PLoS One. 2023 Feb 3;18(2):e0281295. doi: 10.1371/journal.pone.0281295. eCollection 2023.

ABSTRACT

INTRODUCTION: Although pirfenidone slows disease progression in patients with idiopathic pulmonary fibrosis (IPF), in clinical practice, patients often cannot tolerate the recommended dose because of several adverse events. This study aimed to investigate adverse events associated with pirfenidone and factors associated with dose reduction.

METHODS: This single-center retrospective cohort study included 156 consecutive patients with IPF who received pirfenidone. Demographic characteristics, pulmonary function, and pirfenidone-related adverse events were investigated. We compared patients who received standard and reduced doses of pirfenidone.

RESULTS: The mean patient age was 69.7 years. The median follow-up duration was 243 days. The low-dose group (n = 73) included older patients (71.0 years vs. 67.4 years, p = 0.016), fewer smokers (80.8% vs. 96.4%, p = 0.008), and patients with a lower body mass index (BMI; 24.1 kg/m2 vs. 25.7 kg/m2, p = 0.027) than the standard dose group (n = 57). Multivariate logistic regression analysis revealed that older age (odds ratio = 1.066, p = 0.016) was significantly associated with dose reduction of pirfenidone after adjusting for sex, smoking history, emphysema, and BMI. No significant difference was found in the rates of a reduced forced vital capacity and diffusing capacity for carbon monoxide between the two groups.

CONCLUSIONS: Although older patients are more likely to undergo dose reduction of pirfenidone, low-dose pirfenidone might be effective for treating patients with IPF. Low-dose pirfenidone could be considered an effective treatment option for older patients with IPF.

PMID:36735694 | DOI:10.1371/journal.pone.0281295

Evid Based Complement Alternat Med. 2023 Jan 24;2023:1973163. doi: 10.1155/2023/1973163. eCollection 2023.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease. Bilobalide (BB) is a sesquiterpene isolated from Ginkgo biloba, and its role in IPF is poorly understood. Mice were intratracheally instilled with 2.5 mg/kg bleomycin (BLM) to induce IPF and then treated with 2.5, 5, and 10 mg/kg BB daily for 21 days. Treatment with BB ameliorated pathological injury and fibrosis of lung tissues in BLM-induced mice. BB suppressed BLM-induced inflammatory response in mice as demonstrated by reduced inflammatory cells counts (leukocytes, neutrophils, macrophages, and lymphocytes) and pro-inflammatory factors (CCL2 and TNF-α), as well as increased CXCL10 levels in BALF. The expression of BLM-induced hydroxyproline, LDH, and pro-fibrotic mediators including fibronectin, collagen I, α-smooth muscle actin (α-SMA), transforming growth factor (TGF)-β1, matrix metalloproteinase (MMP)-2, and MMP-9 in lung tissue was inhibited by BB treatment, and the tissue inhibitor of metalloproteinase-1 (TIMP-1) expression was increased. BB blocked the phosphorylation of JNK and NF-κB, and the nuclear translocation of NF-κB in the lung tissue of mice induced by BLM. Additionally, it abated the activation of NLRP3 inflammasome in lung tissue induced by BLM, which led to the downregulation of IL-18 and IL-1β in BALF. Our present study suggested that BB might ameliorate BLM-induced pulmonary fibrosis by inhibiting the early inflammatory response, which is probably via the inhibition of the JNK/NF-κB/NLRP3 signal pathway. Thus, BB might serve as a therapeutic potential agent for pulmonary inflammation and fibrosis.

PMID:36733844 | PMC:PMC9889159 | DOI:10.1155/2023/1973163

Respirol Case Rep. 2023 Jan 30;11(3):e01085. doi: 10.1002/rcr2.1085. eCollection 2023 Mar.

ABSTRACT

This is the first case confirmed the association between PI development and nintedanib by the reproducibility of PI development. In patients taking a combination treatment with corticosteroid and nintedanib, clinicians should be careful regarding the development of PI although the patient improved only after discontinuation of nintedanib treatment.

