J Med Virol. 2023 Sep;95(9):e29098. doi: 10.1002/jmv.29098.

ABSTRACT

In China, the emergence of a nationally widespread epidemic infection of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) has appeared within a month since December 7, 2022. To evaluate the risk factors for suffering from coronavirus disease 2019 (COVID-19) pneumonia due to infection with SARS-CoV-2 in different kinds of interstitial lung disease (ILD) patients with diverse immunizations, we conducted this retrospective study on 525 patients with ILDs who underwent regular follow-up in our ILD clinic. Among them, 128 ILD patients (24.4%) suffered from COVID-19 pneumonia after SARS-CoV-2 infection. Patients were older with a male predominance in the pneumonia group than in the nonpneumonia group (65.0 ± 10.0 years vs. 56.4 ± 11.7 years, p < 0.001, 55.5% vs. 39.5%, p = 0.002, respectively). Connective tissue disease-associated ILD (CTD-ILD) (25%), idiopathic pulmonary fibrosis (23.4%), and interstitial pneumonia with autoimmune features (21.1%) were the main pre-existing ILDs in the pneumonia group. In Cox multivariable analysis, only male sex and corticosteroid use were risk factors for COVID-19 pneumonia after infection. Two or three doses of vaccination were a protective factor for pre-existing ILD patients suffering from COVID-19 pneumonia. More than two doses of vaccination were strongly recommended for pre-existing ILD patients, particularly for males who were administered corticosteroids.

PMID:37707416 | DOI:10.1002/jmv.29098

Cureus. 2023 Aug 13;15(8):e43409. doi: 10.7759/cureus.43409. eCollection 2023 Aug.

ABSTRACT

We report 13 cases of pulmonary pneumocystis (PCP) in human immunodeficiency virus (HIV)-uninfected patients. Of eight males and five females, with a mean age of 55 years, one had breast neoplasia, two had common variable immunodeficiency (CVID), one had an autoimmune disease "Goodpasture's syndrome", and one had idiopathic fibrosis (nonspecific interstitial pneumonia/fibrosis (NIP)) undergoing prolonged corticosteroid therapy for two years, with no known immunosuppression in the remaining cases. The clinical picture was characterized by constant dyspnea and severe hypoxia in 11 cases. Lymphopenia was present in nine cases with an average rate of 920.76 elements/mm3. The diagnosis was confirmed by isolation of Pneumocystis jirovecii (PCJ) from induced sputum, except in two cases where analysis of bronchoalveolar lavage (BAL) fluid was required. With trimethoprim/sulfamethoxazole (TMP/SMX) and corticosteroid therapy, the course was favorable in all cases. Prophylactic treatment was indicated in three cases.

PMID:37706120 | PMC:PMC10496727 | DOI:10.7759/cureus.43409

Int J Pharm. 2023 Sep 11:123405. doi: 10.1016/j.ijpharm.2023.123405. Online ahead of print.

ABSTRACT

Fibrosing interstitial lung disease (ILD) is a pathological condition that is highly heterogeneous and lethal, and has few effective treatment choices. Other than pirfenidone and nintedanib for the therapy of idiopathic pulmonary fibrosis, no medications are currently licensed for the treatment of ILD. Luteolin is a common flavonoid with multiple biological effects such as anti-inflammation but with poor solubility and absorption. In this study, we loaded luteolin into γ-cyclodextrin metal-organic frameworks (CD-MOFs) to deliver the medicine to the lungs using dry powder inhalers; in vitro pulmonary deposition results showed LUT@CDMOF had a high fine particle fraction (FPF) (59.77±3.48%). LUT@CDMOF effectively inhibited ILD progression in the BLM-induced fibrosing ILD model rats. When compared to oral administration, the inhalation of LUT@CDMOF dry powder in rats showed considerable improvements in absorption and bioavailability, with a tmax of 0.08 h and a high absolute bioavailability (82%) of LUT (The AUC(0-t) and Cmax of inhal. LUT@CDMOF respectively increased about 4.03 times and 9.11 times, when compared with the i.g. LUT group). These studies demonstrate the potent anti-inflammatory activities of LUT@CDMOF. The inhaled LUT@CDMOF might consider as a promising new strategy in the treatment of fibrosing ILD.

