Pathogenesis Of Idiopathic Pulmonary Fibrosis Research Articles

Molecular Regulation of Heme Oxygenase-1 Expression by E2F Transcription Factor 2 in Lung Fibroblast Cells: Relevance to Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a fatal chronic lung disease. Heme oxygenase-1 (HMOX1/HO-1) is an enzyme that catalyzes the degradation of heme. The role of HO-1 in the pathogenesis of IPF has been studied; however, the molecular regulation of HO-1 and its role in IPF are still unclear. In this study, we found that HO-1 protein levels significantly increased in lung myofibroblasts in IPF patients and in lungs in a murine model of bleomycin-induced lung fibrosis. In addition, we observed that administration of a E2F transcription factor inhibitor elevated HO-1 mRNA and protein levels in lung fibroblasts. Downregulation of E2F2 by siRNA transfection increased HO-1 mRNA and protein levels, while overexpression of E2F2 reduced HO-1 levels. However, overexpression of E2F2 did not alter hemin-induced HO-1 protein levels. Furthermore, modulation of HO-1 levels regulated TGF-β1-induced myofibroblast differentiation without altering the phosphorylation of Smad2/3 in lung fibroblast cells. Moreover, the phosphorylation of protein kinase B (Akt) was significantly upregulated in HO-1-depleted lung fibroblast cells. In summary, this study demonstrated that E2F2 regulates the baseline expression of HO-1, but has no effect on modulating HO-1 expression by hemin. Finally, elevated HO-1 expression contributes to the TGF-β1-induced lung myofibroblast differentiation through the activation of the serine/threonine kinase AKT pathway. Overall, our findings suggest that targeting E2F2/HO-1 might be a new therapeutic strategy to treat fibrotic diseases such as IPF.

Dysregulated Cell-Cell Communication Characterizes Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive disease of older adults characterized by fibrotic replacement of functional gas exchange units in the lung. The strongest risk factor for IPF is a genetic variantin the promoter region of the gel-forming mucin, MUC5B. To better understand how the MUC5B variant influences development of fibrosis, we used the NicheNet R package and leveraged publicly available single-cell RNA sequencing data to identify and evaluate how epithelia participating in gas exchange are influenced by ligands expressed in control, MUC5B variant, and fibrotic environments. We observed that loss of type-I alveolar epithelia (AECI) characterizes the single-cell RNA transcriptome in fibrotic lung and validated the pattern of AECI loss using single nuclear RNA sequencing. Examining AECI transcriptomes, we found enrichment of transcriptional signatures for IL6 and AREG, which we have previously shown to mediate aberrant epithelial fluidization in IPF and murine bleomycin models. Moreover, we found that the protease ADAM17, which is upstream of IL6 trans-signaling, was enriched in control MUC5B variant donors. We used immunofluorescence to validate a role for enhanced expression of ADAM17 among MUC5B variants, suggesting involvement in IPF pathogenesis and maintenance.

Research progress of occupational and environmental exposure and idiopathic pulmonary fibrosis

Occupational and environmental exposure can directly cause specific lung diseases, and can also induce autoimmune diseases that can lead to various types of interstitial lung diseases. In recent years, it was discovered that certain occupational and environmental exposure was related to the increased risk of Idiopathic pulmonary fibrosis (IPF) disease and progression, including metal and mineral dust, wood dust, organic dust, asbestos dust, silica dust, cigarette smoke and air pollution. IPF is a chronic progressive fibrotic lung disease of unknown etiology, with a characteristic imaging and histologic pattern called usual interstitial pneumonia. This article is a review based on the correlation and mechanism of occupational and environmental exposure in the pathogenesis and disease progression of IPF to improve the understanding of the disease and promote the formulation of treatment plans.

