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Biomedicine & Pharmacotherapy =... Oct 2023Lung injury and pulmonary fibrosis contribute to morbidity and mortality, and, in particular, are characterized as leading cause on confirmed COVID-19 death. To date,...
Lung injury and pulmonary fibrosis contribute to morbidity and mortality, and, in particular, are characterized as leading cause on confirmed COVID-19 death. To date, efficient therapeutic approach for such lung diseases is lacking. N-Acetylglucosamine (NAG), an acetylated derivative of glucosamine, has been proposed as a potential protector of lung function in several types of lung diseases. The mechanism by which NAG protects against lung injury, however, remains unclear. Here, we show that NAG treatment improves pulmonary function in bleomycin (BLM)-induced lung injury model measured by flexiVent system. At early phase of lung injury, NAG treatment results in silenced immune response by targeting ARG1 macrophages activation, and, consequently, blocks KRT8 transitional stem cell in the alveolar region to stimulate PDGF Rβ fibroblasts hyperproliferation, thereby attenuating the pulmonary fibrosis. This combinational depression of immune response and extracellular matrix deposition within the lung mitigates lung injury and pulmonary fibrosis induced by BLM. Our findings provide novel insight into the protective role of NAG in lung injury.
Topics: Humans; Pulmonary Fibrosis; Lung Injury; Acetylglucosamine; Bleomycin; COVID-19
PubMed: 37633052
DOI: 10.1016/j.biopha.2023.115069 -
Respirology (Carlton, Vic.) Jan 2022
Topics: Humans; Idiopathic Pulmonary Fibrosis; Lung; Lung Diseases, Interstitial
PubMed: 34846086
DOI: 10.1111/resp.14189 -
International Immunology Nov 2021Pulmonary fibrosis is caused by the interplay between genetic and environmental factors. Recent studies have revealed various genes associated with idiopathic pulmonary... (Review)
Review
Pulmonary fibrosis is caused by the interplay between genetic and environmental factors. Recent studies have revealed various genes associated with idiopathic pulmonary fibrosis, as well as the causative genes for familial pulmonary fibrosis. Although increased death or dysfunction of type 2 alveolar epithelial (AT2) cells has been detected in lung specimens from pulmonary fibrosis patients, it remains unclear whether and how AT2 cell death or dysfunction is responsible for the progression of pulmonary fibrosis. A recent study showed that increased AT2 cell necroptosis is the initial event in pulmonary fibrosis by analyzing patients with familial pulmonary fibrosis and an animal model that harbors the same mutation as patients. The contribution of AT2 cell necroptosis to the pathogenesis of pulmonary fibrosis has not been identified in animal model studies, which validates the effectiveness of genetic analysis of familial diseases to uncover unknown pathogeneses. Thus, further extensive genetic studies of pulmonary fibrosis along with functional studies based on genetic analysis will be crucial not only in elucidating the precise disease process but also, ultimately, in identifying novel treatment strategies for both familial and non-familial pulmonary fibrosis.
Topics: Animals; Disease Models, Animal; Idiopathic Pulmonary Fibrosis
PubMed: 34049386
DOI: 10.1093/intimm/dxab026 -
Apoptosis : An International Journal on... Dec 2023Pulmonary fibrosis (PF) is a disease in which excessive extracellular matrix (ECM) accumulation occurs in pulmonary mesenchyme, which induces the destruction of alveolar... (Review)
Review
Pulmonary fibrosis (PF) is a disease in which excessive extracellular matrix (ECM) accumulation occurs in pulmonary mesenchyme, which induces the destruction of alveolar structures and poor prognosis. Macrophage death is responsible for ECM accumulation after alveolar epithelial injury in PF. Depending on the local micro-environments, macrophages can be polarized to either classically activated (M1) or alternatively activated (M2) macrophage phenotypes. In general, M1 macrophages can promote inflammation and sterilization, stop the continuous damage process and prevent excessive repair, while M2 macrophages are anti-inflammatory and promote tissue repair, and excessive M2 macrophage activity may inhibit the absorption and degradation of ECM. Emerging evidence has revealed that death forms such as pyroptosis mediated by inflammasome affect polarization direction and ultimately lead to the development of PF. Pharmacological manipulation of macrophages death signals may serve as a logical therapeutic strategy for PF. This review will focus on the current state of knowledge regarding the regulation and underlying mechanisms of macrophages and their mediators in the influence of macrophage death on the development of PF. We expect to provide help in developing effective therapeutic strategies in clinical settings.
