Astragalus Mongholicus for Idiopathic Pulmonary Fibrosis Treatment: From Molecules to Systems.

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease (ILD) for which there are no effective treatments. Lung transplantation is the only viable option for patients with end-stage PF but is only available to a minority of patients. Lung lesions in ILDs, including IPF, are characterized by alveolar epithelial cell (AEC) senescence and apoptosis and accumulation of activated myofibroblasts and/or fibrotic lung (fL) fibroblasts (fLfs). These composite populations of fLfs show a high rate of basal proliferation, resist apoptosis and senescence, and have increased migration and invasiveness. They also more readily deposit ECM proteins. These features eventuate in progressive destruction of alveolar architecture and loss of lung function in patients with PF. The identification of new, safer, and more effective therapy is therefore mandatory for patients with IPF or related ILDs. We found that increased caveolin-1 and tumor suppressor protein, p53 expression, and apoptosis in AECs occur prior to and then with the proliferation of fLfs in fibrotic lungs. AECs with elevated p53 typically undergo apoptosis. fLfs alternatively demonstrate strikingly low basal levels of caveolin-1 and p53, while mouse double minute 2 homolog (mdm2) levels and mdm2-mediated degradation of p53 protein are markedly increased. The disparities in the expression of p53 in injured AECs and fLfs appear to be due to increased basal expression of caveolin-1 in apoptotic AECs with a relative paucity of caveolin-1 and increased mdm2 in fLfs. Therefore, targeting caveolin-1 using a caveolin 1 scaffolding domain peptide, CSP7, represents a new and promising approach for patients with IPF, perhaps other forms of progressive ILD or even other forms of organ injury characterized by fibrotic repair. The mechanisms of action differ in the injured AECs and in fLfs, in which differential signaling enables the preservation of AEC viability with concurrent limitation of fLf expansion and collagen secretion. The findings in three models of PF indicate that lung scarring can be nearly abrogated by airway delivery of the peptide. Phase 1 clinical trial testing of this approach in healthy volunteers has been successfully completed; Phase 1b in IPF patients is soon to be initiated and, if successful, will be followed by phase 2 testing in short order. Apart from the treatment of IPF, this intervention may be applicable to other forms of tissue injury characterized by fibrotic repair.

Antifibrotic effects of vitamin D3 on human lung fibroblasts derived from patients with idiopathic pulmonary fibrosis

In Brief Idiopathic pulmonary fibrosis, previously known as cryptogenic fibrosing alveolitis, is a progressive and fatal interstitial lung disease with a fatal prognosis and with no effective treatment. Progress in diagnostic criteria has improved the identification, helped in clinical management, and settled the basis to better study disease pathogenesis. Therefore, recent advances in research have led to new insights for future therapeutic options. Idiopathic pulmonary fibrosis is a progressive and lethal interstitial lung disease. Recently, there have been several studies that improve the knowledge about this disease. The present review is focused on updating clinical, pathologic, and therapeutic aspects of this fibrogenic lung process. Idiopathic pulmonary fibrosis is a progressive and lethal interstitial lung disease. Recently, there have been several studies that improve the knowledge about this disease. The present review is focused on updating clinical, pathological, and therapeutic aspects of this fibrogenic lung process.

Efficacy and potential mechanisms of the main active ingredients of astragalus mongholicus in animal models of liver fibrosis: A systematic review and meta-analysis

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic, and fatal interstitial lung disease (ILD) of unknown etiology that primarily affects the elderly. Patients with IPF suffer from a heavy symptom burden and usually have a poor quality of life. Dyspnea and dry cough are predominant symptoms of IPF. Although pain is not considered one of the main symptoms of IPF, it can occur for a variety of reasons, such as hypoxia, coughing, muscle and nerve damage, deconditioning, and steroid use. The prevalence of pain in IPF patients varies greatly, ranging from around 30 to 80%, with the prevalence being estimated mostly among patients in the end-of-life period. It manifests itself in the form of muscle pain, joint discomfort, or back and chest pain. Approaches to the treatment of chronic musculoskeletal pain in patients with IPF include pharmacological and non-pharmacological measures that are also important to optimize the treatment of other symptoms (dyspnea and cough) and the optimal treatment of comorbidities. Given the scarcity of data on this symptom in the literature, this article summarizes what is currently known about the etiology and treatment of musculoskeletal pain in IPF.