DDR1 activation in macrophage promotes IPF by regulating NLRP3 inflammasome and macrophage reaction

BackgroundDiscoidin Domain Receptor1 (DDR1) is a member of receptor tyrosine kinases (RTKs) which have been reported to be associated with idiopathic pulmonary fibrosis (IPF), but the mechanism remains unclear. MethodsBleomycin-induced IPF mice model was performed in this study, and two DDR1 inhibitors were administered in vivo, to investigate the role of DDR1 in IPF. Lentivirus mediated DDR1-/- stable Raw264.7 macrophage cell line or DDR1 inhibitors treatment in vitro, to study the effect of DDR1 on inflammasome activation and macrophage responses. All of the mechanisms were further tested in the lung sections of IPF patients. ResultHere, we reported that: (i) Both specific inhibitors of DDR1 dramatically alleviated the symptoms of bleomycin-induced IPF models. (ii) Immunofluorescence staining showed that DDR1 signaling is activated in macrophages. In vivo molecular biological analysis proved that DDR1 activation exacerbates IPF inflammation through inflammasome signaling, macrophage activation, and M1/M2 polarization. (iii) Extracellular matrix (ECM) such as Collagen 1 activates DDR1 in macrophage cell line Raw264.7 in vitro, to mediate inflammasome activation and macrophage responses. (iv) DDR1 activation in macrophage was confirmed in IPF patients’ samples, which could be one of the mechanisms for the pathogenesis of IPF. DiscussionIn this study, we firstly reported DDR1 activation in macrophages to play a role in IPF via inflammasome activation and macrophage responses. In addition, DDR1 inhibitors DDR1-IN-1 and DDR1-IN-2 exerted significant anti-inflammatory and anti-fibrotic effects in IPF, all of which provide a potentially effective therapeutic medication for clinical IPF treatment.

Genetic and non-genetic risk factors of idiopathic pulmonary fibrosis: A review

Idiopathic pulmonary fibrosis (IPF) is the most common form of fibrosis of internal organs. The etiology and pathogenesis of IPF are still not well understood. However, a growing line of evidence shows that both genetic and non-genetic factors contribute to IPF development. The release of pro-inflammatory cytokines activates the immune cells. The enhanced synthesis of interleukins and cytokines, especially transforming growth factor β1 leads to the proliferation of fibroblasts, increased extracellular matrix formation, and epithelial-mesenchymal transformation of the lung tissue. These pathological changes could lead to fibrosis. Polymorphisms of genes responsible for the function of mucociliary clearance (MUC5B), telomerases (TERT, TERC), as well as signaling pathway related-genes such as Sonic hedgehog, Wnt, and some other genes are also risk factors for IPF development. Epigenetic regulatory mechanisms, such as methylation and acetylation of DNA and histones, may also influence the development and progression of this disease. At present, the role of non-coding RNAs, in particular long non-coding RNAs (lncRNA) in the development of fibrotic processes, is actively studied. LncRNA is an RNA that is longer than 200 base pairs and does not code for any proteins. LncRNAs perform various functions in the cell, from nuclear compartmentation to epigenetic regulation of gene expression and post-translational modification of proteins. In this review, we present the important aspects in the pathogenesis of IPF.

Role of Mesenchymal Stem Cells and Extracellular Vesicles in Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial fibrotic disease that leads to disability and death within 5 years of diagnosis. Pulmonary fibrosis is a disease with a multifactorial etiology. The concept of aberrant regeneration of the pulmonary epithelium reveals the pathogenesis of IPF, according to which repeated damage and death of alveolar epithelial cells is the main mechanism leading to the development of progressive IPF. Cell death provokes the migration, proliferation and activation of fibroblasts, which overproduce extracellular matrix, resulting in fibrotic deformity of the lung tissue. Mesenchymal stem cells (MSCs) and extracellular vesicles (EVs) are promising therapies for pulmonary fibrosis. MSCs, and EVs derived from MSCs, modulate the activity of immune cells, inhibit the expression of profibrotic genes, reduce collagen deposition and promote the repair of damaged lung tissue. This review considers the molecular mechanisms of the development of IPF and the multifaceted role of MSCs in the therapy of IPF. Currently, EVs-MSCs are regarded as a promising cell-free therapy tool, so in this review we discuss the results available to date of the use of EVs-MSCs for lung tissue repair.

