-
Journal of Personalized Medicine Dec 2023Pulmonary fibrosis, a critical outcome of chronic inflammatory diseases, has gained prominence in the context of post-coronavirus (post-COVID-19) complications. This... (Review)
Review
Pulmonary fibrosis, a critical outcome of chronic inflammatory diseases, has gained prominence in the context of post-coronavirus (post-COVID-19) complications. This review delves into the multifaceted landscape of post-COVID-19 pulmonary fibrosis, elucidating the intricate molecular mechanisms underlying its pathogenesis and highlighting promising therapeutic avenues. Examining the aftermath of severe acute respiratory syndrome-2 (SARS-CoV-2) infection, the review reveals key signaling pathways implicated in the fibrotic cascade. Drawing parallels with previous coronavirus outbreaks enhances our understanding of the distinctive features of post-COVID-19 fibrosis. Antifibrotic drugs, like pirfenidone and nintedanib, take center stage; their mechanisms of action and potential applications in post-COVID-19 cases are thoroughly explored. Beyond the established treatments, this review investigates emerging therapeutic modalities, including anti-interleukin agents, immunosuppressants, and experimental compounds, like buloxybutide, saracatinib, sirolimus, and resveratrol. Emphasizing the critical importance of early intervention, this review highlights the dynamic nature of post-COVID-19 pulmonary fibrosis research. In conclusion, the synthesis of current knowledge offers a foundation for advancing our approaches to the prevention and treatment of these consequential sequelae of COVID-19.
PubMed: 38248752
DOI: 10.3390/jpm14010051 -
Cells Jan 2024Wound repair in the retina is a complex mechanism, and a deeper understanding of it is necessary for the development of effective treatments to slow down or even prevent...
Wound repair in the retina is a complex mechanism, and a deeper understanding of it is necessary for the development of effective treatments to slow down or even prevent degenerative processes leading to photoreceptor loss. In this study, we harnessed a laser-induced retinal degeneration model (532-nm laser photocoagulation with 300 μm spot size, 60 ms duration and 60 mV pulse), enabling a profound molecular elucidation and a comprehensive, prolonged observation of the wound healing sequence in a murine laser-induced degeneration model (C57BL/6J mice, 6-12 weeks) until day 49 post-laser. Our observations included the expression of specific extracellular matrix proteins and myofibroblast activity, along with an analysis of gene expression related to extracellular matrix and adhesion molecules through RNA measurements. Furthermore, the administration of pirfenidone (10 mg/kg via drinking water), an anti-inflammatory and anti-fibrotic compound, was used to modulate scar formation after laser treatment. Our data revealed upregulated collagen expression in late regenerative phases and sustained inflammation in the damaged tissue. Notably, treatment with pirfenidone was found to mitigate scar tissue formation, effectively downregulating collagen production and diminishing the presence of inflammatory markers. However, it did not lead to the regeneration of the photoreceptor layer.
Topics: Animals; Mice; Mice, Inbred C57BL; Cicatrix; Retina; Extracellular Matrix; Inflammation; Eye Injuries; Collagen; Pyridones
PubMed: 38247855
DOI: 10.3390/cells13020164 -
Advanced Science (Weinheim,... Apr 2024Kidney fibrosis is a common fate of chronic kidney diseases (CKDs), eventually leading to renal dysfunction. Yet, no effective treatment for this pathological process...
Kidney fibrosis is a common fate of chronic kidney diseases (CKDs), eventually leading to renal dysfunction. Yet, no effective treatment for this pathological process has been achieved. During the bioassay-guided chemical investigation of the medicinal plant Wikstroemia chamaedaphne, a daphne diterpenoid, daphnepedunin A (DA), is characterized as a promising anti-renal fibrotic lead. DA shows significant anti-kidney fibrosis effects in cultured renal fibroblasts and unilateral ureteral obstructed mice, being more potent than the clinical trial drug pirfenidone. Leveraging the thermal proteome profiling strategy, cell division cycle 42 (Cdc42) is identified as the direct target of DA. Mechanistically, DA targets to reduce Cdc42 activity and down-regulates its downstream phospho-protein kinase Cζ(p-PKCζ)/phospho-glycogen synthase kinase-3β (p-GSK-3β), thereby promoting β-catenin Ser33/37/Thr41 phosphorylation and ubiquitin-dependent proteolysis to block classical pro-fibrotic β-catenin signaling. These findings suggest that Cdc42 is a promising therapeutic target for kidney fibrosis, and highlight DA as a potent Cdc42 inhibitor for combating CKDs.
