ERJ Open Res. 2022 Jun 20;8(2):00115-2022. doi: 10.1183/23120541.00115-2022. eCollection 2022 Apr.

ABSTRACT

Patients with progressive fibrosing interstitial lung diseases (fILD) have increased morbidity and mortality. Lung fibrosis can be associated with lung cancer. The pathogenesis of both diseases shows similarities, although not all mechanisms are understood. The combination of the diseases is challenging, due to the amplified risk of mortality, and also because lung cancer treatment carries additional risks in patients with underlying lung fibrosis. Acute exacerbations in fILD patients are linked to increased mortality, and the risk of acute exacerbations is increased after lung cancer treatment with surgery, chemotherapy or radiotherapy. Careful selection of treatment modalities is crucial to improve survival while maintaining acceptable quality of life in patients with combined lung cancer and fILD. This overview of epidemiology, pathogenesis, treatment and a possible role for antifibrotic drugs in patients with lung cancer and fILD is the summary of a session presented during the virtual European Respiratory Society Congress in 2021. The review summarises current knowledge and identifies areas of uncertainty. Most current data relate to patients with combined idiopathic pulmonary fibrosis and lung cancer. There is a pressing need for additional prospective studies, required for the formulation of a consensus statement or guideline on the optimal care of patients with lung cancer and fILD.

PMID:35747227 | PMC:PMC9209850 | DOI:10.1183/23120541.00115-2022

Cureus. 2022 Jun 18;14(6):e26072. doi: 10.7759/cureus.26072. eCollection 2022 Jun.

ABSTRACT

Interstitial lung disease (ILD) is a rare disease defined as a specific type of chronic fibrosing interstitial pneumonitis whose effects are limited to the lung. Nonspecific interstitial pneumonia (NSIP) was defined as a histopathological form that can be seen in the presence of large different clinical and radiological features. The exact role of thyroid hormone in the pathogenetic mechanism of idiopathic interstitial pneumonitis (IIP) is unclear. But there is a suggestion that the thyroid hormone plays a role in pulmonary inflammation and fibrosis. In this case report, we described the presentation of NSIP which was associated with Hashimoto thyroiditis.

PMID:35747121 | PMC:PMC9209344 | DOI:10.7759/cureus.26072

Life (Basel). 2022 Jun 14;12(6):887. doi: 10.3390/life12060887.

ABSTRACT

Coronavirus disease 2019 (COVID-19) is a pandemic respiratory disease associated with high morbidity and mortality. Although many patients recover, long-term sequelae after infection have become increasingly recognized and concerning. Among other sequelae, the available data indicate that many patients who recover from COVID-19 could develop fibrotic abnormalities over time. To understand the basic pathophysiology underlying the development of long-term pulmonary fibrosis in COVID-19, as well as the higher mortality rates in patients with pre-existing lung diseases, we compared the transcriptomic fingerprints among patients with COVID-19, idiopathic pulmonary fibrosis (IPF), and chronic obstructive pulmonary disease (COPD) using interactomic analysis. Patients who died of COVID-19 shared some of the molecular biological processes triggered in patients with IPF, such as those related to immune response, airway remodeling, and wound healing, which could explain the radiological images seen in some patients after discharge. However, other aspects of this transcriptomic profile did not resemble the profile associated with irreversible fibrotic processes in IPF. Our mathematical approach instead showed that the molecular processes that were altered in COVID-19 patients more closely resembled those observed in COPD. These data indicate that patients with COPD, who have overcome COVID-19, might experience a faster decline in lung function that will undoubtedly affect global health.

PMID:35743918 | DOI:10.3390/life12060887

Int J Mol Sci. 2022 Jun 14;23(12):6613. doi: 10.3390/ijms23126613.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive disease with high mortality and unclear etiology. Previous evidence supports that the origin of this disease is associated with epigenetic alterations, age, and environmental factors. IPF initiates with chronic epithelial lung injuries, followed by basal membrane destruction, which promotes the activation of myofibroblasts and excessive synthesis of extracellular matrix (ECM) proteins, as well as epithelial-mesenchymal transition (EMT). Due to miRNAs' role as regulators of apoptosis, proliferation, differentiation, and cell-cell interaction processes, some studies have involved miRNAs in the biogenesis and progression of IPF. In this context, the analysis and discussion of the probable association of miRNAs with the signaling pathways involved in the development of IPF would improve our knowledge of the associated molecular mechanisms, thereby facilitating its evaluation as a therapeutic target for this severe lung disease. In this work, the most recent publications evaluating the role of miRNAs as regulators or activators of signal pathways associated with the pathogenesis of IPF were analyzed. The search in Pubmed was made using the following terms: "miRNAs and idiopathic pulmonary fibrosis (IPF)"; "miRNAs and IPF and signaling pathways (SP)"; and "miRNAs and IPF and SP and IPF pathogenesis". Additionally, we focus mainly on those works where the signaling pathways involved with EMT, fibroblast differentiation, and synthesis of ECM components were assessed. Finally, the importance and significance of miRNAs as potential therapeutic or diagnostic tools for the treatment of IPF are discussed.

PMID:35743055 | DOI:10.3390/ijms23126613

Cells. 2022 Jun 20;11(12):1973. doi: 10.3390/cells11121973.