PMID:37703957 | DOI:10.1016/j.ijpharm.2023.123405

Sci Rep. 2023 Sep 12;13(1):15073. doi: 10.1038/s41598-023-41294-z.

ABSTRACT

In the repair of injury, some transforming growth factor-[Formula: see text]s (TGF-[Formula: see text]s) and platelet-derived growth factors (PDGFs) bind to fibroblast receptors as ligands and cause the differentiation of fibroblasts into myofibroblasts. When the injury repair is repeated, the myofibroblasts proliferate excessively, forming fibrotic tissue. We goal to control myofibroblasts proliferation and apoptosis with anti-transforming growth factor-[Formula: see text] (anti-TGF-[Formula: see text]) and anti-platelet-derived growth factor (anti-PDGF) medicines. The novel optimal regulator control problem with two controls (medicines) is proposed to simulate how to the preventing pulmonary fibrosis. Idiopathic pulmonary fibrosis (IPF) consists of restoring a system of cells, protein, and tissue networks with injury and scar. Myofibroblasts proliferation back to its equilibrium position after it has been disturbed by abnormal repair. Thus, the optimal regulator control problem with a parabolic partial differential equation as a constraint, zero flux boundary, and given specific initial conditions, is considered. The myofibroblast diffusion equation stands as a governing dynamic system while the objective function is the summation of myofibroblast, anti-TGF-[Formula: see text] and anti-PDGF medicines for the fixed final time. Here, myofibroblast is a nonlinear state of time while anti-TGF-[Formula: see text] and anti-PDGF are two unknown control functions. In order to solve the corresponding problem a weighted Galerkin method is used. Firstly, we convert the myofibroblast diffusion equation to a system of ordinary differential equations using the Lagrangian interpolation polynomials defined at Gauss-Lobatto integration points. Secondly, by the calculus of variations, the optimal control problem is solved successfully using canonical Hamiltonian and extended Riccati equations. Numerical results are given, and the plots are depicted. Moreover, solutions to the problem in which there is no control are compared. Numerical results show that, over time, the myofibroblast increases and then remains constant when there is no control. In contrast, the current solution decreases and vanishes after 300 days by prescribing controller medicines for anti-TGF-[Formula: see text] and anti-PDGF. The optimal strategy proposed in this paper helps practitioners to reduce myofibroblasts by controlling both anti-TGF-[Formula: see text] and anti-PDGF medicines.

PMID:37699920 | DOI:10.1038/s41598-023-41294-z

JAMA. 2023 Sep 12;330(10):973. doi: 10.1001/jama.2023.12637.

NO ABSTRACT

PMID:37698568 | DOI:10.1001/jama.2023.12637

JAMA. 2023 Sep 12;330(10):973-974. doi: 10.1001/jama.2023.12640.

NO ABSTRACT

PMID:37698565 | DOI:10.1001/jama.2023.12640

Cell Transplant. 2023 Jan-Dec;32:9636897231196489. doi: 10.1177/09636897231196489.

ABSTRACT

Chronic lung diseases, such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF), involve progressive and irreversible destruction and pathogenic remodeling of airways and have become the leading health care burden worldwide. Pulmonary tissue has extensive capacities to launch injury-responsive repairing programs (IRRPs) to replace the damaged or dead cells upon acute lung injuries. However, the IRRPs are frequently compromised in chronic lung diseases. In this review, we aim to provide an overview of somatic stem cell subpopulations within distal airway epithelium and the underlying mechanisms mediating their self-renewal and trans-differentiation under both physiological and pathological circumstances. We also compared the differences between humans and mice on distal airway structure and stem cell composition. At last, we reviewed the current status and future directions for the development of targeted therapeutics on defective distal airway regeneration and repairment in chronic lung diseases.