Descurainia sophia seeds (DS), Astragalus mongholicus (AM), and their formulas are widely used to treat heart failure caused by various cardiac diseases in traditional Chinese medicine practice. However, the molecular mechanism of action of DS and AM has not been completely understood. Herein, we first used mass spectrometry coupled to UPLC to characterize the chemical components of DS and AM decoctions, then applied MS-based quantitative proteomic analysis to profile protein expression in the heart of rats with isoproterenol-induced cardiomyopathy (ISO-iCM) before and after treated with DS alone or combined with AM, astragaloside IV (AS4), calycosin-7-glucoside (C7G), and Astragalus polysaccharides (APS) from AM. We demonstrated for the first time that DS decoction alone could reverse the most of differentially expressed proteins in the heart of the rats with ISO-iCM, including the commonly recognized biomarkers natriuretic peptides (NPPA) of cardiomyopathy and sarcomeric myosin light chain 4 (MYL4), relieving ISO-iCM in rats, but AM did not pronouncedly improve the pharmacological efficiency of DS. Significantly, we revealed that AS4 remarkably promoted the pharmacological potency of DS by complementarily reversing myosin motor MYH6/7, and further downregulating NPPA and MYL4. In contrast, APS reduced the efficiency of DS due to upregulating NPPA and MYL4. These findings not only provide novel insights to better understanding in the combination principle of traditional Chinese medicine but also highlight the power of mass spectrometric proteomics strategy combined with conventional pathological approaches for the traditional medicine research.

Inhaled nintedanib nanoparticles for enhanced efficacy in idiopathic pulmonary fibrosis (IPF) treatment – Evidence in disease-relevant in-vitro models

Astragalus polysaccharide (APS) is an important bioactive component of Astragalus membranaceus which is used as an anti-diabetes herb in traditional Chinese medicine. The objective of this study was to investigate the effects and mechanisms of APS on insulin-sensitizing of adipocytes. Mouse 3T3-L1 preadipocytes were used as a model. The results showed that APS increased preadipocytes proliferation in a dose dependent manner, and 0.1 μg/mL APS sufficiently increased Proliferating Cell Nuclear Antigen (PCNA) content (p < 0.01). Moreover, APS enhanced intracellular lipid accumulation and mRNA expression of proliferator-activated receptor γ (PPARγ, p < 0.01), CCAAT/enhancer binding protein α (C/EBPα, p < 0.01) and fatty acid binding protein (aP2, p < 0.01). As expected, corresponding protein contents were elevated. Importantly, APS increased 2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino)-2-Deoxyglucose (2-NBDG) uptake (p < 0.01). Meanwhile, both mRNA and protein content of glucose transporter 4 (Glut4) were elevated by APS (p < 0.01). The APS treatment enhanced tyrosine phosphorylation of insulin receptor substrate 1 (IRS1, p < 0.05) and phosphor-Akt content (p < 0.01). Besides, phosphorylated AMP-activated protein kinase (AMPK) content was increased in the APS treated cells (p < 0.01). Taken together, APS improved insulin sensitivity by enhancing glucose uptake, possibly through AMPK activation. These results suggested that APS might be a therapeutic candidate for insulin resistance.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and fatal interstitial lung disease. Therapeutic options for IPF remain limited. Nintedanib, a tyrosine kinase inhibitor approved for IPF treatment, is known to inhibit fibroblasts proliferation, migration and transformation to myofibroblasts. However, how nintedanib changes gene regulations in IPF has never been systematically investigated. We conducted a next-generation sequencing and bioinformatics study to evaluate the changes of mRNA and miRNA profiles in IPF fibroblasts treated with 2 µM and 4 µM nintedanib, compared to those without treatment. We identified 157 upregulated and 151 downregulated genes and used STRING and DAVID databases for analysis of protein–protein interactions, biological pathways, and molecular functions. We found strong protein–protein interactions within these dysregulated genes, mostly involved in the pathways of cell cycle and mitotic cell cycle. We also discovered 13 potential miRNA–mRNA interactions associated with nintedanib treatment. After validation using miRDB, TargetScan, and RT-qPCR, we identified 4 downregulated genes (DDX11, E2F1,NPTX1, and PLXNA4) which might be repressed by the upregulated hsa-miR-486-3p. According to the proposed functions of DDX11, E2F1, and PLXNA4 reported in previous studies, these gene expression changes together might contribute to decreased proliferation of fibroblasts and decreased angiogenesis in the microenvironment of IPF. Our findings need further studies to confirm.

