Biol Methods Protoc. 2022 May 30;7(1):bpac013. doi: 10.1093/biomethods/bpac013. eCollection 2022.

ABSTRACT

SARS-CoV-2, the virus that causes COVID-19, is a current concern for people worldwide. The virus has recently spread worldwide and is out of control in several countries, putting the outbreak into a terrifying phase. Machine learning with transcriptome analysis has advanced in recent years. Its outstanding performance in several fields has emerged as a potential option to find out how SARS-CoV-2 is related to other diseases. Idiopathic pulmonary fibrosis (IPF) disease is caused by long-term lung injury, a risk factor for SARS-CoV-2. In this article, we used a variety of combinatorial statistical approaches, machine learning, and bioinformatics tools to investigate how the SARS-CoV-2 affects IPF patients' complexity. For this study, we employed two RNA-seq datasets. The unique contributions include common genes identification to identify shared pathways and drug targets, PPI network to identify hub-genes and basic modules, and the interaction of transcription factors (TFs) genes and TFs-miRNAs with common differentially expressed genes also placed on the datasets. Furthermore, we used gene ontology and molecular pathway analysis to do functional analysis and discovered that IPF patients have certain standard connections with the SARS-CoV-2 virus. A detailed investigation was carried out to recommend therapeutic compounds for IPF patients affected by the SARS-CoV-2 virus.

PMID:35734766 | PMC:PMC9210941 | DOI:10.1093/biomethods/bpac013

Sci Adv. 2022 Jun 24;8(25):eabn7162. doi: 10.1126/sciadv.abn7162. Epub 2022 Jun 22.

ABSTRACT

Interleukin-11 (IL-11) is a profibrotic cytokine essential for the differentiation of fibroblasts into collagen-secreting, actin alpha 2, smooth muscle-positive (ACTA2+) myofibroblasts, driving processes underlying the pathogenesis of idiopathic pulmonary fibrosis (IPF). Here, we developed an inhalable and mucus-penetrative nanoparticle (NP) system incorporating siRNA against IL11 (siIL11@PPGC NPs) and investigated therapeutic potential for the treatment of IPF. NPs are formulated through self-assembly of a biodegradable PLGA-PEG diblock copolymer and a self-created cationic lipid-like molecule G0-C14 to enable efficient transmucosal delivery of siIL11. Noninvasive aerosol inhalation hindered fibroblast differentiation and reduced ECM deposition via inhibition of ERK and SMAD2. Furthermore, siIL11@PPGC NPs significantly diminished fibrosis development and improved pulmonary function in a mouse model of bleomycin-induced pulmonary fibrosis without inducing systemic toxicity. This work presents a versatile NP platform for the locally inhaled delivery of siRNA therapeutics and exhibits promising clinical potential in the treatment of numerous respiratory diseases, including IPF.

PMID:35731866 | DOI:10.1126/sciadv.abn7162

Expert Rev Respir Med. 2022 Jun 22. doi: 10.1080/17476348.2022.2093717. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) can combine with emphysema, a condition termed as IPF with emphysema (IPFE). We compared the clinical, radiologic and physiologic features of IPF and IPFE.

RESEARCH DESIGN AND METHODS: Newly diagnosed IPF (n=57) and IPFE (n=44) were recruited between January 2018 and September 2020. Symptoms, high resolution computed tomography (HRCT), pulmonary function test (PFT) data, composite physiologic index (CPI), gender-age-physiology (GAP) scores, and follow-up data were obtained.

RESULTS: The IPFE group had greater proportion of male smoking subjects, and of lung cancer cases. The IPFE group had higher VC, FVC FEV1, and lower FEV1/FVC and DLCO and lower percent fibrosis on HRCT. Both groups had similar symptoms and mortality. Mortality rate was associated with inability to perform PFT, CPI, GAP scores, percent fibrosis, VC, FVC, FEV1 and DLCO, serum SCC-Ag and CA125, and anti-fibrotic therapy (≥12months) in IPF, while it was associated with inability to perform PFT, CPI, percent fibrosis, DLCO, serum CEA, CYFRA21-1 and CA125, and anti-fibrotic therapy (≥12months) in IPFE.

CONCLUSION: IPF and IPFE patients are different in smoking history, physiologic indices, HRCT patterns and prognostic factors, however, they have similar mortality. Anti-fibrotic therapy could improve the survival rate in both IPF and IPFE.