Alveolar Epithelial Type 2 Cell Dysfunction in Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible pulmonary interstitial disease that seriously affects the patient's quality of life and lifespan. The pathogenesis of IPF has not been clarified, and its treatment is limited to pirfenidone and nintedanib, which only delays the decline of lung function. Alveolar epithelial type 2 (AT2) cells are indispensable in the regeneration and lung surfactant secretion of alveolar epithelial cells. Studies have shown that AT2 cell dysfunction initiates the occurrence and progression of IPF. This review expounds on the AT2 cell dysfunction in IPF, involving senescence, apoptosis, endoplasmic reticulum stress, mitochondrial damage, metabolic reprogramming, and the transitional state of AT2 cells. This article also briefly summarizes potential treatments targeting AT2 cell dysfunction.

The potential role of interleukin (IL)-25/IL-33/thymic stromal lymphopoietin (TSLP) on the pathogenesis of idiopathic pulmonary fibrosis.

Interleukin (IL)-25, IL-33, and thymic stromal lymphopoietin (TSLP) are the important drivers for excessive type-2 immunity. It has been well elucidated that IL-25/IL-33/TSLP plays an important role in allergic airway inflammation and remodeling, whereas their roles in idiopathic pulmonary fibrosis (IPF) still remained largely unclear. Herein, the aim of the review is to discuss the potential role and mechanism of IL-25/IL-33/TSLP on IPF by literature analysis and summary. We have done a literature search using the following terms: ("idiopathic pulmonary fibrosis" OR "IPF" OR "lung fibrosis") and (TSLP or "thymic stromal lymphopoietin" or IL-25 OR IL-17E OR IL-33) from the database of PubMed published in English up to July 2018. We have totally found 58 articles by using the retrieval terms mentioned above. By careful title and abstract reading, 10 original research articles of high quality were enrolled for the full text reading and analysis. Two additional relevant studies were also included during the course of literature readings. IL-25/IL-33/TSLP and their corresponding receptors, that is, IL-17BR/ST2L/TSLPR, are shown to be up-regulated both in IPF patients and bleomycin (BLM)-induced lung fibrosis mice model. IL-25 may promote lung fibrosis by activating IL-17BR+fibroblast and IL-17BR+ILC2 (type 2 innate lymphoid cell). Full length (fl)-IL-33, as a transcription factor mainly in the cell nucleus, mediated non-atopic lung inflammation and fibrosis by modulating expressions of several pro-fibrotic mediators, including transforming growth factor (TGF)-b1. By contrast, mature (m)-IL-33 potentiates lung fibrosis by recruiting ST2L+M2 macrophages and ST2L+ILC2 to enlarge type 2 immunity. TSLP was shown to directly promote CCL2 expression in primary human lung fibroblasts (pHLFs). IL-25/IL-33/TSLP contributes to non-allergic lung fibrosis by mediating persistent abnormal epithelial-mesenchymal crosstalk. IL-25/IL-33/TSLP may serve the promising novel target for the treatment of IPF.