p53 and miR-34a Feedback Promotes Lung Epithelial Injury and Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal interstitial lung disease (ILD) with an unpredictable clinical course. Although IPF is rare, healthcare professionals should consider IPF as a potential cause of unexplained chronic dyspnea and/or cough in middle-aged/elderly patients and refer patients to a pulmonologist for evaluation. Making a diagnosis of IPF requires specialist expertise. Multidisciplinary discussion, involving at minimum a pulmonologist and a radiologist with expertise in the differential diagnosis of ILDs, is required to ensure the most accurate diagnosis. Prompt diagnosis of IPF is important to enable patients to receive appropriate care from an early stage. Optimal management of IPF involves the use of antifibrotic drugs, as well as the provision of supportive care to alleviate symptoms and preserve patients’ quality of life. Antifibrotic drugs have been shown to slow lung function decline seen in patients with IPF. Patients’ symptoms and functional capacity can be improved through participation in pulmonary rehabilitation programs and the use of supplemental oxygen. Patient education is essential to help patients understand and manage their disease. The identification and management of comorbidities, such as obstructive sleep apnea, pulmonary hypertension, and emphysema, is also an important element of the overall care of patients with IPF. Patients with IPF should be evaluated for lung transplantation at an early stage to maximize their chances of meeting eligibility criteria. In this review, we describe the clinical course and impact of IPF and best practice in its management, highlighting the importance of taking a patient-centered approach.

Idiopathic pulmonary fibrosis (IPF) is a fatal progressive interstitial lung disease, its etiology is still unknown, and effective treatment for this disease is not established yet. This disease is closely associated with a variety of miRNAs that are known involving the occurrence, diagnosis and treatment of many diseases. This article will review research status of new miRNAs which associated with IPF in three aspects, including profibrosis, antifibrosis and clinical diagnosis, to provide the scientific information for revealing the pathogenesis of IPF and finding effective therapies. Key words: Idiopathic pulmonary fibrosis; miRNAs

Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal interstitial lung disease (ILD) characterized by abnormal extracellular matrix (ECM) remodeling. We hypothesized that ECM remodeling might result in a plasma profile of proteins specific for IPF that could distinguish patients with IPF from other idiopathic ILDs. To identify biomarkers that might assist in distinguishing IPF from non-IPF ILD. We developed a panel of 35 ECM, ECM-related, and lung-specific analytes measured in plasma from 86 patients with IPF (derivation cohort) and in 63 patients with IPF (validation cohort). Comparison groups included patients with rheumatoid arthritis-associated ILD (RA-ILD; n = 33), patients with alternative idiopathic ILDs (a-ILD; n = 41), and healthy control subjects (n = 127). Univariable and multivariable logistic regression models identified biomarkers that differentiated patients with IPF from those with a-ILD. Both continuous and diagnostic threshold versions of biomarkers were considered; thresholds were chosen to maximize summed diagnostic sensitivity and specificity in univariate receiver-operating characteristic curve analysis. A diagnostic score was created from the most promising analytes. Plasma surfactant protein (SP)-D > 31 ng/ml, matrix metalloproteinase (MMP)-7 > 1.75 ng/ml, and osteopontin > 6 ng/ml each significantly distinguished patients with IPF from patients with a-ILD, both individually and in a combined index. The odds ratio for IPF when at least one analyte in the index exceeded the threshold was 4.4 (95% confidence interval, 2.0-9.7; P = 0.0003). When at least two analytes were elevated, the odds ratio for IPF increased to 5.0 (95% confidence interval, 2.2-11.5; P = 0.0002). A biomarker index of SP-D, MMP-7, and osteopontin enhanced diagnostic accuracy in patients with IPF compared with those with non-IPF ILD. Our data suggest that this biomarker index may improve diagnostic confidence in IPF.

Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease that presents with a 5-year survival of 20–30%, hence with a mortality rate as high as many aggressive cancer types.1...

Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal interstitial lung disease (ILD) of unknown etiology. Introduction of acid into the respiratory tree can produce pulmonary fibrosis. Gastroesophageal reflux (GER) has previously been associated with several other respiratory conditions, including pneumonia, bronchitis, and asthma. To investigate prospectively the possible association of GER and IPF, 17 consecutive patients with biopsy-proven IPF and eight control patients with ILD other than IPF underwent dual-channel, ambulatory esophageal pH monitoring. Sixteen of 17 patients with IPF had abnormal distal and/or proximal esophageal acid exposure compared with four of eight control patients (p = 0.02). In the patients with IPF, mean percent distal total (13.6 versus 3.34, p = 0.006), distal upright (12.4 versus 5.1, p = 0.04), distal supine (14.7 versus 0.88, p = 0.02), and proximal supine (7.48 versus 0.24, p = 0.04) esophageal acid exposure times were significantly greater than those in control patients. Only four patients with IPF (25%) with increased acid exposure had typical reflux symptoms such as heartburn or regurgitation. Patients with IPF have a high prevalence of increased esophageal acid exposure, usually without typical GER symptoms. GER in these patients tends to occur at night and extend into the proximal esophagus. Acid reflux may be a contributing factor in the pathogenesis of IPF.