PMID:35731004 | DOI:10.1080/17476348.2022.2093717

Korean J Intern Med. 2022 Jun 22. doi: 10.3904/kjim.2021.442. Online ahead of print.

ABSTRACT

BACKGROUND/AIMS: Neutrophilia is frequently observed in bronchoalveolar lavage fluid (BALF) of idiopathic pulmonary fibrosis (IPF) patients. Granulocyte colony-stimulating factor (G-CSF) is a potent neutrophil-activating glycoprotein. However, the clinical implications of G-CSF remain poorly understood.in patients with IPF. Therefore, we evaluated the relationship between the G-CSF concentration in BALF and the progression of fibrosis, including in terms of the decline in lung function and long-term survival rate.

METHODS: G-CSF concentrations were measured in BALF using enzyme-linked immunosorbent assay (ELISA). The survival rate was estimated using Kaplan-Meier survival analyses.

RESULTS: G-CSF protein levels were significantly higher in IPF (n = 87; 1.88 [0 to 5.68 pg/mL]), nonspecific interstitial pneumonia (n = 22; 0.58 [0 to 11.64 pg/mL]), and hypersensitivity pneumonitis (n = 19; 2.48 [0.46 to 5.71 pg/mL]) patients than in normal controls (n = 33; 0 [0 to 0.68 pg/mL]) (all p < 0.01). A receiver operating characteristic curve showed a difference in G-CSF levels between IPF and NC (area under the curve, 0.769): The G-CSF cut-off of 0.96 pg/mL indicated 84.9% specificity and 63.2% sensitivity for IPF. The survival rate was significantly lower in the group with G-CSF > 2.872 pg/mL than in the group with ≤ 2.872 pg/mL (hazard ratio, 2.69; p = 0.041). The annual decline in diffusing capacity of the lung for carbon monoxide was positively correlated with the G-CSF level (p = 0.018).

CONCLUSIONS: G-CSF may participate in the development of IPF and be useful for predicting the prognosis of IPF. Therefore, G-CSF should be analyzed in BALF, in addition to differential cell counts.

PMID:35730133 | DOI:10.3904/kjim.2021.442

Am J Respir Crit Care Med. 2022 Jun 21. doi: 10.1164/rccm.202106-1503OC. Online ahead of print.

ABSTRACT

RATIONALE: Although persistent fibroblast activation is a hallmark of idiopathic pulmonary fibrosis (IPF), mechanisms regulating persistent fibroblast activation in the lungs have not been fully elucidated.

OBJECTIVE: Based on our observation that lung fibroblasts express thromboxane-prostanoid receptor (TBXA2R) during fibrosis, we investigated the role of TBXA2R signaling in fibrotic remodeling.

METHODS: We identified TBXA2R expression in lungs of IPF patients and mice, and studied primary mouse and human lung fibroblasts to determine the impact of TBXA2R signaling on fibroblast activation. We utilized TBXA2R deficient mice and small molecule inhibitors to investigate TBXA2R signaling in preclinical lung fibrosis models.

MEASUREMENTS AND MAIN RESULTS: TBXA2R expression was up-regulated in fibroblasts in the lungs of IPF patients and in mouse lungs during experimental lung fibrosis. Genetic deletion of TBXA2R, but not inhibition of thromboxane synthase, protected mice from bleomycin-induced lung fibrosis, thereby suggesting an alternative ligand activates profibrotic TBXA2R signaling. In contrast to thromboxane, F2-isoprostanes (F2-IsoPs), which are nonezymatic products of arachidonic acid induced by reactive oxygen species (ROS), were persistently elevated during fibrosis. F2-IsoPs induced TBXA2R signaling in fibroblasts and mediated a myofibroblast activation profile due, at least in part, to potentiation of TGF-β signaling. In vivo treatment with the TBXA2R antagonist ifetroban reduced pro-fibrotic signaling in the lungs, protected mice from lung fibrosis in three pre-clinical models (bleomycin, Hermansky-Pudlak mice, and radiation-induced fibrosis), and markedly enhanced fibrotic resolution following bleomycin treatment.

CONCLUSIONS: TBXA2R links oxidative stress to fibroblast activation during lung fibrosis. TBXA2R antagonists could have utility in treating pulmonary fibrosis.