PMID:36733310 | PMC:PMC9886854 | DOI:10.1002/rcr2.1085

BMC Pulm Med. 2023 Feb 2;23(1):51. doi: 10.1186/s12890-023-02336-4.

ABSTRACT

BACKGROUND: Pulmonary fibrosis (PF) is caused by a heterogeneous group of diseases, with a high inter-individual variability in disease trajectory. Identifying disease progression in patients with PF has impact on clinical management decisions. However, strategies to early identify and predict disease progression for these patients are currently lacking. In this study, we aim to assess long-term FVC change in patients with PF measured with home spirometry, and evaluate the feasibility of a multinational patient-led registry in PF. In addition, we will assess validity of patient-reported outcomes (PROMs) for the different subgroups of patients with PF.

METHODS: In this international, prospective, multicenter, observational study, we aim to include 700 patients across seven European countries. Patients will monitor their disease course for a period of two years using an online home monitoring program (I-FILE), which includes home spirometry, pulse oximetry, and PROMs. Results will be directly sent to the hospital via the online application. Patients will be asked to perform daily home spirometry and pulse oximetry in the first three months, followed by once weekly measurements for a period of two years. PROMs will be completed in the online I-FILE application every six months, including the King's brief Interstitial Lung Disease Health Status, The EuroQol five dimensions five-level, Visual Analogue Scales on cough, dyspnea, fatigue and general complaints, Leicester Cough Questionnaire, Fatigue Assessment Scale, Work Productivity and Activity Impairment Questionnaire, Global Rating of Change Scale, and Living with Pulmonary Fibrosis questionnaire.

DISCUSSION: This study will provide much needed insights in disease trajectories of the different subgroups of patients with PF. Simultaneously, the I-FILE study will yield valuable information on the use and feasibility of home-based data collection. This international patient-led registry will facilitate trans-border collaboration to further optimize care and research for patients with PF.

TRIAL REGISTRATION: The study was registered on the 12th of March 2020 in the International Clinical Trial Registry, www.

CLINICALTRIALS: gov ; Identifier: NCT04304898.

PMID:36732734 | PMC:PMC9893651 | DOI:10.1186/s12890-023-02336-4

Eur Respir J. 2023 Feb 2;61(2):2202113. doi: 10.1183/13993003.02113-2022. Print 2023 Feb.

NO ABSTRACT

PMID:36731901 | DOI:10.1183/13993003.02113-2022

Invest Radiol. 2022 Oct 25. doi: 10.1097/RLI.0000000000000935. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis is responsible for 40,000 deaths annually in the United States. A hallmark of idiopathic pulmonary fibrosis is elevated collagen deposition, which alters lung stiffness. Clinically relevant ways to measure changes in lung stiffness during pulmonary fibrosis are not available, and new noninvasive imaging methods are needed to measure changes in lung mechanical properties.

OBJECTIVES: Magnetic resonance elastography (MRE) is an in vivo magnetic resonance imaging technique proven to detect changes in shear stiffness in different organs. This study used MRE, histology, and bronchoalveolar lavage (BAL) to study changes in the mechanical and structural properties of the lungs after bleomycin-induced pulmonary fibrosis in pigs.

MATERIALS AND METHODS: Pulmonary fibrosis was induced in 9 Yorkshire pigs by intratracheal instillation of 2 doses of bleomycin into the right lung only. Magnetic resonance elastography scans were performed at baseline and week 4 and week 8 postsurgery in a 1.5 T magnetic resonance imaging scanner using a spin-echo echo planar imaging sequence to measure changes in lung shear stiffness. At the time of each scan, a BAL was performed. After the final scan, whole lung tissue was removed and analyzed for histological changes.

