ERJ Open Res. 2023 Jul 17;9(4):00738-2022. doi: 10.1183/23120541.00738-2022. eCollection 2023 Jul.

ABSTRACT

BACKGROUND: The Lung Allocation Score (LAS) prioritises lung transplantation candidates, balancing waitlist mortality and post-transplant survival. The score groups sarcoidosis candidates based on mean pulmonary artery pressure: those with ≤30 mmHg (sarcoidosis A) are grouped with COPD and those with >30 mmHg (sarcoidosis D) with idiopathic pulmonary fibrosis (IPF). We hypothesise that sarcoidosis candidates have a higher waitlist mortality than other candidates within their LAS grouping.

METHODS: This is a retrospective cohort study of consecutive lung transplantation candidates from the Scientific Registry of Transplant Recipients database from May 2005 to May 2019. We included candidates aged ≥18 years diagnosed with sarcoidosis, COPD or IPF. Univariate, multivariate and survival estimate analyses were performed.

RESULTS: We identified 385 sarcoidosis A, 642 sarcoidosis D, 7081 COPD and 10 639 IPF lung transplantation candidates. 17.3% of sarcoidosis D, 14.8% of IPF, 14.3% of sarcoidosis A and 9.8% of COPD candidates died awaiting transplant. Sarcoidosis A was an independent risk factor for waitlist mortality. Sarcoidosis A had a lower waitlist survival probability compared to COPD. Sarcoidosis D had the highest waitlist mortality. IPF candidates had lower waitlist survival probability than sarcoidosis D in the first 60 days after listing.

CONCLUSION: Based on our results, the grouping of candidates with sarcoidosis in allocation systems should be revised to mitigate waitlist mortality disparity.

PMID:37465560 | PMC:PMC10350678 | DOI:10.1183/23120541.00738-2022

ERJ Open Res. 2023 Jul 17;9(4):00690-2022. doi: 10.1183/23120541.00690-2022. eCollection 2023 Jul.

ABSTRACT

This study provides the first evidence for a role of airway sCSF1R in IPF https://bit.ly/3KTBrCA.

PMID:37465557 | PMC:PMC10350676 | DOI:10.1183/23120541.00690-2022

J Med Chem. 2023 Jul 18. doi: 10.1021/acs.jmedchem.3c00644. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis is incurable, and its progression is difficult to control and thus can lead to pulmonary deterioration. Pan-histone deacetylase inhibitors such as SAHA have shown potential for modulating pulmonary fibrosis yet with off-target effects. Therefore, selective HDAC inhibitors would be beneficial for reducing side effects. Toward this goal, we designed and synthesized 24 novel HDAC6, HDAC8, or dual HDAC6/8 inhibitors and established a two-stage screening platform to rapidly screen for HDAC inhibitors that effectively mitigate TGF-β-induced pulmonary fibrosis. The first stage consisted of a mouse NIH-3T3 fibroblast prescreen and yielded five hits. In the second stage, human pulmonary fibroblasts (HPFs) were used, and four out of the five hits were tested for caco-2 permeability and liver microsome stability to give two potential leads: J27644 (15) and 20. This novel two-stage screen platform will accelerate the discovery and reduce the cost of developing HDAC inhibitors to mitigate TGF-β-induced pulmonary fibrosis.

PMID:37463500 | DOI:10.1021/acs.jmedchem.3c00644

J Clin Invest. 2023 Jul 17;133(14):e170498. doi: 10.1172/JCI170498.