PMID:35728047 | DOI:10.1164/rccm.202106-1503OC

Nurs Open. 2022 Jun 20. doi: 10.1002/nop2.1274. Online ahead of print.

ABSTRACT

AIMS: This study evaluated the acceptability of a dignity-centred palliative care programme for people with idiopathic pulmonary fibrosis by converging perceptions of living with idiopathic pulmonary fibrosis qualitative data and quantitative data.

DESIGN: The qualitative-driven mixed methods research addressed the study aim by using a convergent design. This single arm, non-randomized study used purposive sampling.

METHODS: Interviews with 12 stable outpatients with IPF provided qualitative data. Their quantitative data were from six scales: self-esteem, health-related quality of life, anxiety, depression, dyspnoea, cough and programme satisfaction. Intervention was three educational modules: symptom management, enhancing daily activities and life reviews.

RESULTS: Semi-structured interviews yielded eight categories. Self-esteem was not statistically significantly changed. Dyspnoea symptoms improved significantly. Participants (n = 9) holding positive attitudes for living with idiopathic pulmonary fibrosis, had improved lifestyle behaviour and improved or maintained self-esteem. The meta-inference regarding idiopathic pulmonary fibrosis perceptions were related to changes in self-esteem.

PMID:35726124 | DOI:10.1002/nop2.1274

Respir Res. 2022 Jun 20;23(1):162. doi: 10.1186/s12931-022-02088-5.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and severe disease characterized by excessive matrix deposition in the lungs. Macrophages play crucial roles in maintaining lung homeostasis but are also central in the pathogenesis of lung diseases like pulmonary fibrosis. Especially, macrophage polarization/activation seems to play a crucial role in pathology and epigenetic reprograming is well-known to regulate macrophage polarization. DNA methylation alterations in IPF lungs have been well documented, but the role of DNA methylation in specific cell types, especially macrophages, is poorly defined.

METHODS: In order to determine the role of DNA methylation in macrophages during pulmonary fibrosis, we subjected macrophage specific DNA methyltransferase (DNMT)3B, which mediates the de novo DNA methylation, deficient mice to the bleomycin-induced pulmonary fibrosis model. Macrophage polarization and fibrotic parameters were evaluated at 21 days after bleomycin administration. Dnmt3b knockout and wild type bone marrow-derived macrophages were stimulated with either interleukin (IL)4 or transforming growth factor beta 1 (TGFB1) in vitro, after which profibrotic gene expression and DNA methylation at the Arg1 promotor were determined.

RESULTS: We show that DNMT3B deficiency promotes alternative macrophage polarization induced by IL4 and TGFB1 in vitro and also enhances profibrotic macrophage polarization in the alveolar space during pulmonary fibrosis in vivo. Moreover, myeloid specific deletion of DNMT3B promoted the development of experimental pulmonary fibrosis.

CONCLUSIONS: In summary, these data suggest that myeloid DNMT3B represses fibrotic macrophage polarization and protects against bleomycin induced pulmonary fibrosis.

PMID:35725453 | DOI:10.1186/s12931-022-02088-5

Front Pharmacol. 2022 Jun 2;13:899469. doi: 10.3389/fphar.2022.899469. eCollection 2022.

ABSTRACT

Background and aim: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease causing irreparable scarring of lung tissue, with most patients succumbing rapidly after diagnosis. The mevalonate pathway, which is involved in the regulation of cell proliferation, survival, and motility, is targeted by the bisphosphonate zoledronic acid (ZA). The aim of this study was to assess the antifibrotic effects of ZA and to elucidate the mechanisms by which potential IPF treatment occurs. Methods: A series of in vitro and in vivo models were employed to identify the therapeutic potential of ZA in treating IPF. In vitro transwell assays were used to assess the ability of ZA to reduce fibrotic-related immune cell recruitment. Farnesyl diphosphate synthase (FDPS) was screened as a potential antifibrotic target using a bleomycin mouse model. FDPS-targeting siRNA and ZA were administered to mice following the onset of experimentally-induced lung fibrosis. Downstream analyses were conducted on murine lung tissues and lung fluids including 23-plex cytokine array, flow cytometry, histology, Western blotting, immunofluorescent staining, and PCR analysis. Results: In vitro administration of ZA reduced myofibroblast transition and blocked NF-κB signaling in macrophages leading to impaired immune cell recruitment in a transwell assay. FDPS-targeting siRNA administration significantly attenuated profibrotic cytokine production and lung damage in a murine lung fibrosis model. Furthermore, ZA treatment of mice with bleomycin-induced lung damage displayed decreased cytokine levels in the BALF, plasma, and lung tissue, resulting in less histologically visible fibrotic scarring. Bleomycin-induced upregulation of the ZA target, FDPS, was reduced in lung tissue and fibroblasts upon ZA treatment. Confirmatory increases in FDPS immunoreactivity was seen in human IPF resected lung samples compared to control tissue indicating potential translational value of the approach. Additionally, ZA polarized macrophages towards a less profibrotic phenotype contributing to decreased IPF pathogenesis. Conclusion: This study highlights ZA as an expedient and efficacious treatment option against IPF in a clinical setting.