PMID:37698245 | DOI:10.1177/09636897231196489

Am J Physiol Cell Physiol. 2023 Sep 11. doi: 10.1152/ajpcell.00302.2023. Online ahead of print.

ABSTRACT

Pulmonary fibrosis (PF) results from a plethora of abnormal pathogenetic events. In Idiopathic Pulmonary Fibrosis (IPF), inhalational, environmental, or occupational exposures in genetically and epigenetically predisposed individuals, triggers recurrent cycles of alveolar epithelial cell injury, activation of coagulation pathways, chemoattraction, and differentiation of monocytes into monocyte-derived alveolar macrophages (Mo-AMs). When these events happen intermittently and repeatedly throughout the individual's life cycle, the wound repair process becomes aberrant leading to bronchiolization of distal airspaces, fibroblast accumulation, extracellular matrix deposition and loss of the alveolar-capillary architecture. The role of immune dysregulation in IPF pathogenesis and progression has been underscored in the past mainly after the disappointing results of immunosuppressant use in IPF patients, however, recent reports highlighting the prognostic and mechanistic roles of monocytes and Mo-AMs revived the interest of immune dysregulation in IPF. In this review, we will discuss the role of these cells in the onset and progression of IPF, as well as potential targeted therapies.

PMID:37694283 | DOI:10.1152/ajpcell.00302.2023

Bioeng Transl Med. 2023 Jun 2;8(5):e10555. doi: 10.1002/btm2.10555. eCollection 2023 Sep.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease characterized by chronic, progressive, and fibrotic lung injury. Although remarkable progress has been made toward understanding the pathogenesis of PF, finding more effective treatments for this fatal disease remains a challenge. In this study, we describe an innovative macrophage-based approach to deliver anti-fibrotic protein to the lung and inhibit PF in a mouse model of bleomycin (BLM)-induced lung injury. We engineered macrophages to continuously secrete three types of proteins: interleukin-10, which prevents inflammation; TGFRcFc, a soluble truncated TGF-βR2 that blocks TGF-β; and CD147, which induces matrix metalloproteinases (MMPs) and causes collagen degradation. Infusing these engineered macrophages into the lungs of BLM-induced PF mouse models in an optimal pattern significantly ameliorated PF in mice. Specifically, the most effective therapeutic outcome was achieved by infusing IL-10-secreting macrophages on day 1, followed by TGFRcFc-secreting macrophages on day 7 and CD147-secreting macrophages on day 14 into the same mice after BLM treatment. Our data suggest that macrophage-based delivery of anti-fibrotic proteins to the lungs is a promising therapy for fibrotic lung disorders.

PMID:37693057 | PMC:PMC10486326 | DOI:10.1002/btm2.10555

Am J Transl Res. 2023 Aug 15;15(8):5159-5167. eCollection 2023.

ABSTRACT

OBJECTS: Epidemiologic studies have linked exposure to airborne pollutant particulate matter (PM) with increased rates of chronic cardiopulmonary diseases, including asthma and idiopathic pulmonary fibrosis (IPF). Several investigations have suggested that the epithelial-to-mesenchymal transition (EMT) may contribute to the complex pathobiology of environmental exposure-mediated pulmonary fibrosis. The present study was designed to characterize the mechanisms of PM-mediated EMT in human lung epithelial cells (HBECs).

METHODS AND RESULTS: PM induced significant dose (0-100 μg/ml) and time (0-72 h)-dependent increases in transforming growth factor β (TGFβ) and fibronectin (FN) protein levels in HBECs lysates. PM-activated TGFβ and FN protein production in HBECs was prevented by the antioxidant N-acetyl-cysteine (NAC, 5 mM). Furthermore, the NF-κB inhibitor BAY11-7082 (5 μM) abolished PM-induced FN production in HBECs. Biomarkers of EMT (ACTA2, SNAIL1 and SNAIL2) in PM-treated HBECs were significantly increased at the mRNA level compared to control cells.