ABSTRACT

Mesenchymal cells are uniquely located at the interface between the epithelial lining and the stroma, allowing them to act as a signaling hub among diverse cellular compartments of the lung. During embryonic and postnatal lung development, mesenchyme-derived signals instruct epithelial budding, branching morphogenesis, and subsequent structural and functional maturation. Later during adult life, the mesenchyme plays divergent roles wherein its balanced activation promotes epithelial repair after injury while its aberrant activation can lead to pathological remodeling and fibrosis that are associated with multiple chronic pulmonary diseases, including bronchopulmonary dysplasia, idiopathic pulmonary fibrosis, and chronic obstructive pulmonary disease. In this Review, we discuss the involvement of the lung mesenchyme in various morphogenic, neomorphogenic, and dysmorphogenic aspects of lung biology and health, with special emphasis on lung fibroblast subsets and smooth muscle cells, intercellular communication, and intrinsic mesenchymal mechanisms that drive such physiological and pathophysiological events throughout development, homeostasis, injury repair, regeneration, and aging.

PMID:37463440 | DOI:10.1172/JCI170498

PLoS Genet. 2023 Jul 18;19(7):e1010856. doi: 10.1371/journal.pgen.1010856. Online ahead of print.

ABSTRACT

Premature telomere shortening is a known factor correlated to idiopathic pulmonary fibrosis (IPF) occurrence, which is a chronic, progressive, age-related disease with high mortality. The etiology of IPF is still unknown. Here, we found that UBQLN1 plays a key role in telomere length maintenance and is potentially relevant to IPF. UBQLN1 involves in DNA replication by interacting with RPA1 and shuttling it off from the replication fork. The deficiency of UBQLN1 retains RPA1 at replication fork, hinders replication and thus causes cell cycle arrest and genome instability. Especially at telomere regions of the genome, where more endogenous replication stress exists because of G rich sequences, UBQLN1 depletion leads to rapid telomere shortening in HeLa cells. It revealed that UBQLN1 depletion also shortens telomere length at mouse lung and accelerates mouse lung fibrosis. In addition, the UBQLN1 expression level in IPF patients is downregulated and correlated to poor prognosis. Altogether, these results uncover a new role of UBQLN1 in ensuring DNA replication and maintaining telomere stability, which may shed light on IPF pathogenesis and prevention.

PMID:37463174 | DOI:10.1371/journal.pgen.1010856

Cell Biol Toxicol. 2023 Jul 18. doi: 10.1007/s10565-023-09799-5. Online ahead of print.

ABSTRACT

Gasdermin (GSDM) family, the key executioners of pyroptosis, play crucial roles in anti-pathogen and anti-tumor immunities, although little is known about the expression of GSDM in lung diseases at single-cell resolution, especially in lung epithelial cells. We comprehensively investigated the transcriptomic profiles of GSDM members in various lung tissues from healthy subjects or patients with different lung diseases at single cell level, e.g., chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), lung adenocarcinoma (LUAD), or systemic sclerosis (SSC). The expression of GSDM members varied among pulmonary cell types (immune cells, structural cells, and especially epithelial cells) and even across lung diseases. Regarding disease-associated specificities, we found that GSDMC or GSDMD altered significantly in ciliated epithelia of COPD or LUAD, GSDMD in mucous, club, and basal cells of LUAD and GSDMC in mucous epithelia of para-tumor tissue, as compared with the corresponding epithelia of other diseases. The phenomic specificity of GSDM in lung cancer subtypes was noticed by comparing with 15 non-pulmonary cancers and para-cancer samples. GSDM family gene expression changes were also observed in different lung epithelial cell lines (e.g., HBE, A549, H1299, SPC-1, or H460) in responses to external challenges, including lipopolysaccharide (LPS), lysophosphatidylcholine (lysoPC), cigarette smoking extract (CSE), cholesterol, and AR2 inhibitor at various doses or durations. GSDMA is rarely expressed in those cell lines, while GSDMB and GSDMC are significantly upregulated in human lung epithelia. Our data indicated that the heterogeneity of GSDM member expression exists at different cells, pathologic conditions, challenges, probably dependent upon cell biological phenomes, functions, and behaviors, upon cellular responses to external changes, and the nature and severity of lung disease. Thus, the deep exploration of GSDM phenomes may provide new insights into understanding the single-cell roles in the tissue, regulatory roles of the GSDM family in the pathogenesis, and potential values of biomarker identification and development.