RESULTS: Mean MRE-derived stiffness measurements at baseline, week 4, and week 8 for the control (left) lungs were 1.02 ± 0.27 kPa, 0.86 ± 0.29 kPa, and 0.68 ± 0.20 kPa, respectively. The ratio of the shear stiffness in the injured (right) lung to the uninjured control (left) lung at baseline, week 4, and week 8 was 0.98 ± 0.23, 1.52 ± 0.41, and 1.64 ± 0.40, respectively. High-dose animals showed increased protein in BAL fluid, elevated inflammation observed by the presence of patchy filtrates, and enhanced collagen and α-smooth muscle actin staining on histological sections. Low-dose animals and the control (left) lungs of high-dose animals did not show significant histopathological changes.

CONCLUSION: This study demonstrated that MRE can be used to detect changes in lung stiffness in pigs after bleomycin challenge.

PMID:36730906 | DOI:10.1097/RLI.0000000000000935

ATS Sch. 2022 Nov 15;3(4):576-587. doi: 10.34197/ats-scholar.2022-0054OC. eCollection 2022 Dec.

ABSTRACT

BACKGROUND: Information regarding idiopathic pulmonary fibrosis (IPF) on the internet is often outdated, inaccurate, and potentially harmful. Twitter is a social media platform that allows users to post content in the form of "tweets".

OBJECTIVE: We sought to assess the prevalence of inaccurate information regarding IPF on Twitter. We hypothesized that foundations and medical organizations would be the least likely to post inaccurate information and that inaccurate tweets would have higher user engagement.

METHODS: All tweets posted between 2011 and 2019 were gathered using "snscrape" on Python 3.8 while searching for the phrase "idiopathic pulmonary fibrosis". Quantitative analysis was performed to describe trends in IPF-related tweet frequency over time. A subset of tweets made between 2018 and 2019 was screened for verifiable medical statements, which were then analyzed for accuracy compared with contemporary clinical practice guidelines, with descriptive statistics reported. Logistic regression was used to compare tweet accuracy and recommendation of nonindicated therapies across sources, with adjustment for tweet age and character count. Wilcoxon rank-sum tests were used to determine if user engagement (favorites, retweets, and replies) differed between accurate and inaccurate tweets.

RESULTS: A total of 16,787 tweets were identified between 2011 and 2019. Between 2018 and 2019, 4,861 tweets were included, of which 1,612 (33%) contained verifiable medical statements. Tweets from sources other than foundations or medical organizations were more likely to contain inaccurate information and to recommend nonindicated therapies in both unadjusted and adjusted analyses. News and media sources had the highest odds of communicating potentially harmful information in both adjusted (odds ratio [OR], 12.00; 95% confidence interval [CI], 5.87-27.16) and unadjusted (OR, 11.62; 95% CI, 5.70-26.21) analyses when compared with foundations and medical organizations. Tweets containing inaccurate information had significantly lower numbers of favorites and retweets (P < 0.001 for both).

CONCLUSION: Misinformation regarding IPF is present on Twitter and is more often presented by news and media sources. Medically inaccurate tweets displayed less user engagement than accurate tweets. This differs from findings on IPF-related information on YouTube and Facebook, which may reflect differences in both author and consumer qualities across social media platforms.

PMID:36726707 | PMC:PMC9886131 | DOI:10.34197/ats-scholar.2022-0054OC

BMJ Open Respir Res. 2023 Feb;10(1):e001391. doi: 10.1136/bmjresp-2022-001391.

ABSTRACT

RATIONALE: Contribution of central lung tissues to pathogenesis of idiopathic pulmonary fibrosis (IPF) remains unknown.

OBJECTIVE: To ascertain the relationship between cell types of IPF-central and IPF-peripheral lung explants using RNA sequencing (RNA-seq) transcriptome.

METHODS: Biopsies of paired IPF-central and IPF-peripheral along with non-IPF lungs were selected by reviewing H&E data. Criteria for differentially expressed genes (DEG) were set at false discovery rate <5% and fold change >2. Computational cell composition deconvolution was performed. Signature scores were computed for each cell type.