Contribution of Adiponectin/Carnitine Palmityl Transferase 1A-Mediated Fatty Acid Metabolism during the Development of Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease that leads rapidly to death. The present study is aimed at discovering the in-depth pathogenesis of IPF, exploring the role of adiponectin/carnitine palmityl transferase 1A- (APN/CPT1A-) mediated fatty acid metabolism during the development of IPF, and excavating its potential mechanism. Here, THP-1 cells were differentiated into M0 macrophages, followed by polarization to M1 macrophages upon hypoxia. Subsequently, lung fibroblast HFL-1 cells were stimulated by M1 macrophages to simulate hypoxia-related IPF condition in vitro. It was discovered that the stimulation of M1 macrophages promoted fibroblast proliferation and fibrosis formation in vitro, accompanied with a disorder of the APN/CPT1A pathway, an overproduction of lipid peroxides, and a low level of autophagy in HFL-1 cells. Thereafter, APN treatment or CPT1A overexpression greatly suppressed above lipid peroxide accumulation, fibroblast proliferation, and fibrosis but activated autophagy in vitro. Furthermore, an in vivo IPF rat model was established by injection of bleomycin (BLM). Consistently, CPT1A overexpression exerted a protective role against pulmonary fibrosis in vivo; however, the antifibrosis property of CPT1A was partly abolished by 3-methyladenine (an autophagy inhibitor). In summary, APN/CPT1A-mediated fatty acid metabolism exerted its protective role in IPF partly through activating autophagy, shedding a new prospective for the treatment of IPF.

Inhibition of AHNAK nucleoprotein 2 alleviates pulmonary fibrosis by downregulating the TGF-β1/Smad3 signaling pathway.

Idiopathic pulmonary fibrosis (IPF) is a chronic and advanced interstitial lung disease with poor prognosis. AHNAK nucleoprotein 2 (AHNAK2) is a macromolecular protein that is important for cell migration and muscle membrane repair. The protein acts via epithelial-mesenchymal transition (EMT), which is a key mechanism in the pathogenesis of IPF. However, very few studies have elucidated the effect of AHNAK2 in the development of IPF. Therefore, we aimed to determine the role of AHNAK2 in IPF development. C57BL/6 mice were induced with bleomycin, while A549 and Beas-2b pulmonary epithelial cell lines were treated with TGF-β1 to induce IPF model. The expression of AHNAK2 was detected using immunohistochemistry staining in vivo, and real-time quantitative polymerase chain reaction (RT-qPCR) and western blotting (WB) in vitro. C57BL/6 mice were injected with adeno-associated virus (AAV)-sh NC or AAV-sh AHNAK2 and the pulmonary function and EMT marker expression were measured. The migratory abilities of the two transforming growth factor beta 1 (TGF-β1)-induced cell lines were examined using wound-healing and Transwell assays after transfection with si-NC, si-AHNAK2-1 and -2. EMT marker expression was detected using RT-qPCR and WB. Smad3 and phosphorylated-Smad3 of the two cells were examined using WB. Following Smad3 inhibition by Smad3 phosphorylation inhibitor (SIS3), TGF-β1-induced cell migration and EMT marker expression were evaluated again after different transfections. AHNAK2 expression was higher in the IPF model than in the normal model in vivo and in vitro. Partial inhibition of AHNAK2 suppressed the EMT process and improved pulmonary ventilation and compliance in the mouse model of IPF. Similarly, knockdown of AHNAK2 suppressed the migration of pulmonary epithelial cells and reversed EMT. Furthermore, Smad3 of the two TGF-β1-induced cell lines was not activated when AHNAK2 was inhibited. When SIS3 inhibited the activation of Smad3, the suppression of AHNAK2 had no effect on A549 and Beas-2b, regardless of TGF-β1 induction. Inhibition of AHNAK2 alleviates pulmonary fibrosis and partially reverses EMT by inhibiting the TGF-β1/Smad3 signaling pathway. Therefore, AHNAK2 is a potential therapeutic target for IPF.

Overexpression of Decay Accelerating Factor Mitigates Fibrotic Responses to Lung Injury.