PMID:37462807 | DOI:10.1007/s10565-023-09799-5

Cell Death Discov. 2023 Jul 17;9(1):252. doi: 10.1038/s41420-023-01538-3.

ABSTRACT

Cellular senescence is involved in the development of pulmonary fibrosis as well as in lung tissue repair and regeneration. Therefore, a strategy of removal of senescent cells by senolytic drugs may not produce the desired therapeutic result. Previously we reported that tyrosine kinase Fgr is upregulated in ionizing irradiation-induced senescent cells. Inhibition of Fgr reduces the production of profibrotic proteins by radiation-induced senescent cells in vitro; however, a mechanistic relationship between senescent cells and radiation-induced pulmonary fibrosis (RIPF) has not been established. We now report that senescent cells from the lungs of mice with RIPF, release profibrotic proteins for target cells and secrete chemotactic proteins for marrow cells. The Fgr inhibitor TL02-59, reduces this release of profibrotic chemokines from the lungs of RIPF mice, without reducing numbers of senescent cells. In vitro studies demonstrated that TL02-59 abrogates the upregulation of profibrotic genes in target cells in transwell cultures. Also, protein arrays using lung fibroblasts demonstrated that TL02-59 inhibits the production of chemokines involved in the migration of macrophages to the lung. In thoracic-irradiated mice, TL02-59 prevents RIPF, significantly reduces levels of expression of fibrotic gene products, and significantly reduces the recruitment of CD11b+ macrophages to the lungs. Bronchoalveolar lavage (BAL) cells from RIPF mice show increased Fgr and other senescent cell markers including p16. In human idiopathic pulmonary fibrosis (IPF) and in RIPF, Fgr, and other senescent cell biomarkers are increased. In both mouse and human RIPF, there is an accumulation of Fgr-positive proinflammatory CD11b+ macrophages in the lungs. Thus, elevated levels of Fgr in lung senescent cells upregulate profibrotic gene products, and chemokines that might be responsible for macrophage infiltration into lungs. The detection of Fgr in senescent cells that are obtained from BAL during the development of RIPF may help predict the onset and facilitate the delivery of medical countermeasures.

PMID:37460469 | DOI:10.1038/s41420-023-01538-3

Am J Physiol Cell Physiol. 2023 Jul 17. doi: 10.1152/ajpcell.00239.2023. Online ahead of print.

ABSTRACT

Pulmonary fibrosis comprises a range of chronic interstitial lung diseases (ILD) that significantly burden patients and public health. Among these, idiopathic pulmonary fibrosis (IPF), a disease of aging, is the most common and most severe form of ILD and is treated largely by lung transplantation. The lack of effective treatments to stop or reverse lung fibrosis - in fact, fibrosis in most organs - has sparked the need to understand causative mechanisms with the goal of identifying critical points for potential therapeutic intervention. Findings from many groups have indicated that repeated injury to the alveolar epithelium - where gas exchange occurs - leads to stem cell exhaustion and impaired alveolar repair that, in turn, triggers in the onset and progression of fibrosis. Cellular senescence of alveolar epithelial progenitors is a critical cause of stemness failure. Hence, senescence impairs repair and thus contributes significantly to fibrosis. In this review, we discuss recent evidence indicating that senescence of epithelial progenitor cells impairs alveolar homeostasis and repair, creating a profibrotic environment. Moreover, we discuss the impact of senescence alveolar epithelial progenitors, alveolar type 2 (AT2) cells, and AT2-derived transitional epithelial cells in fibrosis. Emerging evidence indicates that transitional epithelial cells are prone to senescence and, hence, are a new player involved in senescence-associated lung fibrosis. Understanding the complex interplay of cell types and cellular regulatory factors contributing to alveolar epithelial progenitor senescence will be crucial to developing targeted therapies to mitigate their downstream profibrotic sequelae and to promote normal alveolar repair.