FINDINGS: Comparison of central IPF versus non-IPF identified 1723 DEG (1522 upregulated and 201 downregulated). Sixty-two per cent (938/1522) of the mutually upregulated genes in central IPF genes were also upregulated in peripheral IPF versus non-IPF. Moreover, 85 IPF central-associated genes (CAG) were upregulated in central IPF versus both peripheral IPF and central non-IPF. IPF single-cell RNA-seq analysis revealed the highest CAG signature score in myofibroblasts and significantly correlated with a previously published activated fibroblasts signature (r=0.88, p=1.6×10-4). CAG signature scores were significantly higher in IPF than in non-IPF myofibroblasts (p=0.013). Network analysis of central-IPF genes identified a module significantly correlated with the deconvoluted proportion of myofibroblasts in central IPF and anti-correlated with inflammation foci trait in peripheral IPF. The module genes were over-represented in idiopathic pulmonary fibrosis signalling pathways.

INTERPRETATION: Gene expression in central IPF lung regions demonstrates active myofibroblast features that contributes to disease progression. Further elucidation of pathological transcriptomic state of cells in the central regions of the IPF lung that are relatively spared from morphological rearrangements may provide insights into molecular changes in the IPF progression.

PMID:36725082 | DOI:10.1136/bmjresp-2022-001391

RMD Open. 2023 Jan;9(1):e002828. doi: 10.1136/rmdopen-2022-002828.

ABSTRACT

BACKGROUND: Interstitial lung disease (ILD) occasionally occurs in rheumatoid arthritis (RA) and confers a dismal prognosis. We previously reported that a single-nucleotide variant (SNV) of MUC5B was associated with ILD in RA. However, the pathogenesis of ILD in Japanese patients with RA could not be explained solely by this SNV because its frequency is extremely low in the Japanese population. Here, we examined whether a different idiopathic pulmonary fibrosis susceptibility SNV might be associated with ILD in Japanese patients with RA.

METHODS: Genotyping of rs2609255 (G/T) in FAM13A was conducted in 208 patients with RA with ILD and 420 without chronic lung disease using TaqMan assays.

RESULTS: A significant association with usual interstitial pneumonia (UIP) in RA was detected for rs2609255 under the allele model (p=0.0092, Pc=0.0276, OR 1.53, 95% CI 1.12 to 2.11) and recessive model for the G allele (p=0.0003, Pc=0.0009, OR 2.63, 95% CI 1.59 to 4.32). FAM13A rs2609255 was significantly associated with UIP in male patients with RA (p=0.0043, OR 3.65, 95% CI 1.52 to 8.73) under the recessive model.

CONCLUSIONS: This study is the first to document an association of rs2609255 with ILD in Japanese patients with RA, implicating it in the pathogenesis of UIP, though studies on the function of rs2609255 are warranted.

PMID:36717188 | DOI:10.1136/rmdopen-2022-002828

Curr Tissue Microenviron Rep. 2022 Dec;3(4):83-97. doi: 10.1007/s43152-022-00040-9. Epub 2022 Jul 13.

ABSTRACT

PURPOSE OF REVIEW: The current paradigm of idiopathic pulmonary fibrosis (IPF) pathogenesis involves recurrent injury to a sensitive alveolar epithelium followed by impaired repair responses marked by fibroblast activation and deposition of extracellular matrix. Multiple cell types are involved in this response with potential roles suggested by advances in single-cell RNA sequencing and lung developmental biology. Notably, recent work has better characterized the cell types present in the pulmonary endothelium and identified vascular changes in patients with IPF.

RECENT FINDINGS: Lung tissue from patients with IPF has been examined at single-cell resolution, revealing reductions in lung capillary cells and expansion of a population of vascular cells expressing markers associated with bronchial endothelium. In addition, pre-clinical models have demonstrated a fundamental role for aging and vascular permeability in the development of pulmonary fibrosis.

SUMMARY: Mounting evidence suggests that the endothelium undergoes changes in the context of fibrosis, and these changes may contribute to the development and/or progression of pulmonary fibrosis. Additional studies will be needed to further define the functional role of these vascular changes.