CD55 or decay accelerating factor (DAF), a ubiquitously expressed glycosylphosphatidylinositol (GPI)-anchored protein, confers a protective threshold against complement dysregulation which is linked to the pathogenesis of idiopathic pulmonary fibrosis (IPF). Since lung fibrosis is associated with downregulation of DAF, we hypothesize that overexpression of DAF in fibrosed lungs will limit fibrotic injury by restraining complement dysregulation. Normal primary human alveolar type II epithelial cells (AECs) exposed to exogenous complement 3a or 5a, and primary AECs purified from IPF lungs demonstrated decreased membrane-bound DAF expression with concurrent increase in the endoplasmic reticulum (ER) stress protein, ATF6. Increased loss of extracellular cleaved DAF fragments was detected in normal human AECs exposed to complement 3a or 5a, and in lungs of IPF patients. C3a-induced ATF6 expression and DAF loss was inhibited using pertussis toxin (an enzymatic inactivator of G-protein coupled receptors), in murine AECs. Treatment with soluble DAF abrogated tunicamycin-induced C3a secretion and ER stress (ATF6 and BiP expression) and restored epithelial cadherin. Bleomycin-injured fibrotic mice subjected to lentiviral overexpression of DAF demonstrated diminished levels of local collagen deposition and complement activation. Further analyses showed diminished release of DAF fragments, as well as reduction in apoptosis (TUNEL and caspase 3/7 activity), and ER stress-related transcripts. Loss-of-function studies using Daf1 siRNA demonstrated worsened lung fibrosis detected by higher mRNA levels of Col1a1 and epithelial injury-related Muc1 and Snai1, with exacerbated local deposition of C5b-9. Our studies provide a rationale for rescuing fibrotic lungs via DAF induction that will restrain complement dysregulation and lung injury.

FLUOROFENIDONE ATTENUATES PULMONARY INFLAMMATION AND FIBROSIS BY INHIBITING THE IL-11/MEK/ERK SIGNALING PATHWAY.

Idiopathic pulmonary fibrosis is defined as a specific form of chronic, progressive fibrosing interstitial pneumonia of unknown cause. Interleukin (IL)-11 plays an important role in the pathogenesis of idiopathic pulmonary fibrosis. In this study, we explore whether a potential antifibrotic agent fluorofenidone (FD) exerts its anti-inflammatory and antifibrotic effects through suppressing activation of the IL-11/MEK/ERK signaling pathway in vivo and in vitro. Male C57BL/6 J mice were intratracheally injected with bleomycin or saline. Fluorofenidone was administered throughout the course of the experiment. Lung tissue sections were stained with hemotoxylin and eosin, and Masson trichrome. Cytokines were measured using the enzyme-linked immunosorbent assay. The α-smooth muscle actin (α-SMA), fibronectin, and collagen I were measured using immunohistochemistry, and the phosphorylated extracellular signal-regulated kinase, phosphorylated mitogen-activated protein kinase, IL-11RA, and gp130 were measured using Western blot. The RAW264.7 cells and the normal human lung fibroblasts were treated with IL-11 and/or FD, IL-11RA-siRNA, or MEK inhibitor. The expressions of phosphorylated extracellular signal-regulated kinase, phosphorylated mitogen-activated protein kinase, IL-11RA, gp130, α-SMA, fibronectin, and collagen I were measured using Western blot and/or real-time polymerase chain reaction, and the cytokines were measured using enzyme-linked immunosorbent assay. Results showed that FD markedly reduced the expressions of IL-8, IL-18, IL-11, monocyte chemotactic protein-1, α-SMA, fibronectin, and collagen I in mice lung tissues. In addition, FD attenuated IL-11-induced expressions of α-SMA, fibronectin, and collagen I and inhibited IL-11RA, gp130, and phosphorylation of the ERK and MEK protein expression, as well as reduced the expressions of IL-8, IL-18, and monocyte chemotactic protein-1 in vitro. This study demonstrated that FD attenuated bleomycin-induced pulmonary inflammation and fibrosis in mice by inhibiting the IL-11/MEK/ERK signaling pathway.

Aberrant Expression of ACO1 in Vasculatures Parallels Progression of Idiopathic Pulmonary Fibrosis.