PMID:37458437 | DOI:10.1152/ajpcell.00239.2023

Front Med (Lausanne). 2023 Jun 30;10:1067149. doi: 10.3389/fmed.2023.1067149. eCollection 2023.

ABSTRACT

BACKGROUND: Health-related quality of life (HRQoL) captures different aspects of the fibrotic interstitial lung disease (FILD) evaluation from the patient's perspective. However, little is known about how HRQoL changes in patients with non-idiopathic pulmonary fibrosis (IPF) FILD, especially in those with progressive pulmonary fibrosis (PPF). The aim of this study is to clarify whether HRQoL deteriorates in patients with non-IPF FILD and to evaluate the differences in the changes in HRQoL between those with and without PPF.

METHODS: We collected data from consecutive patients with non-IPF FILD and compared annual changes in HRQoL over 2 years between patients with PPF and those without. The St George's respiratory questionnaire (SGRQ) and COPD assessment test (CAT) were used to assess HRQoL. Changes in the SGRQ and CAT scores for 24 months from baseline were evaluated with a mixed-effect model for repeated measures.

RESULTS: A total of 396 patients with non-IPF FILD were reviewed. The median age was 65 years and 202 were male (51.0%). The median SGRQ and CAT scores were 29.6 and 11, respectively. Eighty-six (21.7%) showed PPF. Both SGRQ and CAT scores were significantly deteriorated in patients with PPF compared to those without PPF (p < 0.01 for both). Clinically important deterioration in the SGRQ and CAT scores were observed in 40.0 and 35.7% of patients with PPF and 11.7 and 16.7% of those without, respectively. PPF was significantly associated with clinically important deterioration in the SGRQ score (odds ratio 5.04; 95%CI, 2.61-9.76, p < 0.01) and CAT score (odds ratio 2.78; 95%CI, 1.27-6.06, p = 0.02).

CONCLUSION: The SGRQ and CAT scores were significantly deteriorated in patients with non-IPF FILD and PPF. Considering an evaluation of HRQoL would be needed when assessing PPF.

PMID:37457568 | PMC:PMC10347395 | DOI:10.3389/fmed.2023.1067149

Int J Mol Sci. 2023 Jun 28;24(13):10748. doi: 10.3390/ijms241310748.

ABSTRACT

Hypersensitivity pneumonitis (HP) is an exposure-related interstitial lung disease with two phenotypes-fibrotic and non-fibrotic. Genetic predisposition is an important factor in the disease pathogenesis and fibrosis development. Several genes are supposed to be associated with the fibrosing cascade in the lungs. One of the best-recognized and most prevalent is the common MUC5B gene promoter region polymorphism variant rs35705950. The aim of our study was to establish the frequency of the minor allele of the MUC5B gene in the population of patients with HP and to find the relationship between the MUC5B promoter region polymorphism and the development of lung fibrosis, the severity of the disease course, and the response to the treatment in patients with HP. Eighty-six consecutive patients with HP were tested for the genetic variant rs35705950 of the MUC-5B gene. Demographic, radiological, and functional parameters were collected. The relationship between the presence of the T allele and lung fibrosis, pulmonary function test parameters, and the treatment response were analyzed. The minor allele frequency in the study group was 17%, with the distribution of the genotypes GG in 69.8% of subjects and GT/TT in 30.2%. Patients with the GT/TT phenotype had significantly lower baseline forced vital capacity (FVC) and significantly more frequently had a decline in FVC with time. The prevalence of lung fibrosis in high-resolution computed tomography (HRCT) was not significantly increased in GT/TT variant carriers compared to GG ones. The patients with the T allele tended to respond worse to immunomodulatory treatment and more frequently received antifibrotic drugs. In conclusions: The frequency of MUC5B polymorphism in HP patients is high. The T allele may indicate a worse disease course, worse immunomodulatory treatment response, and earlier need for antifibrotic treatment.