PMID:36712832 | PMC:PMC9881604 | DOI:10.1007/s43152-022-00040-9

Respir Med Case Rep. 2023 Jan 19;42:101815. doi: 10.1016/j.rmcr.2023.101815. eCollection 2023.

ABSTRACT

Diffuse pulmonary ossification (DPO) is a rare pulmonary condition characterized by the diffuse formation of mature bone in the lungs. Pulmonary ossification, in general, can be subdivided into diffuse pulmonary ossification (DPO) and nodular pulmonary ossification (NPO). DPO occurs most commonly in the settings of chronic pulmonary conditions; however, idiopathic cases have been reported. We present a case of DPO in a 36-year-old man with progressive exertional dyspnea, productive cough, and occasional hemoptysis. Imaging studies showed innumerable pulmonary nodules scattered throughout both lungs. Initially, the diagnoses of pulmonary alveolar microlithiasis (PAM) or, less likely miliary tuberculosis (TB) were considered. However, Quantiferon TB test was negative and genetic testing was negative for SLC34A2, lowering the probability of PAM. The patient underwent a segmentectomy. Microscopic examination showed ramifying spicules of mature woven bone and fatty marrow consistent with DPO. There were no significant underlying pathologic findings, such as interstitial fibrosis, granulomas, organizing pneumonia, or significant inflammation in the background lung parenchyma. In conclusion, clinicians and radiologists need to be aware of DPO in the differential diagnosis of miliary tuberculosis and pulmonary alveolar microlithiasis. The absence of an underlying chronic pulmonary condition does not exclude the possibility of DPO.

PMID:36712477 | PMC:PMC9874059 | DOI:10.1016/j.rmcr.2023.101815

Can Respir J. 2023 Jan 18;2023:1522593. doi: 10.1155/2023/1522593. eCollection 2023.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic disease characterized by excessive deposition of extracellular matrix in the interstitial lung parenchyma, often manifested by dyspnea and progressive loss of lung function. The role of inflammation in the pathogenesis of IPF is not well understood. This study evaluated the histopathological and inflammatory components of bleomycin-induced pulmonary fibrosis in mouse and sheep models, in terms of their ability to translate to the human IPF. Merino sheep (n = 8) were bronchoscopically administered with two bleomycin infusions, two weeks apart, into a caudal lung segment, with a saline (control) administered into a caudal segment in the opposite lung. Balb/c mice were twice intranasally instilled, one week apart, with either bleomycin (n = 7); or saline (control, n = 7). Lung samples were taken for the histopathological assessment 28 days in sheep and 21 days in mice after the first bleomycin administration. We observed tertiary lymphoid aggregates, in the fibrotic lung parenchyma of sheep, but not in mouse lung tissues exposed to bleomycin. B-cell and T-cell infiltration significantly increased in sheep lung tissues compared to mouse lung tissues due to bleomycin injury. Statistical analysis showed that the fibrotic score, fibrotic fraction, and tissue fraction significantly increased in sheep lung tissues compared to murine lung tissues. The presence of tertiary lymphoid aggregates in the lung parenchyma and increased infiltration of T-cells and B-cells, in the sheep model, may be useful for the future study of the underlying inflammatory disease mechanisms in the lung parenchyma of IPF patients.

PMID:36710924 | PMC:PMC9876680 | DOI:10.1155/2023/1522593

Biomed Pharmacother. 2023 Jan 26;159:114258. doi: 10.1016/j.biopha.2023.114258. Online ahead of print.