Topics: Animals; Mice; beta Catenin; Fibrosis; Glycogen Synthase Kinase 3 beta; Kidney; Kidney Diseases; Wikstroemia; Diterpenes; cdc42 GTP-Binding Protein
PubMed: 38240457
DOI: 10.1002/advs.202307850 -
Journal of Pharmaceutical Analysis Dec 2023Excessive -acetyl--benzoquinone imine (NAPQI) formation is a starting event that triggers oxidative stress and subsequent hepatocyte necrosis in acetaminophen (APAP)...
Excessive -acetyl--benzoquinone imine (NAPQI) formation is a starting event that triggers oxidative stress and subsequent hepatocyte necrosis in acetaminophen (APAP) overdose caused acute liver failure (ALF). glutathionylation is a reversible redox post-translational modification and a prospective mechanism of APAP hepatotoxicity. Glutaredoxin-1 (Glrx1), a glutathione-specific thioltransferase, is a primary enzyme to catalyze deglutathionylation. The objective of this study was to explored whether and how Glrx1 is associated with the development of ALF induced by APAP. The knockout mice () and liver-specific overexpression of () mice were produced and underwent APAP-induced ALF. Pirfenidone (PFD), a potential inducer of Glrx1, was administrated preceding APAP to assess its protective effects. Our results revealed that the hepatic total protein glutathionylation (PSSG) increased and the Glrx1 level reduced in mice after APAP toxicity. mice were more sensitive to APAP overdose, with higher oxidative stress and more toxic metabolites of APAP. This was attributed to Glrx1 deficiency increasing the total hepatic PSSG and the glutathionylation of cytochrome p450 3a11 (Cyp3a11), which likely increased the activity of Cyp3a11. Conversely, mice were defended against liver damage caused by APAP overdose by inhibiting the glutathionylation and activity of Cyp3a11, which reduced the toxic metabolites of APAP and oxidative stress. PFD precede administration upregulated Glrx1 expression and alleviated APAP-induced ALF by decreasing oxidative stress. We have identified the function of Glrx1 mediated PSSG in liver injury caused by APAP overdose. Increasing Glrx1 expression may be investigated for the medical treatment of APAP-caused hepatic injury.
PubMed: 38223455
DOI: 10.1016/j.jpha.2023.08.004 -
Respirology (Carlton, Vic.) Feb 2024Idiopathic pulmonary fibrosis (IPF) is a progressive disease leading to significant morbidity and mortality. In 2017 the Thoracic Society of Australia and New Zealand...
Idiopathic pulmonary fibrosis (IPF) is a progressive disease leading to significant morbidity and mortality. In 2017 the Thoracic Society of Australia and New Zealand (TSANZ) and Lung Foundation Australia (LFA) published a position statement on the treatment of IPF. Since that time, subsidized anti-fibrotic therapy in the form of pirfenidone and nintedanib is now available in both Australia and New Zealand. More recently, evidence has been published in support of nintedanib for non-IPF progressive pulmonary fibrosis (PPF). Additionally, there have been numerous publications relating to the non-pharmacologic management of IPF and PPF. This 2023 update to the position statement for treatment of IPF summarizes developments since 2017 and reaffirms the importance of a multi-faceted approach to the management of IPF and progressive pulmonary fibrosis.
Topics: Humans; New Zealand; Idiopathic Pulmonary Fibrosis; Fibrosis; Australia; Pyridones
PubMed: 38211978
DOI: 10.1111/resp.14656 -
International Journal of Molecular... Dec 2023Interstitial lung diseases (ILDs) are a heterogeneous group of pulmonary disorders characterized by variable degrees of inflammation, interstitial thickening, and... (Review)
Review
Interstitial lung diseases (ILDs) are a heterogeneous group of pulmonary disorders characterized by variable degrees of inflammation, interstitial thickening, and fibrosis leading to distortion of the pulmonary architecture and gas exchange impairment. Among them, idiopathic pulmonary fibrosis (IPF) displays the worst prognosis. The only therapeutic options consist of the two antifibrotic drugs, pirfenidone and nintedanib, which limit fibrosis progression but do not reverse the lung damage. The shift of the pathogenetic paradigm from inflammatory disease to epithelium-derived disease has definitively established the primary role of type II alveolar cells, which lose their epithelial phenotype and acquire a mesenchymal phenotype with production of collagen and extracellular matrix (EMC) deposition. Some predisposing environmental and genetic factors (e.g., smoke, pollution, gastroesophageal reflux, variants of telomere and surfactant genes) leading to accelerated senescence set a pro-fibrogentic microenvironment and contribute to the loss of regenerative properties of type II epithelial cells in response to pathogenic noxae. This review provides a complete overview of the different pathogenetic mechanisms leading to the development of IPF. Then, we summarize the currently approved therapies and the main clinical trials ongoing. Finally, we explore the potentialities offered by agents not only interfering with the processes of fibrosis but also restoring the physiological properties of alveolar regeneration, with a particular focus on potentialities and concerns about cell therapies based on mesenchymal stem cells (MSCs), whose anti-inflammatory and immunomodulant properties have been exploited in other fibrotic diseases, such as graft versus host disease (GVHD) and COVID-19-related ARDS.