PMID:35721132 | PMC:PMC9201219 | DOI:10.3389/fphar.2022.899469

Front Pharmacol. 2022 Jun 3;13:918771. doi: 10.3389/fphar.2022.918771. eCollection 2022.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial lung disease of unknown origin that usually results in death from secondary respiratory failure within 2-5 years of diagnosis. Recent studies have identified key roles of cytokine and growth factor pathways in the pathogenesis of IPF. Although there have been numerous clinical trials of drugs investigating their efficacy in the treatment of IPF, only Pirfenidone and Nintedanib have been approved by the FDA. However, they have some major limitations, such as insufficient efficacy, undesired side effects and poor pharmacokinetic properties. To give more insights into the discovery of potential targets for the treatment of IPF, this review provides an overview of cytokines, growth factors and their signaling pathways in IPF, which have important implications for fully exploiting the therapeutic potential of targeting cytokine and growth factor pathways. Advances in the field of cytokine and growth factor pathways will help slow disease progression, prolong life, and improve the quality of life for IPF patients in the future.

PMID:35721111 | PMC:PMC9204157 | DOI:10.3389/fphar.2022.918771

Front Immunol. 2022 Jun 2;13:842745. doi: 10.3389/fimmu.2022.842745. eCollection 2022.

ABSTRACT

Surfactant proteins (SPs) are important for normal lung function and innate immunity of the lungs and their genes have been identified with significant genetic variability. Changes in quantity or quality of SPs due to genetic mutations or natural genetic variability may alter their functions and contribute to the host susceptibility for particular diseases. Alternatively, SP single nucleotide polymorphisms (SNPs) can serve as markers to identify disease risk or response to therapies, as shown for other genes in a number of other studies. In the current study, we evaluated associations of SFTP SNPs with idiopathic pulmonary fibrosis (IPF) by studying novel computational models where the epistatic effects (dominant, additive, recessive) of SNP-SNP interactions could be evaluated, and then compared the results with a previously published hypersensitivity pneumonitis (HP) study where the same novel models were used. Mexican Hispanic patients (IPF=84 & HP=75) and 194 healthy control individuals were evaluated. The goal was to identify SP SNPs and SNP-SNP interactions that associate with IPF as well as SNPs and interactions that may be unique to each of these interstitial diseases or common between them. We observed: 1) in terms of IPF, i) three single SFTPA1 SNPs to associate with decreased IPF risk, ii) three SFTPA1 haplotypes to associate with increased IPF risk, and iii) a number of three-SNP interactions to associate with IPF susceptibility. 2) Comparison of IPF and HP, i) three SFTPA1 and one SFTPB SNP associated with decreased risk in IPF but increased risk in HP, and one SFTPA1 SNP associated with decreased risk in both IPF and HP, ii) a number of three-SNP interactions with the same or different effect pattern associated with IPF and/or HP susceptibility, iii) one of the three-SNP interactions that involved SNPs of SFTPA1, SFTPA2, and SFTPD, with the same effect pattern, was associated with a disease-specific outcome, a decreased and increased risk in HP and IPF, respectively. This is the first study that compares the SP gene variants in these two phenotypically similar diseases. Our findings indicate that SNPs of all SFTPs may play an important role in the genetic susceptibility to IPF and HP. Importantly, IPF and HP share some SP genetic variants, suggesting common pathophysiological mechanisms and pathways regarding surfactant biogenesis, but also some differences, highlighting the diverse underlying pathogenic mechanisms between an inflammatory-driven fibrosis (HP) and an epithelial-driven fibrosis (IPF). Alternatively, the significant SNPs identified here, along with SNPs of other genes, could serve as markers to distinguish these two devastating diseases.