CONCLUSIONS: These results demonstrate that PM increases protein levels of TGFβ and FN via reactive oxygen species (ROS)-dependent pathways. In addition, PM exposure induces EMT in human lung epithelial cells, supporting a novel mechanism for PM-induced pulmonary fibrosis.

PMID:37692935 | PMC:PMC10492054

J Thorac Dis. 2023 Aug 31;15(8):4503-4521. doi: 10.21037/jtd-23-209. Epub 2023 Jul 24.

ABSTRACT

BACKGROUND AND OBJECTIVE: Interstitial lung disease (ILD) encompasses several diverse pulmonary pathologies that result in abnormal diffuse parenchymal changes. When prescribing rehabilitation, several additional factors need to be considered as a result of aging, polypharmacy, and comorbidities manifested in ILD patients. This review aims to discuss issues related to frailty, skeletal muscle and cognitive function that limit physical activities in ILD patients. It will also highlight exercise training and propose complementary strategies for pulmonary rehabilitation.

METHODS: A literature search was performed in MEDLINE, CINAHL (inception to October 19th, 2022) using search terms based on concepts of: idiopathic pulmonary fibrosis or interstitial lung disease; frailty; muscular atrophy; skeletal muscle dysfunction; cognitive dysfunction; sleep quality; sleep disorders; anxiety disorders; or depressive disorders. After eligible texts were screened, additional references were included from references cited in the screened articles.

KEY CONTENT AND FINDINGS: Frailty and skeletal muscle dysfunction are common in ILD. Weight loss, exhaustion, and anti-fibrotic medications can impact frailty, whereas physical inactivity, aging, corticosteroids and hypoxemia can contribute to sarcopenia (loss of muscle mass and function). Frailty is associated with worse clinical status, exercise intolerance, skeletal muscle dysfunction, and decreased quality of life in ILD. Sarcopenia appears to influence wellbeing and can potentially affect overall physical conditioning, cognitive function and the progression of ILD. Optimal assessment tools and effective strategies to prevent and counter frailty and sarcopenia need to be determined in ILD patients. Even though cognitive impairment is evident in ILD, its prevalence and underlying neurobiological model of contributing factors (i.e., inflammation, disease severity, cardiopulmonary status) requires further investigation. How ILD affects cognitive interference, motor control and consequently physical daily activities is not well defined. Strategies such as pulmonary rehabilitation, which primarily focuses on strength and aerobic conditioning have demonstrated improvements in ILD patient outcomes. Future incorporation of interval training and the integration of motor learning could improve transfer of rehabilitation strategies to daily activities.

CONCLUSIONS: Numerous underlying etiologies of ILD contribute to frailty, skeletal muscle and cognitive function, but their respective neurobiologic mechanisms require further investigation. Exercise training increases physical measures, but complementary approaches may improve their applicability to improve daily activities.

PMID:37691666 | PMC:PMC10482628 | DOI:10.21037/jtd-23-209

Clin Radiol. 2023 Sep 1:S0009-9260(23)00372-0. doi: 10.1016/j.crad.2023.08.011. Online ahead of print.

ABSTRACT

AIM: To assess the relationship between idiopathic pulmonary fibrosis (IPF) prognosis, baseline skeletal muscle mass, and attenuation on computed tomography (CT) and clinical parameters.

MATERIAL AND METHODS: This retrospective cohort study enrolled 195 patients. The mean follow-up duration was 42.52 months. Erector spinae muscle area (ESMA), pectoralis muscle area (PMA), and the attenuation of the erector spinae muscle at the level of T12 vertebrae were measured. Muscle indexes were obtained by adjusting the measured muscle areas to the patients' heights. The relationship between baseline CT-derived muscle metrics and clinical parameters including short- and long-term mortality were evaluated.