Topics: Humans; Idiopathic Pulmonary Fibrosis; Alveolar Epithelial Cells; Pulmonary Surfactants; COVID-19; Fibrosis
PubMed: 38203718
DOI: 10.3390/ijms25010547 -
Frontiers in Pharmacology 2023Recent studies have suggested that combination therapy with pirfenidone and nintedanib is safe and tolerable in patients with idiopathic pulmonary fibrosis (IPF)....
Recent studies have suggested that combination therapy with pirfenidone and nintedanib is safe and tolerable in patients with idiopathic pulmonary fibrosis (IPF). However, data from real-world practice are limited. Thus, we aimed to investigate the safety and efficacy of this combination therapy in patients with IPF in a real-world setting. A multicenter retrospective cohort study was conducted to investigate the safety and efficacy of combination therapy with pirfenidone and nintedanib in 45 patients with IPF. Incidences of adverse events and rates of lung function decline were compared before and after the combination therapy. Propensity score matching was performed to compare the outcomes between the combination and monotherapy groups. The mean age of the patients was 68.8 years, and 82.2% of them were male. The median follow-up duration after combination therapy was 12.1 months. The majority of the patients (97.8%) received nintedanib as an add-on to pirfenidone. The most common adverse events after the combination therapy were diarrhea and anorexia. Pirfenidone or nintedanib was stopped in 12 patients owing to gastrointestinal AEs, lung transplantation, or financial problems. In patients with serial lung function data, the rate of decline in the forced vital capacity was significantly reduced after the combination therapy. In the matched analysis, the combination group had a higher incidence of diarrhea than the monotherapy group without an increase in serious adverse events; however, the two groups had similar changes in forced vital capacity (FVC). The combination of pirfenidone and nintedanib in patients with IPF has the potential to reduce the rate of FVC decline. However, in the matched analysis, FVC decline was comparable between the patients on combination therapy and those on monotherapy. The incidence of certain adverse events, particularly diarrhea, was higher with combination therapy, but serious adverse events were similar between the groups.
PubMed: 38192410
DOI: 10.3389/fphar.2023.1301923 -
Immune Network Dec 2023Interstitial lung disease (ILD) involves persistent inflammation and fibrosis, leading to respiratory failure and even death. Adult tissue-derived mesenchymal stem cells...
Promising Therapeutic Effects of Embryonic Stem Cells-Origin Mesenchymal Stem Cells in Experimental Pulmonary Fibrosis Models: Immunomodulatory and Anti-Apoptotic Mechanisms.
Interstitial lung disease (ILD) involves persistent inflammation and fibrosis, leading to respiratory failure and even death. Adult tissue-derived mesenchymal stem cells (MSCs) show potential in ILD therapeutics but obtaining an adequate quantity of cells for drug application is difficult. Daewoong Pharmaceutical's MSCs (DW-MSCs) derived from embryonic stem cells sustain a high proliferative capacity following long-term culture and expansion. The aim of this study was to investigate the therapeutic potential of DW-MSCs in experimental mouse models of ILD. DW-MSCs were expanded up to 12 passages for application in bleomycin-induced pulmonary fibrosis and collagen-induced connective tissue disease-ILD mouse models. We assessed lung inflammation and fibrosis, lung tissue immune cells, fibrosis-related gene/protein expression, apoptosis and mitochondrial function of alveolar epithelial cells, and mitochondrial transfer ability. Intravenous administration of DW-MSCs consistently improved lung fibrosis and reduced inflammatory and fibrotic markers expression in both models across various disease stages. The therapeutic effect of DW-MSCs was comparable to that following daily oral administration of nintedanib or pirfenidone. Mechanistically, DW-MSCs exhibited immunomodulatory effects by reducing the number of B cells during the early phase and increasing the ratio of Tregs to Th17 cells during the late phase of bleomycin-induced pulmonary fibrosis. Furthermore, DW-MSCs exhibited anti-apoptotic effects, increased cell viability, and improved mitochondrial respiration in alveolar epithelial cells by transferring their mitochondria to alveolar epithelial cells. Our findings indicate the strong potential of DW-MSCs in the treatment of ILD owing to their high efficacy and immunomodulatory and anti-apoptotic effects.