PMID:35720392 | PMC:PMC9201215 | DOI:10.3389/fimmu.2022.842745

Drug Des Devel Ther. 2022 Jun 13;16:1793-1809. doi: 10.2147/DDDT.S361748. eCollection 2022.

ABSTRACT

PURPOSE: Idiopathic pulmonary fibrosis is a chronic and irreversible fibrotic interstitial pneumonia of unknown etiology and therapeutic strategies are limited. Emerging evidence suggests that the continuous activation of the central nucleotide-binding oligomerization-, leucine-rich repeat-, and pyrin domain-containing protein 3 (NLRP3) inflammasome is involved in the pathogenesis of pulmonary fibrosis. Ginsenoside Rb1 (G-Rb1) is the most abundant component in the traditional Chinese herb ginseng and has anti-inflammatory and anti-fibrotic activities. The purpose of this study was to explore whether G-Rb1 exerts anti-inflammatory and anti-fibrotic activities in vivo and in vitro by suppressing the activation of the NLRP3 inflammasome and NF-κB pathway.

METHODS: Forty-eight male C57BL/6 mice were randomly divided into four groups (n=12/group) as follows: control, bleomycin (BLM), BLM/G-Rb1, and G-Rb1. A pulmonary fibrosis model was developed via an intratracheal injection of BLM. Six mice from each group were euthanized on days 3 and 21. The degree of pulmonary fibrosis was examined by histological evaluation and assessing α-smooth muscle actin levels. THP-1 cells were differentiated into macrophages, and stimulated by lipopolysaccharide and adenosine triphosphate. Activation of the NLRP3 inflammasome and NF-κB pathway was determined by Western blotting. Interleukin-1 beta and interleukin-18 levels were measured by ELISA. MRC-5 cells were cultured in the conditioned medium of the treated macrophages, after which markers of myofibroblasts were determined by Western blotting.

RESULTS: G-Rb1 ameliorated BLM-induced pulmonary inflammation and fibrosis in mice, and suppressed NLRP3 inflammasome activation and the NF-κB pathway in lung tissues. Moreover, interleukin-1 beta secreted after NLRP3 inflammasome activation in macrophages promoted fibroblast differentiation. G-Rb1 inhibited lipopolysaccharide- and adenosine triphosphate-induced NLRP3 inflammasome activation in macrophages and disturbed the crosstalk between macrophages and fibroblasts.

CONCLUSION: G-Rb1 ameliorates BLM-induced pulmonary inflammation and fibrosis by suppressing NLRP3 inflammasome activation and the NF-κB pathway. Hence, G-Rb1 is a potential novel therapeutic drug for idiopathic pulmonary fibrosis.

PMID:35719213 | PMC:PMC9205635 | DOI:10.2147/DDDT.S361748

PLoS One. 2022 Jun 17;17(6):e0270056. doi: 10.1371/journal.pone.0270056. eCollection 2022.

ABSTRACT

Nintedanib is a multi-tyrosine kinase inhibitor widely used to treat progressive fibrosing interstitial lung diseases because it slows the reduction in forced vital capacity. However, the prognosis for patients treated with nintedanib remains poor. To improve nintedanib treatment, we examined the effects of nintedanib on gene expression in the lungs of induced-rheumatoid arthritis-associated interstitial lung disease model mice, which develop rheumatoid arthritis and subsequent pulmonary fibrosis. Using next-generation sequencing, we identified 27 upregulated and 130 downregulated genes in the lungs of these mice after treatment with nintedanib. The differentially expressed genes included mucin 5B and heat shock protein 70 family genes, which are related to interstitial lung diseases, as well as genes associated with extracellular components, particularly the myocardial architecture, suggesting unanticipated effects of nintedanib. Of the genes upregulated in the nintedanib-treated lung, expression of regulatory factor X2, which is suspected to be involved in cilia movement, and bone morphogenetic protein receptor type 2, which is involved in the pathology of pulmonary hypertension, was detected by immunohistochemistry and RNA in situ hybridization in peripheral airway epithelium and alveolar cells. Thus, the present findings indicate a set of genes whose expression alteration potentially underlies the effects of nintedanib on pulmonary fibrosis. It is expected that these findings will contribute to the development of improved nintedanib strategies for the treatment of progressive fibrosing interstitial lung diseases.