RESULTS: There was a moderate correlation between ESMA and PMA and pectoralis muscle index (PMI; r=0.536, p<0001 and r=0.403, p<0.001 respectively). ESMA correlated significantly with forced expiratory volume in 1 second (FEV1; hazard ratio [HR] = 0.488 p<0.001) and forced vital capacity (FVC; HR=0.501, p<0.001). Compared with PMA, ESMA was more strongly associated with 1- and 2-year mortality in patients with IPF (HR=0.957, p=0.022). The survival rate in male patients with sarcopenia was significantly worse (p=0.040).

CONCLUSION: ESMA measurements obtained from CT correlated with clinical parameters in IPF patients and were also predictors of short- and long-term survival.

PMID:37690976 | DOI:10.1016/j.crad.2023.08.011

Arch Biochem Biophys. 2023 Sep 8:109730. doi: 10.1016/j.abb.2023.109730. Online ahead of print.

ABSTRACT

Epithelial-mesenchymal transition (EMT) of alveolar epithelial cells is a vital process in idiopathic pulmonary fibrosis (IPF), which results in the accumulation of fibroblasts and myofibroblasts and excessive extracellular matrix deposition. Based on RNA sequencing analysis and GEO dataset reanalysis, we screened out MICALL2, a gene upregulated in the lungs of IPF mice and alveolar epithelial type II (ATII) cells from IPF patients, and aimed to explore its role in IPF. We validated the expression of MICALL2 in bleomycin (BLM)-induced IPF mice and TGF-β1-stimulated ATII cells (primary murine ATII cells and A549 cells), and explored the role of MICALL2 in IPF by knockdown of MICALL2 in BLM-induced mice and TGF-β1-stimulated ATII cells. We found that MICALL2 was upregulated in the lungs of BLM-induced mice and TGF-β1-stimulated ATII cells. MICALL2-deficient mice had reduced fibrogenesis and restrained EMT upon BLM challenge. Knockdown of MICALL2 restrained the EMT process, in vitro, through impeding β-catenin nuclear translocation. Mechanistically, we demonstrated that NPAS2 is directly bound to the promoter of MICALL2. Altogether, our data revealed transactivation of MICALL2 induced by NPAS2, contributing to activation of the Wnt/β-catenin pathway in ATII cells, thus leading to the EMT process and subsequent pulmonary fibrosis. Interfering with MICALL2 may represent an innovative therapeutic target to mitigate the extent of IPF.

PMID:37690696 | DOI:10.1016/j.abb.2023.109730

QJM. 2023 Sep 9:hcad206. doi: 10.1093/qjmed/hcad206. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is increasingly recognized as a chronic, progressive, and fatal lung disease with an unknown etiology. Current studies focus on revealing the genetic factors in the risk of IPF, making the integrative analysis of genetic variations and transcriptomic alterations of substantial value.

AIM: This study aimed to improve the understanding of the molecular basis of IPF through an integrative analysis of whole-exome sequencing (WES), bulk RNA sequencing (RNA-seq), and single-cell RNA sequencing (scRNA-seq) data.

METHODS: WES is a powerful tool for studying the genetic basis of IPF, allowing for the identification of genetic variants that may be associated with the development of the disease. RNA-seq data provide a comprehensive view of the transcriptional changes in IPF patients, while scRNA-seq data offer a more granule view of cell-type-specific alterations.

RESULTS: In this study, we identified a comprehensive mutational landscape of recurrent genomic and transcriptomic variations, including SNPs, CNVs, and differentially expressed genes, in IPF populations, which may play a significant role in the development and progression of IPF.

CONCLUSIONS: Our study provided valuable insights into the genetic and transcriptomic variations associated with IPF, revealing changes in gene expression that may contribute to disease development and progression. These findings highlight the importance of an integrative approach to understanding the molecular mechanisms underlying IPF and may pave the way for identifying potential therapeutic targets.