PMID:37445925 | PMC:PMC10341926 | DOI:10.3390/ijms241310748

Biochim Biophys Acta Mol Cell Res. 2023 Jul 12:119535. doi: 10.1016/j.bbamcr.2023.119535. Online ahead of print.

ABSTRACT

Ferroptosis, a newly discovered type of regulated cell death, has been implicated in numerous human diseases. Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal interstitial lung disease with poor prognosis and limited treatment options. Emerging evidence has linked ferroptosis and glutamate-determined cell fate which is considered a new light on the etiology of pulmonary fibrosis. Here, we observed that N-methyl d-aspartate receptor (NMDAR) activation promoted cell damage and iron deposition in MLE-12 cells in a dose-, time-, and receptor-dependent manner. This mediated substantial Ca2+ influx, upregulated the expression levels of nNOS and IRP1, and affected intracellular iron homeostasis by regulating the expression of iron transport-related proteins (i.e., TFR1, DMT1, and FPN). Excessive iron load promoted the continuous accumulation of total intracellular and mitochondrial reactive oxygen species, which ultimately led to ferroptosis. NMDAR inhibition reduced lung injury and pulmonary fibrosis in bleomycin-induced mice. Bleomycin stimulation upregulated the expression of NMDAR1, nNOS, and IRP1 in mouse lung tissues, which ultimately led to iron deposition via regulation of the expression of various iron metabolism-related genes. NMDAR activation initiated the pulmonary fibrosis process by inducing iron deposition in lung tissues and ferroptosis of alveolar type II cells. Our data suggest that NMDAR activation regulates the expression of iron metabolism-related genes by promoting calcium influx, increasing nNOS and IRP1 expression, and increasing iron deposition by affecting cellular iron homeostasis, ultimately leading to mitochondrial damage, mitochondrial dysfunction, and ferroptosis. NMDAR activation-induced ferroptosis of alveolar type II cells might be a key event to the initiation of pulmonary fibrosis.

PMID:37451346 | DOI:10.1016/j.bbamcr.2023.119535

J Cell Biochem. 2023 Jul 14. doi: 10.1002/jcb.30446. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a dreadful and fatal disease of unknown etiology, for which no cure exists. Autophagy, a lysosomal cellular surveillance pathway is insufficiently activated in both alveolar epithelial type II cells and fibroblasts of IPF patient lungs. Fine-tuning this pathway may result in the degradation of the accumulated cargo and influence cell fate. Based on our previous data, we here present our view on modulating autophagy via a unique co-chaperone, namely Bcl2-associated athanogene3 (BAG3) in IPF and discuss about how repurposing drugs that modulate this pathway may emerge as a promising novel therapeutic approach for IPF.

PMID:37450692 | DOI:10.1002/jcb.30446

Int J Mol Sci. 2023 Jul 4;24(13):11049. doi: 10.3390/ijms241311049.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive, relentless, and deadly disease. Little is known about its pathogenetic mechanisms; therefore, developing efficient pharmacological therapies is challenging. This work aimed to apply a therapeutic alternative using immunomodulatory peptides in a chronic pulmonary fibrosis murine model. BALB/c mice were intratracheally instilled with bleomycin (BLM) and followed for 30 days. The mice were treated with the immune modulatory peptides ToAP3 and ToAP4 every three days, starting on the 5th day post-BLM instillation. ELISA, qPCR, morphology, and respiratory function analyses were performed. The treatment with both peptides delayed the inflammatory process observed in the non-treated group, which showed a fibrotic process with alterations in the production of collagen I, III, and IV that were associated with significant alterations in their ventilatory mechanics. The ToAP3 and ToAP4 treatments, by lung gene modulation patterns, indicated that distinct mechanisms determine the action of peptides. Both peptides controlled the experimental IPF, maintaining the tissue characteristics and standard function properties and regulating fibrotic-associated cytokine production. Data obtained in this work show that the immune response regulation by ToAP3 and ToAP4 can control the alterations that cause the fibrotic process after BLM instillation, making both peptides potential therapeutic alternatives and/or adjuvants for IPF.