PMID:35714115 | DOI:10.1371/journal.pone.0270056

Respir Res. 2022 Jun 17;23(1):157. doi: 10.1186/s12931-022-02077-8.

ABSTRACT

BACKGROUND: Interstitial lung abnormalities (ILA) are radiologic findings that may progress to idiopathic pulmonary fibrosis (IPF). Blood gene expression profiles can predict IPF mortality, but whether these same genes associate with ILA and ILA outcomes is unknown. This study evaluated if a previously described blood gene expression profile associated with IPF mortality is associated with ILA and all-cause mortality.

METHODS: In COPDGene and ECLIPSE study participants with visual scoring of ILA and gene expression data, we evaluated the association of a previously described IPF mortality score with ILA and mortality. We also trained a new ILA score, derived using genes from the IPF score, in a subset of COPDGene. We tested the association with ILA and mortality on the remainder of COPDGene and ECLIPSE.

RESULTS: In 1469 COPDGene (training n = 734; testing n = 735) and 571 ECLIPSE participants, the IPF score was not associated with ILA or mortality. However, an ILA score derived from IPF score genes was associated with ILA (meta-analysis of test datasets OR 1.4 [95% CI: 1.2-1.6]) and mortality (HR 1.25 [95% CI: 1.12-1.41]). Six of the 11 genes in the ILA score had discordant directions of effects compared to the IPF score. The ILA score partially mediated the effects of age on mortality (11.8% proportion mediated).

CONCLUSIONS: An ILA gene expression score, derived from IPF mortality-associated genes, identified genes with concordant and discordant effects on IPF mortality and ILA. These results suggest shared, and unique biologic processes, amongst those with ILA, IPF, aging, and death.

PMID:35715807 | DOI:10.1186/s12931-022-02077-8

Sci Rep. 2022 Jun 17;12(1):10275. doi: 10.1038/s41598-022-14491-5.

ABSTRACT

Chronic inflammation of the human intestine in Crohn's disease (CD) causes bowel wall thickening, which typically progresses to stricturing and a recurrent need for surgery. Current therapies have limited success and CD remains idiopathic and incurable. Recent evidence shows a key role of intestinal smooth muscle cell (ISMC) hyperplasia in stricturing, which is not targeted by current anti-inflammatory therapeutics. However, progression of idiopathic pulmonary fibrosis, resembling CD in pathophysiology, is controlled by the tyrosine kinase inhibitors nintedanib (NIN) or pirfenidone, and we investigated these drugs for their effect on ISMC. In a culture model of rat ISMC, NIN inhibited serum- and PDGF-BB-stimulated growth and cell migration, and promoted the differentiated phenotype, while increasing secreted collagen. NIN did not affect signaling through PDGF-Rβ or NFκB but did inhibit cytokine-induced expression of the pro-inflammatory cytokines IL-1β and TNFα, supporting a transcriptional level of control. In TNBS-induced colitis in mice, which resembles CD, NIN decreased ISMC hyperplasia as well as expression of TNFα and IL-1β, without effect in control animals. NIN also inhibited growth of human ISMC in response to human serum or PDGF-BB, which further establishes a broad range of actions of NIN that support further trial in human IBD.

PMID:35715562 | DOI:10.1038/s41598-022-14491-5

Rev Mal Respir. 2022 Jun 14:S0761-8425(22)00161-9. doi: 10.1016/j.rmr.2022.03.011. Online ahead of print.

ABSTRACT

Genetic studies of familial forms of interstitial lung disease (ILD) have led to the discovery of telomere-related gene (TRG) mutations (TERT, TERC, RTEL1, PARN, DKC1, TINF2, NAF1, NOP10, NHP2, ACD, ZCCH8) in approximately 30% of familial ILD forms. ILD patients with TRG mutation are also subject to extra-pulmonary (immune-hematological, hepatic and/or mucosal-cutaneous) manifestations. TRG mutations may be associated not only with idiopathic pulmonary fibrosis (IPF), but also with non-IPF ILDs, including idiopathic and secondary ILDs, such as hypersensitivity pneumonitis (HP). The presence of TRG mutation may also be associated with an accelerated decline of forced vital capacity (FVC) or poorer prognosis after lung transplantation, notwithstanding which, usual ILD treatments may be proposed. Lastly, patients and their relatives are called upon to reduce their exposure to environmental lung toxicity, and are likely to derive benefit from specific genetic counseling and pre-symptomatic genetic testing.