PMID:37688571 | DOI:10.1093/qjmed/hcad206

Int J Mol Sci. 2023 Aug 27;24(17):13305. doi: 10.3390/ijms241713305.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease, but its pathogenesis is still unclear. Bioinformatics methods were used to explore the differentially expressed genes (DEGs) and to elucidate the pathogenesis of IPF at the genetic level. The microarray datasets GSE110147 and GSE53845 were downloaded from the Gene Expression Omnibus (GEO) database and analyzed using GEO2R to obtain the DEGs. The DEGs were further analyzed for Gene Ontology (GO) and Kyoto Encyclopedia of Genomes (KEGG) pathway enrichment using the DAVID database. Then, using the STRING database and Cytoscape, a protein-protein interaction (PPI) network was created and the hub genes were selected. In addition, lung tissue from a mouse model was validated. Lastly, the network between the target microRNAs (miRNAs) and the hub genes was constructed with NetworkAnalyst. A summary of 240 genes were identified as DEGs, and functional analysis highlighted their role in cell adhesion molecules and ECM-receptor interactions in IPF. In addition, eight hub genes were selected. Four of these hub genes (VCAM1, CDH2, SPP1, and POSTN) were screened for animal validation. The IHC and RT-qPCR of lung tissue from a mouse model confirmed the results above. Then, miR-181b-5p, miR-4262, and miR-155-5p were predicted as possible key miRNAs. Eight hub genes may play a key role in the development of IPF. Four of the hub genes were validated in animal experiments. MiR-181b-5p, miR-4262, and miR-155-5p may be involved in the pathophysiological processes of IPF by interacting with hub genes.

PMID:37686108 | DOI:10.3390/ijms241713305

Front Immunol. 2023 Aug 23;14:1215450. doi: 10.3389/fimmu.2023.1215450. eCollection 2023.

ABSTRACT

OBJECTIVES: This study aims to assess the efficacy of tofacitinib (TOF) plus iguratimod (IGU) in rheumatoid arthritis (RA) with usual interstitial pneumonia (UIP) (RA-UIP).

METHODS: This was a prospective observational cohort, single-center study. Data from 78 RA-UIP patients treated with TOF plus IGU, IGU plus conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), and csDMARDs were analyzed. Clinically relevant responses in RA activity assessment, pulmonary function tests (PFTs), and high-resolution computed tomography (HRCT) assessment at baseline and follow-up were compared between groups to evaluate the efficacy of TOF plus IGU.

RESULTS: A total of 78 patients were followed up for at least 6 months after treatment. There were significant changes in sedimentation rate (ESR), C reactive protein (CRP), and disease activity score (DAS) 28-CRP during the follow-up within each treatment group, but there was no statistically significant difference between the two groups. After 6 months of TOF plus IGU treatment, forced vital capacity (FVC)% (84.7 ± 14.7 vs. 90.7 ± 15.4) and HRCT fibrosis score (7.3 ± 3.4 vs. 7.0 ± 5.6) showed a significant improvement compared to the csDMARDs group (P = 0.031, P = 0.015). The TOF plus IGU-treated patients had a significantly higher regression and lower deterioration than the csDMARDs-treated patients (P = 0.026, P = 0.026) and had a significantly higher response (regression + stability), with overall response rates of 66.7% (16/24) vs. 35.7% (10/28) (P = 0.027), respectively.

CONCLUSION: Our results indicate that TOF plus IGU can simultaneously relieve RA and RA-UIP and be better than the csDMARDs with a higher response rate in RA-UIP, which may be a potential choice for "dual treat-to-target".