PMID:37446227 | DOI:10.3390/ijms241311049

Int J Mol Sci. 2023 Jun 29;24(13):10876. doi: 10.3390/ijms241310876.

ABSTRACT

Pulmonary fibrosis (PF) is a chronic lung disorder characterized by the presence of scarred and thickened lung tissues. Although the Food and Drug Administration approved two antifibrotic drugs, pirfenidone, and nintedanib, that are currently utilized for treating idiopathic PF (IPF), the clinical therapeutic efficacy remains unsatisfactory. It is crucial to develop new drugs or treatment schemes that combine pirfenidone or nintedanib to achieve more effective outcomes for PF patients. Understanding the complex mechanisms underlying PF could potentially facilitate drug discovery. Previous studies have found that the activation of inflammasomes, including nucleotide-binding and oligomerization domain (NOD)-like receptor protein (NLRP)1, NLRP3, NOD-like receptor C4, and absent in melanoma (AIM)2, contributes to lung inflammation and fibrosis. This article aims to summarize the cellular and molecular regulatory cues that contribute to PF with a particular emphasis on the role of AIM2 inflammasome in mediating pathophysiologic events during PF development. The insights gained from this research may pave the way for the development of more effective strategies for the prevention and treatment of PF.

PMID:37446052 | DOI:10.3390/ijms241310876

AAPS PharmSciTech. 2023 Jul 13;24(6):152. doi: 10.1208/s12249-023-02618-4.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is an ailment with no cure and a very high rate of progression that ultimately leads to death. The exact reason for this disease is still not acknowledged. Many underlying mechanisms of wound healing and various types of stimuli that trigger the pathogenesis of IPF continue to be intensively explored. The exact therapy for the reversal of this disease is not yet known and is constantly in progress. Existing treatments only slow down the process or mitigate the symptoms to enhance the patient's healthcare system. The only two Food and Drug Administration-approved oral medications include pirfenidone and nintedanib whose high dose and systemic circulation can have side effects to a greater extent. Further research on restorative and extra-curative therapies for IPF is necessary due to the absence of viable therapeutic choices. To assure minimum off-targeted site delivery and longer duration of action, techniques that offer a sustainable release of the drug, better bioavailability, and patient compliance can be used.The work is an overview of the main therapeutic targets and pertinent developing therapies for the management of IPF. This study is an attempt to focus on various drug delivery systems that are responsible for showing effectiveness in defense mechanisms against IPF.

PMID:37442839 | DOI:10.1208/s12249-023-02618-4

Pulm Ther. 2023 Jul 12. doi: 10.1007/s41030-023-00235-x. Online ahead of print.

NO ABSTRACT

PMID:37436686 | DOI:10.1007/s41030-023-00235-x

EClinicalMedicine. 2023 Jun 29;61:102071. doi: 10.1016/j.eclinm.2023.102071. eCollection 2023 Jul.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with poor prognosis and a high economic burden for individuals and healthcare resources. Studies of the costs associated with the efficiency of IPF medications are scarce. We aimed to conduct a network meta-analysis (NMA) and cost-effectiveness analysis to identify the optimum pharmacological strategy among all currently available IPF regimens.

METHODS: We first performed a systematic review and network meta-analysis. We searched eight databases for eligible randomised controlled trials (RCTs) published, in any language, between January 1, 1992 and July 31, 2022, that investigated the efficacy or tolerability (or both) of drug therapies for the treatment of IPF. The search was updated on February 1, 2023. Eligible RCTs were enrolled, with no restriction on dose, duration, or length of follow-up, if they included at least one of: all-cause mortality, acute exacerbation rate, disease progression rate, serious adverse events, and any adverse events under investigation. A subsequent Bayesian NMA within random-effects models was performed, followed by a cost-effectiveness analysis using the data obtained from our NMA, by developing a Markov model from the US payer's perspective. Assumptions were checked by deterministic and probabilistic sensitivity approaches to identify sensitive factors. We prospectively registered the protocol (CRD42022340590) in PROSPERO.

