] 1.21-7.98, P = 0.019) and never smoking (OR 3.11, CI 1.12-8.63, P = 0.029) were associated with disease progression whereas platelet count (OR 2.06 per 100 units increase, CI 0.96-4.45, P = 0.065) did not quite reach statistical significance.

CONCLUSION: Higher extent of reticulation on HRCT and never smoking appeared to associate with the risk of disease progression within 24 months in ILD patients without honeycombing. Approximately half of the patients with ILD revealed disease progression, and similar proportions were observed in patients with IPF and in other types of ILD.

PMID:35965320 | DOI:10.1186/s12890-022-02105-9

Eur J Pharmacol. 2022 Aug 11:175184. doi: 10.1016/j.ejphar.2022.175184. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrosing interstitial pneumonia with limited therapeutic options. Eucalyptol, a terpenoid oxide isolated from eucalyptus species, reportedly exhibits various biological activities such as anti-inflammatory and antioxidant effects. In the present study, we aimed to determine whether eucalyptol could alleviate bleomycin (BLM)-induced pulmonary fibrosis and inhibit interleukin (IL)-13-induced M2 macrophage polarization. Upon treatment with eucalyptol, BLM-induced pulmonary fibrosis and lung inflammation were significantly reduced. The pulmonary neutrophil accumulation and pulmonary permeability were inhibited and the expression of hydroxyproline, alpha-smooth muscle actin, and fibronectin was significantly down-regulated. Eucalyptol also markedly inhibited the expression of arginase-1, Ym-1, IL-13, and transforming growth factor (TGF)-β1, reduced the production of IL-13, IL-6, tumor necrosis factor (TNF)-α, and attenuated the activity of TGF-β1 in bronchoalveolar lavage fluid (BALF). Furthermore, the in vitro assay revealed that eucalyptol disturbed M2 macrophage polarization and reduced the macrophage-mediated secretion of the profibrotic factor TGF-β1. Eucalyptol inhibited the nuclear location of signal transducer and activator of transcription 6 (STAT6) and the phosphorylation of STAT6 and p38 mitogen-activated protein kinase (p38 MAPK), and reduced the expression of their downstream transcription factors, krupple-like factor 4 (KLF4) and peroxisome proliferator-activated receptor gamma (PPAR-γ). These findings indicated that eucalyptol alleviates BLM-induced pulmonary fibrosis by regulating M2 macrophage polarization, which, in turn, inhibits the activation of signaling molecules (e.g., STAT6 and p38 MAPK) and the expression of transcription factors (e.g., KLF4 and PPAR-γ). Thus, eucalyptol might be a potential therapeutic agent for IPF.

PMID:35964659 | DOI:10.1016/j.ejphar.2022.175184