Rationale: Idiopathic pulmonary fibrosis (IPF) is characterized by mitochondrial dysfunction. However, details about the non-mitochondrial enzymes that sustain the proliferative nature of IPF are unclear. Aconitases are a family of enzymes that sustain metabolism inside and outside mitochondria. It is hypothesized that aconitase 1 (ACO1) plays an important role in the pathogenesis of IPF given that ACO1 represents an important metabolic hub in the cytoplasm. Objectives: To determine if ACO1 expression in IPF lungs shows specific patterns that may be important in the pathogenesis of IPF. To determine the similarities and differences in ACO1 expression in IPF, bleomycin-treated, and aging lungs. Methods: ACO1 expression in IPF lungs were characterized and compared to non-IPF controls by western blotting, immunostaining, and enzymatic activity assay. ACO1-expressing cell types were identified by multicolor immunostaining. Using similar methods, the expression profiles of ACO1 in IPF lungs versus bleomycin-treated and aged mice were investigated. Measurements and main results: Lower lobes of IPF lungs, unlike non-IPF controls, exhibit significantly high levels of ACO1. Most of the signals colocalize with von Willebrand factor (vWF), a lineage marker for vascular endothelial cells. Bleomycin-treated lungs also show high ACO1 expressions. However, most of the signals colocalize with E-cadherin and/or prosurfactant protein C, representative epithelial cell markers, in remodeled areas. Conclusions: A characteristic ACO1 expression profile observed in IPF vasculatures may be a promising diagnostic target. It also may give clues as to how de novo angiogenesis contributes to the irreversible nature of IPF.

Impact of gastroesophageal reflux disease on idiopathic pulmonary fibrosis and lung transplant recipients.

Idiopathic pulmonary fibrosis (IPF) is a prevalent subset of interstitial lung disease (ILD) that often progresses to require lung transplantation. Gastroesophageal reflux disease (GERD) is common in the IPF population, and GER-related micro-aspiration appears to be an important risk factor for IPF pathogenesis and for the deterioration of transplanted lung function. Many patients with IPF have elevated esophageal acid exposure on reflux testing despite having no or minimal symptoms. Studies on the effects of medical GERD therapy on IPF-related outcomes have had mixed results. Antireflux surgery is safe in appropriately selected IPF patients, and appears to have potential for slowing the decline of lung function. GERD can persist, improve or develop after lung transplantation, and the presence of GERD is associated with allograft injury and pulmonary function decline in lung transplant recipients. Clinicians should have a low threshold to assess for objective evidence of GERD in IPF patients. Antireflux surgery in IPF patients with GERD appears to improve lung function, but further studies are needed before surgical treatment can be recommended routinely in this setting. In lung transplant recipients, reflux testing after transplant is the most accurate way to guide GERD treatment decisions.

Regeneration or Repair? The Role of Alveolar Epithelial Cells in the Pathogenesis of Idiopathic Pulmonary Fibrosis (IPF).

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease (ILD) with unknown etiology in which gradual fibrotic scarring of the lungs leads to usual interstitial pneumonia (UIP) and, ultimately, to death. IPF affects three million people worldwide, and the only currently available treatments include the antifibrotic drugs nintedanib and pirfenidone, which effectively reduce fibrosis progression are, unfortunately, not effective in curing the disease. In recent years, the paradigm of IPF pathogenesis has shifted from a fibroblast-driven disease to an epithelium-driven disease, wherein, upon recurrent microinjuries, dysfunctional alveolar type II epithelial cells (ATII) are not only unable to sustain physiological lung regeneration but also promote aberrant epithelial–mesenchymal crosstalk. This creates a drift towards fibrosis rather than regeneration. In the context of this review article, we discuss the most relevant mechanisms involved in IPF pathogenesis with a specific focus on the role of dysfunctional ATII cells in promoting disease progression. In particular, we summarize the main causes of ATII cell dysfunction, such as aging, environmental factors, and genetic determinants. Next, we describe the known mechanisms of physiological lung regeneration by drawing a parallel between embryonic lung development and the known pathways involved in ATII-driven alveolar re-epithelization after injury. Finally, we review the most relevant interventional clinical trials performed in the last 20 years with the aim of underlining the urgency of developing new therapies against IPF that are not only aimed at reducing disease progression by hampering ECM deposition but also boost the physiological processes of ATII-driven alveolar regeneration.