FINDINGS: 51 publications comprising 12,551 participants with IPF were analysed for the NMA, and the findings indicated that pirfenidone and N-acetylcysteine (NAC) + pirfenidone were the most efficacious and tolerable. The pharmacoeconomic analysis showed that NAC + pirfenidone was associated with the highest potentiality of being cost-effective at willingness-to-pay (WTP) thresholds of US$150,000 and $200,000, on the basis of quality-adjusted life years (QALYs), disability-adjusted life years (DALYs) and mortality, with the probability ranging from 53% to 92%. NAC was the minimum cost agent. Compared with placebo, NAC + pirfenidone improved effectiveness by increasing QALYs by 7.02, and reducing DALYs by 7.10 and deaths by 8.40, whilst raising overall costs by $516,894.

INTERPRETATION: This NMA and cost-effectiveness analysis suggests that NAC + pirfenidone is the most cost-effective option for treatment of IPF at WTP thresholds of $150,000 and $200,000. However, given that clinical practice guidelines have not addressed the application of this therapy, large well-designed and multicentre trials are warranted to provide a better picture of IPF management.

FUNDING: None.

PMID:37434745 | PMC:PMC10331814 | DOI:10.1016/j.eclinm.2023.102071

BMC Pulm Med. 2023 Jul 11;23(1):255. doi: 10.1186/s12890-023-02532-2.

ABSTRACT

INTRODUCTION: Acute exacerbation (AE) is a devastating complication of rheumatoid arthritis-associated interstitial lung disease (RA-ILD) and leads to high mortality. This study aimed to investigate the incidence, risk factors, and prognosis of acute exacerbation of rheumatoid arthritis-associated interstitial lung disease (AE-RA-ILD).

METHODS: PubMed, EMBASE, Web of Science, and Medline were searched through 8 February 2023. Two independent researchers selected eligible articles and extracted available data. The Newcastle Ottawa Scale was used to assess the methodological quality of studies used for meta-analysis. The incidence and prognosis of AE-RA-ILD were investigated. Weighted mean differences (WMDs) with corresponding 95% confidence intervals (CIs) and pooled odds ratios (ORs) with 95% CIs were calculated to explore the risk factors of AE in RA-ILD.

RESULTS: Twenty-one of 1,589 articles were eligible. A total of 385 patients with AE-RA-ILD, of whom 53.5% were male, were included. The frequency of AE in patients with RA-ILD ranged from 6.3 to 55.6%. The 1-year and 5-year AE incidences were 2.6-11.1% and 11-29.4%, respectively. The all-cause mortality rate of AE-RA-ILD was 12.6-27.9% at 30 days and 16.7-48.3% at 90 days. Age at RA diagnosis (WMD: 3.61, 95% CI: 0.22-7.01), male sex (OR: 1.60, 95% CI:1.16-2.21), smoking (OR: 1.50, 95% CI: 1.08-2.08), lower forced vital capacity predicted (FVC%; WMD: -8.63, 95% CI: -14.68 to - 2.58), and definite usual interstitial pneumonia (UIP) pattern (OR: 1.92, 95% CI: 1.15-3.22) were the risk factors of AE-RA-ILD. Moreover, the use of corticosteroids, methotrexate, and biological disease-modifying anti-rheumatic drugs, was not associated with AE-RA-ILD.

CONCLUSION: AE-RA-ILD was not rare and had a poor prognosis. Age at RA diagnosis, male sex, smoking, lower FVC%, and definite UIP pattern increased the risk of AE-RA-ILD. The use of medications, especially methotrexate and biological disease-modifying anti-rheumatic drugs, may not be related to AE-RA-ILD.

REGISTRATION: CRD42023396772.