ABSTRACT

Cyclin-dependent protein kinase 8 (CDK8) plays important roles in regulating fibrotic growth factors and inflammatory signaling pathways. Long-term chronic inflammation of the lungs can lead to idiopathic pulmonary fibrosis (IPF). Abnormal alveolar epithelial regeneration leads to the release of various fibrotic growth factors and the activation of inflammatory cells. CDK8 regulates profibrotic cytokines broadly implicated in the pathogenesis of fibrosis. Therefore, inhibition of CDK8 is considered a promising strategy for treating IPF. Here, CDK8 inhibitors were designed and optimized using a fragment-based drug design strategy. Testing results revealed that 71% of the synthesized compounds inhibited CDK8 activity better than the original compound E966-0530. Of these compounds, compound 4k exhibited the strongest CDK8 enzyme-inhibiting activity (IC50 =129 nM). Notably, it displayed a 13-fold increase in potency when compared to E966-0530. Experiments on toxicity and inhibition of epithelial-mesenchymal transition (EMT) protein expressions showed that compound 4k can inhibit EMT protein expressions, but with no significant cytotoxicity for alveolar epithelial cells. Compound 4k showed a potent inhibitory effect in cell migration assays. Furthermore, compound 4k significantly inhibited the phosphorylation of p-Smad3 and RNA Pol II, which are critical mediators in the fibrotic response signaling pathway. Compound 4k remarkably reduced TGF-β1-induced oxidative stress. The above results reveal optimized CDK8 inhibitors with potential use for IPF therapeutic treatment.

PMID:36708700 | DOI:10.1016/j.biopha.2023.114258

Front Pharmacol. 2023 Jan 10;13:1025947. doi: 10.3389/fphar.2022.1025947. eCollection 2022.

ABSTRACT

Background: Pirfenidone, an antifibrotic medication approved for the treatment of idiopathic pulmonary fibrosis (IPF), often requires dose reduction owing to adverse events. In this study, we evaluated if pirfenidone's reduced dose has any impact on clinical outcomes in patients with IPF. Methods: We used the data of a prospective post-marketing study of pirfenidone conducted at 10 hospitals in South Korea from 2014 to 2017. Dose reduction was defined when the pirfenidone dose was temporarily or permanently reduced to manage adverse events or when the treatment dose failed to reach the standard dose. Study patients were classified based on the most frequently administered dose during 48-week follow-up-1800 mg, 1,200 mg, and <1,200 mg/days. The following clinical outcomes were compared between the groups: death, hospitalization, acute exacerbation, pulmonary function decline, and changes in severity of dyspnea and cough. Results: The median follow-up duration in all 143 patients was 11 months. During the study period, 70.6% experienced at least one dose reduction. Patients treated with standard-dose pirfenidone tended to be young and had the lowest diffusing capacity. Pulmonary function changes did not differ depending on the pirfenidone dose. The three groups were not significantly different in terms of the proportion of death, hospitalization, and acute exacerbation. The symptom changes were also similar between the groups. Conclusion: Reduced doses did not negatively impact clinical outcomes compared with the standard-dose pirfenidone in patients with IPF. Dose reduction may be a useful method to manage adverse events while maintaining therapeutic efficacy.

PMID:36703754 | PMC:PMC9871582 | DOI:10.3389/fphar.2022.1025947

Eur Respir J. 2023 Jan 26:2200957. doi: 10.1183/13993003.00957-2022. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease characterized by worsening respiratory symptoms and physiologic impairment. Increasing awareness of the clinical manifestations of IPF, more widespread use of computed tomography scans, and other potential factors have contributed to a rising prevalence of IPF over the last two decades, especially among people over the age of 65. Significant advances in the understanding of the pathobiology of IPF have emerged, and multiple genetic and nongenetic contributors have been identified. The individual patient course and the rate of disease progression in IPF are often unpredictable and heterogeneous. The rate of lung function decline is further modified by treatment with antifibrotic therapies, which have been shown to slow down disease progression. The presence of comorbid conditions may increase symptom burden and impact survival. Clinical monitoring at regular intervals to assess for disease progression by worsening symptoms, physiologic parameters, and/or radiological features is essential to assess the natural disease course, and to guide further management, including prompt detection of complications and comorbid conditions that warrant additional treatment considerations, and timely consideration of referral to palliative care and lung transplantation for the appropriate patient. More studies are needed to determine whether early detection of IPF might improve patient outcomes. The purpose of this concise clinical review is to provide an update on IPF diagnosis, epidemiology, natural history and treatment in the context of new knowledge and latest clinical practice guidelines.