Caveolin-1 scaffolding domain peptide abrogates autophagy dysregulation in pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is the most common and fatal form of interstitial lung disease. IPF is characterized by irreversible scarring of the lungs leading to lung function decline. Although the etiology remains poorly understood, dysregulated autophagy in alveolar-epithelial cells (AECs) together with interplay between apoptotic-AECs and proliferative-myofibroblasts have been strongly implicated in IPF pathogenesis. Recent studies have revealed that a caveolin-1-derived 7-mer peptide, CSP7, mitigates established PF at least in part by improving AEC viability. In the present study, we aimed to determine whether and how CSP7 regulates autophagy in fibrotic-lung AECs. We found that p53 and autophagic proteins were markedly upregulated in AECs from mice with single/multi-doses of bleomycin—or silica-induced PF. This was abolished following treatment of PF-mice with CSP7. Further, CSP7 abrogated silica- or bleomycin-induced p53 and autophagy proteins in AECs. Immunoprecipitation further revealed that CSP7 abolishes the interaction of caveolin-1 with LC3BII and p62 in AECs. AEC-specific p53-knockout mice resisted silica- or bleomycin-induced changes in autophagy proteins, or CSP7 treatment. Our findings provide a novel mechanism by which CSP7 inhibits dysregulated autophagy in injured AECs and mitigates existing PF. These results affirm the potential of CSP7 for treating established PF, including IPF and silicosis.

Inhaled siRNA nanoparticles targeting IL11 inhibit lung fibrosis and improve pulmonary function post-bleomycin challenge.

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.

Induced Pluripotent Stem-cells Inhibit Experimental Bleomycin-induced Pulmonary Fibrosis through Regulation of the Insulin-like Growth Factor Signaling.

Idiopathic pulmonary fibrosis (IPF) is among the illnesses with a high mortality rate, yet no specific cause has been identified; as a result, successful treatment has not been achieved. Among the novel approaches for treating such hard-to-cure diseases are induced pluripotent stem cells (IPSCs). Some studies have shown these cells' potential in treating IPF. Therefore, we aimed to investigate the impact of IPSCs on insulin-like growth factor (Igf) signaling as a major contributor to IPF pathogenesis. C57BL/6 mice were intratracheally instilled with Bleomycin (BLM) or phosphate-buffered saline; the next day, half of the bleomycin group received IPSCs through tail vein injection. Hydroxyproline assay and histologic examinations have been performed to assess lung fibrosis. The gene expression was evaluated using specific primers for Igf-1, Igf-2, and insulin receptor substrate 1 (Irs-1) genes and SYBR green qPCR master mix. The data have been analyzed using the 2-ΔΔCT method. The mice that received Bleomycin showed histological characteristics of the fibrotic lung injury, which was significantly ameliorated after treatment with IPSCs comparable to the control group. Furthermore, gene expression analyses revealed that in the BLM group, Igf1, Igf2, and Irs1 genes were significantly upregulated, which were returned to near-normal levels after treatment with IPSCs. IPSCs could modulate the bleomycin-induced upregulation of Igf1, Igf2, and Irs1 genes. This finding reveals a new aspect of the therapeutic impact of the IPSCs on IPF, which could be translated into other fibrotic disorders.

Role of MicroRNAs in Signaling Pathways Associated with the Pathogenesis of Idiopathic Pulmonary Fibrosis: A Focus on Epithelial-Mesenchymal Transition.

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.

Targeting Growth Factor and Cytokine Pathways to Treat Idiopathic Pulmonary Fibrosis.

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.