PubMed: 38188598
DOI: 10.4110/in.2023.23.e45 -
Biomedicine & Pharmacotherapy =... Feb 2024Fibrosis is a process of tissue repair that results in the slow creation of scar tissue to replace healthy tissue and can affect any tissue or organ. Its primary feature... (Review)
Review
Fibrosis is a process of tissue repair that results in the slow creation of scar tissue to replace healthy tissue and can affect any tissue or organ. Its primary feature is the massive deposition of extracellular matrix (mainly collagen), eventually leading to tissue dysfunction and organ failure. The progression of fibrotic diseases has put a significant strain on global health and the economy, and as a result, there is an urgent need to find some new therapies. Previous studies have identified that inflammation, oxidative stress, some cytokines, and remodeling play a crucial role in fibrotic diseases and are essential avenues for treating fibrotic diseases. Among them, matrix metalloproteinases (MMPs) are considered the main targets for the treatment of fibrotic diseases since they are the primary driver involved in ECM degradation, and tissue inhibitors of metalloproteinases (TIMPs) are natural endogenous inhibitors of MMPs. Through previous studies, we found that MMP-9 is an essential target for treating fibrotic diseases. However, it is worth noting that MMP-9 plays a bidirectional regulatory role in different fibrotic diseases or different stages of the same fibrotic disease. Previously identified MMP-9 inhibitors, such as pirfenidone and nintedanib, suffer from some rather pronounced side effects, and therefore, there is an urgent need to investigate new drugs. In this review, we explore the mechanism of action and signaling pathways of MMP-9 in different tissues and organs, hoping to provide some ideas for developing safer and more effective biologics.
Topics: Humans; Matrix Metalloproteinase 9; Fibrosis; Matrix Metalloproteinases; Tissue Inhibitor of Metalloproteinases; Inflammation; Extracellular Matrix; Matrix Metalloproteinase 3; Matrix Metalloproteinase Inhibitors
PubMed: 38181715
DOI: 10.1016/j.biopha.2023.116116 -
Tuberkuloz Ve Toraks Dec 2023The aim of this study was to evaluate the real-life treatment and follow-up data of patients with idiopathic pulmonary fibrosis (IPF) in a singlecenter setting.
INTRODUCTION
The aim of this study was to evaluate the real-life treatment and follow-up data of patients with idiopathic pulmonary fibrosis (IPF) in a singlecenter setting.
MATERIALS AND METHODS
The study included consecutive patients diagnosed with IPF who were followed up at the Akdeniz University, between January 1, 2014 and December 31, 2022. Patient information was obtained from the hospital automation system.
RESULT
A total of 227 patients with a mean age of 72.0 ± 8.2 years were included in the study. One hundred sixty-seven patients (73.6%) received pirfenidone while 60 patients (26.4%) received nintedanib treatment. Radiological findings were used to diagnose IPF in 79.3% (n= 180) of cases. Mean duration of antifibrotic treatment was 26.3 ± 19.9 months. Of the patients, 49.8% experienced hospital admissions during the treatment course, with respiratory reasons accounting for a majority of these admissions (33.6%). Disease exacerbation was detected in 26.6% of the patients during the treatment period. At least one side effect was observed in 126 patients (55.5%), with a significant portion of these side effects being mild to moderate (n= 79, 34.8%). Disease progression was observed in 21.6% of the patients under antifibrotic treatment. Dose reduction was necessary in 22.9% of the patients, with an average duration of dose reduction of 29 months. Antifibrotic treatment was switched to another medication in 24.2% of the patients. There were no statistically significant differences in baseline forced vital capacity (FVC) levels between the two groups (p= 0.314) while the diffusing capacity of the lungs for carbon monoxide (DLCO) level was higher in the nintedanib group (p= 0.024), and the six-minute walk distance was shorter (p= 0.049).
CONCLUSIONS
In this study evaluating patients with IPF under follow-up in our hospital, it was observed that the majority of patients consisted of elderly male individuals, frequent hospitalizations were due to respiratory reasons, and both antifibrotic medications were well tolerated with a similar side effect profile.
Topics: Humans; Male; Aged; Middle Aged; Aged, 80 and over; Follow-Up Studies; Treatment Outcome; Idiopathic Pulmonary Fibrosis; Lung; Vital Capacity; Disease Progression; Retrospective Studies
PubMed: 38152005
DOI: 10.5578/tt.20239603