PMID:37434169 | PMC:PMC10337154 | DOI:10.1186/s12890-023-02532-2

Respirology. 2023 Jul 11. doi: 10.1111/resp.14552. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: Little is known about the association between ambient air pollution and idiopathic pulmonary fibrosis (IPF) in areas with lower levels of exposure. We aimed to investigate the impact of air pollution on lung function and rapid progression of IPF in Australia.

METHODS: Participants were recruited from the Australian IPF Registry (n = 570). The impact of air pollution on changes in lung function was assessed using linear mixed models and Cox regression was used to investigate the association with rapid progression.

RESULTS: Median (25th-75th percentiles) annual fine particulate matter (<2.5 μm, PM2.5 ) and nitrogen dioxide (NO2 ) were 6.8 (5.7, 7.9) μg/m3 and 6.7 (4.9, 8.2) ppb, respectively. Compared to living more than 100 m from a major road, living within 100 m was associated with a 1.3% predicted/year (95% confidence interval [CI] -2.4 to -0.3) faster annual decline in diffusing capacity of the lungs for carbon monoxide (DLco). Each interquartile range (IQR) of 2.2 μg/m3 increase in PM2.5 was associated with a 0.9% predicted/year (95% CI -1.6 to -0.3) faster annual decline in DLco, while there was no association observed with NO2 . There was also no association between air pollution and rapid progression of IPF.

CONCLUSION: Living near a major road and increased PM2.5 were both associated with an increased rate of annual decline in DLco. This study adds to the evidence supporting the negative effects of air pollution on lung function decline in people with IPF living at low-level concentrations of exposure.

PMID:37433646 | DOI:10.1111/resp.14552

Acta Biomater. 2023 Jul 9:S1742-7061(23)00375-6. doi: 10.1016/j.actbio.2023.06.043. Online ahead of print.

ABSTRACT

Decellularized lung scaffolds and hydrogels are increasingly being utilized in ex vivo lung bioengineering. However, the lung is a regionally heterogenous organ with proximal and distal airway and vascular compartments of different structures and functions that may be altered as part of disease pathogenesis. We previously described decellularized normal whole human lung extracellular matrix (ECM) glycosaminoglycan (GAG) composition and functional ability to bind matrix-associated growth factors. We now determine differential GAG composition and function in airway, vascular, and alveolar-enriched regions of decellularized lungs obtained from normal, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF) patients. Significant differences were observed in heparan sulfate (HS), chondroitin sulfate (CS), and hyaluronic acid (HA) content and CS/HS compositions between both different lung regions and between normal and diseased lungs. Surface plasmon resonance demonstrated that HS and CS from decellularized normal and COPD lungs similarly bound fibroblast growth factor 2, but that binding was decreased in decellularized IPF lungs. Binding of transforming growth factor β to CS was similar in all three groups but binding to HS was decreased in IPF compared to normal and COPD lungs. In addition, cytokines dissociate faster from the IPF GAGs than their counterparts. The differences in cytokine binding features of IPF GAGs may result from different disaccharide compositions. The purified HS from IPF lung is less sulfated than that from other lungs, and the CS from IPF contains more 6-O-sulfated disaccharide. These observations provide further information for understanding functional roles of ECM GAGs in lung function and disease. STATEMENT OF SIGNIFICANCE: : Lung transplantation remains limited due to donor organ availability and need for life-long immunosuppressive medication. One solution, the ex vivo bioengineering of lungs via de- and recellularization has not yet led to a fully functional organ. Notably, the role of glycosaminoglycans (GAGs) remaining in decellularized lung scaffolds is poorly understood despite their important effects on cell behaviors. We have previously investigated residual GAG content of native and decellularized lungs and their respective functionality, and role during scaffold recellularization. We now present a detailed characterization of GAG and GAG chain content and function in different anatomical regions of normal diseased human lungs. These are novel and important observations that further expand knowledge about functional GAG roles in lung biology and disease.

PMID:37433361 | DOI:10.1016/j.actbio.2023.06.043