PMID:37680626 | PMC:PMC10482028 | DOI:10.3389/fimmu.2023.1215450

Eur J Med Chem. 2023 Aug 25;260:115762. doi: 10.1016/j.ejmech.2023.115762. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is the most common fibrotic form of idiopathic diffuse lung disease. Due to limited treatment options, IPF patients suffer from poor survival. About ten years ago, Pirfenidone (Shionogi, 2008; InterMune, 2011) and Nintedanib (Boehringer Ingelheim, 2014) were approved, greatly changing the direction of IPF drug design. However, limited efficacy and side effects indicate that neither can reverse the process of IPF. With insights into the occurrence of IPF, novel targets and agents have been proposed, which have fundamentally changed the treatment of IPF. With the next-generation agents, targeting pro-fibrotic pathways in the epithelial-injury model offers a promising approach. Besides, several next-generation IPF drugs have entered phase II/III clinical trials with encouraging results. Due to the rising IPF treatment requirements, there is an urgent need to completely summarize the mechanisms, targets, problems, and drug design strategies over the past ten years. In this review, we summarize known mechanisms, target types, drug design, and novel technologies of IPF drug discovery, aiming to provide insights into the future development and clinical application of next-generation IPF drugs.

PMID:37683364 | DOI:10.1016/j.ejmech.2023.115762

Cells. 2023 Sep 1;12(17):2193. doi: 10.3390/cells12172193.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a lethal interstitial lung disease of unknown etiology with a poor prognosis. It is a chronic and progressive disease that has a distinct radiological and pathological pattern from common interstitial pneumonia. The use of immunosuppressive medication was shown to be completely ineffective in clinical trials, resulting in years of neglect of the immune component. However, recent developments in fundamental and translational science demonstrate that immune cells play a significant regulatory role in IPF, and macrophages appear to be among the most crucial. These highly plastic cells generate multiple growth factors and mediators that highly affect the initiation and progression of IPF. In this review, we will provide an update on the role of macrophages in IPF through a systemic discussion of various regulatory mechanisms involving immune receptors, cytokines, metabolism, and epigenetics.

PMID:37681924 | DOI:10.3390/cells12172193

Mol Ther Nucleic Acids. 2023 Aug 18;33:898-907. doi: 10.1016/j.omtn.2023.08.014. eCollection 2023 Sep 12.

ABSTRACT

MicroRNAs are attractive therapeutic targets in many diseases, including chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. Among microRNA inhibitors antimiRs have been proven successful in lowering aberrant microRNA levels in the clinic. We present a set of antimiRs targeting miR-34a, which has been shown to be dysregulated in chronic lung diseases. The tool compounds were taken up by a bronchial epithelial cell line and primary human bronchial epithelial cells, followed by efficient knockdown of miR-34a. Similar results were observed in 3D differentiated primary human bronchial epithelial cells cultured at the air-liquid interface. Varying chemical properties of antimiRs had significant impact on cellular uptake and potency, resulting in effective tool compounds for use in lung-relevant cellular systems. This report demonstrates gymnotic antimiR uptake and activity in 3D epithelial cell culture after apical administration, mimicking inhalation conditions.

PMID:37680982 | PMC:PMC10480572 | DOI:10.1016/j.omtn.2023.08.014

Drug Des Devel Ther. 2023 Sep 2;17:2679-2690. doi: 10.2147/DDDT.S415453. eCollection 2023.

ABSTRACT

Due to the complex mechanism and limited treatments available for pulmonary fibrosis, the development of targeted drugs or inhibitors based on their molecular mechanisms remains an important strategy for prevention and treatment. In this paper, the downstream signaling pathways mediated by VEGFR and LPAR1 in pulmonary cells and the role of these pathways in pulmonary fibrosis, as well as the current status of drug research on the targets of LPAR1 and VEGFR2, are described. The mechanism by which these two pathways regulate vascular leakage and collagen deposition leading to the development of pulmonary fibrosis are analyzed, and the mutual promotion of the two pathways is discussed. Here we propose the development of drugs that simultaneously target LPAR1 and VEGFR2, and discuss the important considerations in targeting and safety.

PMID:37680863 | PMC:PMC10482219 | DOI:10.2147/DDDT.S415453