PMID:36702498 | DOI:10.1183/13993003.00957-2022

Eur J Med Chem. 2023 Jan 23;249:115130. doi: 10.1016/j.ejmech.2023.115130. Online ahead of print.

ABSTRACT

Robust experimental evidence has highlighted the role of Autotaxin (ATX)/Lysophosphatidic acid (LPA) axis not only in the pathogenesis of chronic inflammatory conditions and especially in fibroproliferative diseases but also in several types of cancer. As a result, different series of substrate-, lipid-based and small-molecule ATX inhibitors have been identified thus far by both academia and pharma. The "crowning achievement" of these drug discovery campaigns was the development and entry of the first-in-class ATX inhibitor (ziritaxestat, GLPG-1690) in advanced clinical trials against idiopathic pulmonary fibrosis. Herein, the potency optimization efforts of a new series of Autotaxin inhibitors, namely 2-substituted-2,6-dihydro-4H-thieno[3,4-c]pyrazol-1-substituted amide, is described using a previously identified novel chemical scaffold as a "hit". The mode of inhibition of the most promising ATX inhibitors was investigated, while their cellular activity, aqueous solubility and cytotoxicity were evaluated. Our pharmacological results were corroborated by chemoinformatic tools (molecular docking and molecular dynamics simulations) deployed, to provide insight into the binding mechanism of the synthesized inhibitors to ATX.

PMID:36702053 | DOI:10.1016/j.ejmech.2023.115130

Int Immunopharmacol. 2023 Jan;114:109570. doi: 10.1016/j.intimp.2022.109570. Epub 2022 Dec 19.

ABSTRACT

The understanding of pathogenesis underlying idiopathic pulmonary fibrosis (IPF) is still limited presently. Monocytes or macrophages are involved in progression of the pulmonary injury and repair. The aim of this study is to investigate the roles of CD11b+ monocytes/macrophages in the progression of pulmonary fibrosis. In this study, the expression levels of CD11B gene and inflammatory genes in the IPF patients are evaluated using the available datasets. CD11b cells are conditionally depleted in a CD11b-diptheria toxin receptor (CD11b-DTR) mouse by administration of diptheria toxin (DT). Pulmonary fibrosis in mice is induced using intranasalbleomycin. The mRNAs and proteins expression in lung tissues are determined by quantitative real-time polymerase chain reaction (qRT-PCR), immunofluorescence (IF) staining and Western-blot assays. It shows that the expression of CD11B mRNA is up-regulated in fibrotic lungs and alveolar macrophages of IPF patients and bleomycin-treated rodents. Selective depletion of CD11b+ monocytes/macrophages in CD11b-DTR mice potently halts bleomycin-induced pulmonary fibrosis progression. CD11b depletion inhibits the polarization of macrophages in the fibrotic lungs. Mechanically, CD11b deficiency represses the activation of sphingosine 1-phosphate receptor 2 (S1PR2)/sphingosine kinase 2 (SphK2) signaling during pulmonary fibrosis. In conclusion, our data suggest that CD11b+ monocytes/macrophages contribute to pulmonary fibrosis and represent a potential therapeutic target for IPF.