ABSTRACT

Insulin-like growth factor (IGF) signaling controls the development and growth of many organs, including the lung. Loss of function of Igf1 or its receptor Igf1r impairs lung development and leads to neonatal respiratory distress in mice. Although many components of the IGF signaling pathway have shown to be dysregulated in idiopathic pulmonary fibrosis (IPF), the expression pattern of such components in different cellular compartments of the developing and/or fibrotic lung has been elusive. In this study, we provide a comprehensive transcriptional profile for such signaling components during embryonic lung development in mice, bleomycin-induced pulmonary fibrosis in mice and in human IPF lung explants. During late gestation, we found that Igf1 is upregulated in parallel to Igf1r downregulation in the lung mesenchyme. Lung tissues derived from bleomycin-treated mice and explanted IPF lungs revealed upregulation of IGF1 in parallel to downregulation of IGF1R, in addition to upregulation of several IGF binding proteins (IGFBPs) in lung fibrosis. Finally, treatment of IPF lung fibroblasts with recombinant IGF1 led to myogenic differentiation. Our data serve as a resource for the transcriptional profile of IGF signaling components and warrant further research on the involvement of this pathway in both lung development and pulmonary disease.

PMID:35741102 | DOI:10.3390/cells11121973

Biomolecules. 2022 Jun 13;12(6):823. doi: 10.3390/biom12060823.

ABSTRACT

Reactive oxygen species (ROS) can be beneficial or harmful in health and disease. While low levels of ROS serve as signaling molecules to regulate vascular tone and the growth and proliferation of endothelial cells, elevated levels of ROS contribute to numerous pathologies, such as endothelial dysfunctions, colon cancer, and fibrosis. ROS and their cellular sources have been extensively studied as potential targets for clinical intervention. Whereas various ROS sources are important for different pathologies, four NADPH oxidases (NOX1, NOX2, NOX4, and NOX5) play a prominent role in homeostasis and disease. NOX1-generated ROS have been implicated in hypertension, suggesting that inhibition of NOX1 may be a promising therapeutic approach. NOX2 and NOX4 oxidases are of specific interest due to their role in producing extra- and intracellular hydrogen peroxide (H2O2). NOX4-released hydrogen peroxide activates NOX2, which in turn stimulates the release of mitochondrial ROS resulting in ROS-induced ROS release (RIRR) signaling. Increased ROS production from NOX5 contributes to atherosclerosis. This review aims to summarize recent findings on NOX enzymes and clinical trials inhibiting NADPH oxidases to target pathologies including diabetes, idiopathic pulmonary fibrosis (IPF), and primary biliary cholangitis (PBC).

PMID:35740948 | DOI:10.3390/biom12060823

Biomedicines. 2022 Jun 15;10(6):1423. doi: 10.3390/biomedicines10061423.

ABSTRACT

In the lungs, fibrosis is a growing clinical problem that results in shortness of breath and can end up in respiratory failure. Even though the main fibrotic disease affecting the lung is idiopathic pulmonary fibrosis (IPF), which affects the interstitial space, there are many fibrotic events that have high and dangerous consequences for the lungs. Asthma, chronic obstructive pulmonary disease (COPD), excessive allergies, clearance of infection or COVID-19, all are frequent diseases that show lung fibrosis. In this review, we describe the different kinds of fibrosis and analyse the main types of cells involved-myofibroblasts and other cells, like macrophages-and review the main fibrotic mechanisms. Finally, we analyse present treatments for fibrosis in the lungs and highlight potential targets for anti-fibrotic therapies.

PMID:35740444 | DOI:10.3390/biomedicines10061423

Chest. 2022 Jun 20:S0012-3692(22)01102-3. doi: 10.1016/j.chest.2022.06.013. Online ahead of print.

ABSTRACT

Recent clinical practice guidelines have addressed the diagnosis of idiopathic pulmonary fibrosis (IPF) and fibrotic hypersensitivity pneumonitis (fHP). These disease-specific guidelines were developed independently, without clear direction on how to concurrently apply their respective recommendations within a single patient, where discrimination between these two fibrotic interstitial lung diseases represents a frequent diagnostic challenge. The objective of this document, created by an international group of experts, was to suggest a pragmatic approach on how to apply existing guidelines to distinguish IPF and fHP. Key clinical, radiological, and pathological features described in previous guidelines are integrated in a set of diagnostic algorithms, which are then placed in the broader context of multidisciplinary discussion to guide the generation of a consensus diagnosis. While these algorithms necessarily reflect some uncertainty wherever strong evidence is lacking, they provide insight into the current approach favored by experts in the field based on currently available knowledge. The authors further identify priorities for future research to clarify ongoing uncertainties in the diagnosis of fibrotic interstitial lung diseases.

PMID:35738345 | DOI:10.1016/j.chest.2022.06.013

Radiologie (Heidelb). 2022 Jun 23. doi: 10.1007/s00117-022-01025-3. Online ahead of print.

ABSTRACT

CLINICAL ISSUE: Smoking-related interstitial lung diseases are a heterogeneous group of pulmonary abnormalities. The correct diagnosis has prognostic and therapeutic implications. This article introduces the most common smoking-related interstitial lung diseases and describes a structured approach to support the diagnostic workflow.

PRACTICAL RECOMMENDATIONS: Computed tomography is pivotal in the diagnostic workflow of smoking-related interstitial lung diseases and may reduce the number of unnecessary lung biopsies. To achieve high diagnostic accuracy, a standardized scanning protocol, and a structured assessment approach should be utilized. During inflammatory stages of respiratory bronchiolitis (RB), respiratory bronchiolitis interstitial lung diseases (RB-ILD), and desquamative interstitial pneumonia (DIP), cessation of smoking as well as the use of steroids are the treatment of choice. In case of fibrotic changes (e.g., in idiopathic pulmonary fibrosis [IPF]), antifibrotic therapy with nintedanib and pirfenidone may be used. Patients with suspected smoking-related interstitial lung disease should be discussed in interdisciplinary board meetings.

PMID:35736996 | DOI:10.1007/s00117-022-01025-3

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