PMID:35715316 | DOI:10.1016/j.rmr.2022.03.011

BMJ Open Respir Res. 2022 Jun;9(1):e001202. doi: 10.1136/bmjresp-2022-001202.

ABSTRACT

RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease. Patients present at different stages and disease course is varied. Blood monocytes have been linked to all-cause mortality, and neutrophils to progression to IPF in patients with the indeterminate for usual interstitial pneumonia CT pattern.

OBJECTIVE: To determine association between blood monocytes, neutrophils and lymphocytes levels (and their derived indexes), with lung function decline and mortality in IPF.

METHODS: We performed a retrospective analysis of an IPF cohort (n=128) who had their first clinical visit at the Oxford Interstitial Lung Disease Service between 2013 and 2017. Association between blood monocytes, neutrophils, lymphocytes and derived indexes (within 4 months of visit) and decline in forced vital capacity (FVC) and all-cause mortality were assessed using Cox proportional hazard regression analysis. Kaplan-Meier analysis was used to assess time-to-event for 10% FVC decline and mortality for patients dichotomised to high and low leucocyte counts.

RESULTS: Median length of follow-up was 31.0 months (IQR 16.2-42.4); 41.4% demonstrated FVC decline >10% per year and 43.8% died. In multivariate models (incorporating age, gender and initial FVC%), raised neutrophils, lymphopaenia and neutrophil:lymphocyte ratio were associated with FVC decline (p≤0.01); while both monocytes and neutrophil levels (and their derived indexes) were associated with all-cause mortality (p≤0.01). Kaplan-Meier analysis also showed association between neutrophils and its derived indexes but not monocyte, with FVC decline.

CONCLUSION: Blood neutrophil and lymphopaenia are more sensitive than monocytes as prognostic indicators of disease progression in those with established IPF.

PMID:35715193 | DOI:10.1136/bmjresp-2022-001202

Front Med (Lausanne). 2022 May 31;9:941008. doi: 10.3389/fmed.2022.941008. eCollection 2022.

NO ABSTRACT

PMID:35712108 | PMC:PMC9195006 | DOI:10.3389/fmed.2022.941008

Eur J Pharm Sci. 2022 Jun 13:106236. doi: 10.1016/j.ejps.2022.106236. Online ahead of print.

ABSTRACT

Current pathophysiological findings indicate that damage to the alveolar epithelium plays a decisive role in the development of idiopathic pulmonary fibrosis (IPF). The available pharmacological interventions (i.e., oral pirfenidone and nintedanib) only slow down progression of the disease, but do not offer a cure. In order to develop new drug candidates, the pathophysiology of IPF needs to be better understood on a molecular level. It has previously been reported that a loss of caveolin-1 (Cav-1) contributes to profibrotic processes by causing reduced alveolar barrier function and fibrosis-like alterations of the lung-parenchyma. Conversely, overexpression of caveolin-1 appears to counteract the development of fibrosis by inhibiting the inflammasome NLRP3 and the associated expression of interleukin-1β. In this study, the interaction between Fyn-kinase and caveolin-1 in the alveolar epithelium of various bleomycin (BLM)/TGF-β damage models using precision-cut lung slices (PCLS), wildtype (WT) and caveolin-1 knockout (KO) mice as well as the human NCI-H441 cell line, were investigated. In WT mouse lung tissues, strong signals for Fyn-kinase were detected in alveolar epithelial type I cells, whereas in caveolin-1 KO animals, expression shifted to alveolar epithelial type II cells. Caveolin-1 and Fyn-kinase were found to be co-localized in isolated lipid rafts of NCI-H441 cell membrane fractions. These findings were corroborated by co-immunoprecipitation studies in which a co-localization of Cav-1 and Fyn-kinase was detected in the cell membrane of the alveolar epithelium. After TGF-β and BLM-induced damage to the alveolar epithelium both in PCLS and cell culture experiments, a decrease in caveolin-1 and Fyn-kinase was found. Furthermore, TEER (transepithelial electrical resistance) measurements indicated that TGF-β and BLM have a damaging effect on cell-cell contacts and thus impair the barrier function in NCI-H441 cell monolayers. This effect was attenuated after co-incubation with the Fyn-kinase inhibitor, PP-2. Our data suggest an involvement of Fyn-kinase and caveolin-1 in TGF-β/bleomycin-induced impairment of alveolar barrier function and thus a possible role in the early stages of pulmonary fibrosis. Fyn-kinase and/or its complex with caveolin-1 might, therefore, be novel therapeutic targets in IPF.