PMID:36700767 | DOI:10.1016/j.intimp.2022.109570

AJP Rep. 2023 Jan 23;13(1):e1-e4. doi: 10.1055/s-0043-1760758. eCollection 2023 Jan.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive restrictive lung disease. Data on the impact of pregnancy on IPF and maternal outcome is extremely limited. We present the case of a 35-year-old woman, gravida 1 para 0 with familial IPF with no oxygen requirement prior to pregnancy. The patient demonstrated significant deterioration in her lung function beginning at 22 weeks' gestation and underwent hospitalization at 27 2/7 weeks gestation due to acute on chronic hypoxic respiratory failure, ultimately requiring delivery at 28 weeks' gestation. The patient has not regained her baseline pulmonary function and remains oxygen dependent at 5 months postpartum. Based on limited available data, significant maternal morbidity and mortality is reported for women with IPF who become pregnant. Key Points Pregnancy outcomes in IPF are more severe than chronic interstitial lung disease due to connective tissue disorders.Deterioration in lung function amongst pregnant women with IPF occurs predominantly in the late second trimester, and lung function does not appear to recover postpartum.Significant maternal morbidity and mortality (40% at 1 year postpartum) is reported for women with IPF who become pregnant.

PMID:36699133 | PMC:PMC9870671 | DOI:10.1055/s-0043-1760758

Int Immunopharmacol. 2023 Jan 23;116:109723. doi: 10.1016/j.intimp.2023.109723. Online ahead of print.

ABSTRACT

Systemic sclerosis (SSc) is an autoimmune fibrotic disorder notably characterized by the production of antinuclear autoantibodies, which have been linked to an excess of apoptotic cells, normally eliminated by a macrophagic efferocytosis. As interferon (IFN) signature and phosphorylation of JAK-STAT proteins are hallmarks of SSc tissues, we tested the hypothesis that a JAK inhibitor, ruxolitinib, targeting the IFN signaling, could improve efferocytosis of IFN-exposed human macrophages in vitro as well as skin and lung fibrosis. In vivo, BLM- and HOCl-induced skin thickness and fibrosis is associated with an increase of caspase-3 positive dermal cells and a significant increase of IFN-stimulated genes expression. In BLM-SSc model, ruxolitinib prevented dermal thickness, fibrosis and significantly decreased the number of cleaved caspase-3 cells in the dermis. Ruxolitinib also improved lung architecture and fibrosis although IFN signature was not entirely decreased by ruxolitinib. In vitro, ruxolitinib improves efferocytosis capacity of human monocyte-differentiated macrophages exposed to IFN-γ or IFN-β. In human fibroblasts derived from lung (HLF) biopsies isolated from patients with idiopathic pulmonary fibrosis, the reduced mRNA expression of typical TGF-β-activated markers by ruxolitinib was associated with a decrease of the phosphorylation of SMAD2 /3 and STAT3. Our finding supports the anti-fibrotic properties of ruxolitinib in a systemic SSc mouse model and in vitro in human lung fibroblasts.

PMID:36696855 | DOI:10.1016/j.intimp.2023.109723

Rev Endocr Metab Disord. 2023 Jan 25. doi: 10.1007/s11154-023-09786-5. Online ahead of print.

ABSTRACT

Phase angle (PhA) represents a raw variable measured with bioelectrical impedance analysis (BIA) that is used to assess malnutrition in many diseases, including respiratory diseases, mainly chronic obstructive pulmonary disease (COPD). COPD patients with reduced PhA are older, more hypoxic and hypercapnic; patients with more severe COPD have reduced cell mass, evident skeletal muscle depletion, and worsening gas exchange. Malnourished patients with stable COPD in long-term oxygen therapy (LTOT) have more intense dyspnea at rest, greater weight loss over the past 12 months, and more exacerbations per year. Multiple regression analysis highlighted the significance of PhA° in the estimation of muscle strength: hand grip strength (HGS) and in that of respiratory muscles: maximal inspiratory pressure / max. expiratory pressure ratio (MIP/MEP). Furthermore, the relationship between PhA° and all-cause mortality in COPD patients was confirmed with the Cox regression model, Kaplan-Meier test, and log-rank tests. The role of malnutrition in idiopathic pulmonary fibrosis (IPF) is confirmed by the PhA° measurements which, regardless of body weight, is associated with the reduction in muscle mass of these patients, reduces their strength and exercise capacity, and greatly influences the prognosis. In conclusion PhA is a novel biomarker of morbidity and mortality in patients with severe respiratory diseases.

PMID:36694055 | DOI:10.1007/s11154-023-09786-5