PMID:35710078 | DOI:10.1016/j.ejps.2022.106236

Oxid Med Cell Longev. 2022 Jun 6;2022:8002566. doi: 10.1155/2022/8002566. eCollection 2022.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a refractory chronic respiratory disease with progressively exacerbating symptoms and a high mortality rate. There are currently only two effective drugs for IPF; thus, there is an urgent need to develop new therapeutics. Previous experiments have shown that ginkgolic acid (GA), as a SUMO-1 inhibitor, exerted an inhibitory effect on cardiac fibrosis induced by myocardial infarction. Regarding the pathogenesis of PF, previous studies have concluded that small ubiquitin-like modifier (SUMO) polypeptides bind multiple target proteins and participate in fibrosis of multiple organs, including PF. In this study, we found altered expression of SUMO family members in lung tissues from IPF patients. GA mediated the reduced expression of SUMO1/2/3 and the overexpression of SENP1 in a PF mouse model, which improved PF phenotypes. At the same time, the protective effect of GA on PF was also confirmed in the SENP1-KO transgenic mice model. Subsequent experiments showed that SUMOylation of SMAD4 was involved in PF. It was inhibited by TGF-β1, but GA could reverse the effects of TGF-β1. SENP1 also inhibited the SUMOylation of SMAD4 and then participated in epithelial-mesenchymal transition (EMT) downstream of TGF-β1. We also found that SENP1 regulation of SMAD4 SUMOylation affected reactive oxygen species (ROS) production during TGF-β1-induced EMT and that GA prevented this oxidative stress through SENP1. Therefore, GA may inhibit the SUMOylation of SMAD4 through SENP1 and participate in TGF-β1-mediated pulmonary EMT, all of which reduce the degree of PF. This study provided potential novel targets and a new alternative for the future clinical testing in PF.

PMID:35707278 | PMC:PMC9192210 | DOI:10.1155/2022/8002566

BMJ Open. 2022 Jun 15;12(6):e055077. doi: 10.1136/bmjopen-2021-055077.

ABSTRACT

OBJECTIVES: To describe 6-min walk test (6MWT) outcomes, and to investigate their correlations with cardiopulmonary and lung function among patients with interstitial lung disease (ILD) which was not limited to idiopathic pulmonary fibrosis.

METHODS: We collected patients' demographic data and obtained minute-by-minute 6MWT outcomes. Modified Borg scale was employed to assess patients' dyspnoea, whereas New York Heart Association (NYHA) classification and pulmonary function test were used to evaluate patients' cardiopulmonary functions.

RESULTS: Heart rate (HR) exhibited a continuous upward trend, while SpO2 exhibited an overall downward with a slight increase at the fifth minute. The SpO2 nadir for 70 patients (9.3%) was lower than 80%. Further, the SpO2 nadir for 78.27% of the participants appeared at the end of the fourth minute. The 6-min walk distance (6MWD) had the strongest correlation with NYHA classification (r=0.82, p<0.01). The ratio of 6MWD to predicted 6MWD was most correlated to forced expiratory volume in the first second (r=0.30, p<0.01) and forced vital capacity (r=0.30, p<0.01). SpO2 at 3 min had the strongest correlation to patients' diffusing capacity of the lungs for carbon monoxide (r=0.41, p<0.01). We found significant differences in 6MWD (F=2.44, p=0.033), SpO2 change (F=2.58, p=0.025), HR at 0 min (F=2.87, p=0.014), HR at end of 6 min (F=2.58, p=0.025) and HR zenith (F=2.64, p=0.022) between the subtypes of ILD.

CONCLUSION: This observation provided an important evidence regarding oxygen titration. It is better to maintain SpO2 above 88% for 4 min instead of 3 min. SpO2 at the third minute was the most valuable predictor of patients' lung function. 6MWD and SpO2 changes were more discriminative in subtypes.

PMID:35705338 | DOI:10.1136/bmjopen-2021-055077