Topics: Humans; Macrophages, Alveolar; Pulmonary Fibrosis; Apoptosis; Macrophages; Inflammation
PubMed: 37707713
DOI: 10.1007/s10495-023-01888-4 -
JCI Insight Jul 2023Multiorgan fibrosis in systemic sclerosis (SSc) accounts for substantial mortality and lacks effective therapies. Lying at the crossroad of TGF-β and TLR signaling,...
Multiorgan fibrosis in systemic sclerosis (SSc) accounts for substantial mortality and lacks effective therapies. Lying at the crossroad of TGF-β and TLR signaling, TGF-β-activated kinase 1 (TAK1) might have a pathogenic role in SSc. We therefore sought to evaluate the TAK1 signaling axis in patients with SSc and to investigate pharmacological TAK1 blockade using a potentially novel drug-like selective TAK1 inhibitor, HS-276. Inhibiting TAK1 abrogated TGF-β1 stimulation of collagen synthesis and myofibroblasts differentiation in healthy skin fibroblasts, and it ameliorated constitutive activation of SSc skin fibroblasts. Moreover, treatment with HS-276 prevented dermal and pulmonary fibrosis and reduced the expression of profibrotic mediators in bleomycin-treated mice. Importantly, initiating HS-276 treatment even after fibrosis was already established prevented its progression in affected organs. Together, these findings implicate TAK1 in the pathogenesis of SSc and identify targeted TAK1 inhibition using a small molecule as a potential strategy for the treatment of SSc and other fibrotic diseases.
Topics: Mice; Animals; Fibrosis; Scleroderma, Systemic; Pulmonary Fibrosis; Fibroblasts
PubMed: 37306632
DOI: 10.1172/jci.insight.165358 -
Biomolecules Mar 2023Pulmonary fibrosis (PF) is an interstitial lung disease characterized by the destruction of the pulmonary parenchyma caused by excessive extracellular matrix deposition.... (Review)
Review
Pulmonary fibrosis (PF) is an interstitial lung disease characterized by the destruction of the pulmonary parenchyma caused by excessive extracellular matrix deposition. Despite the well-known etiological factors such as senescence, aberrant epithelial cell and fibroblast activation, and chronic inflammation, PF has recently been recognized as a metabolic disease and abnormal lipid signature was observed both in serum and bronchoalveolar lavage fluid (BALF) of PF patients and mice PF model. Clinically, observational studies suggest a significant link between high-fat diet (HFD) and PF as manifested by high intake of saturated fatty acids (SFAs) and meat increases the risk of PF and mice lung fibrosis. However, the possible mechanisms between HFD and PF remain unclear. In the current review we emphasize the diversity effects of the epigenetic dysregulation induced by HFD on the fibrotic factors such as epithelial cell injury, abnormal fibroblast activation and chronic inflammation. Finally, we discuss the potential ways for patients to improve their conditions and emphasize the prospect of targeted therapy based on epigenetic regulation for scientific researchers or drug developers.
Topics: Animals; Mice; Pulmonary Fibrosis; Diet, High-Fat; Epigenesis, Genetic; Lung; Inflammation
PubMed: 36979493
DOI: 10.3390/biom13030558 -
Acta Pharmacologica Sinica May 2023Pulmonary fibrosis (PF) is a chronic interstitial lung disease with no effective therapies. Galectin-3 (Gal-3), a marker of oxidative stress, plays a key role in the...
Pulmonary fibrosis (PF) is a chronic interstitial lung disease with no effective therapies. Galectin-3 (Gal-3), a marker of oxidative stress, plays a key role in the pathogenesis of PF. Fibroblast-myofibroblast differentiation (FMD) is an important source of fibrotic cells in PF. Previous studies showed that melatonin (MT) exerted anti-fibrotic effect in many diseases including PF through its antioxidant activity. In the present study we investigated the relationships among Gal-3, NRF2, ROS in FMD and their regulation by MT. We established an in vitro model of FMD in TGF-β1-treated human fetal lung fibroblast1 (HFL1) cells and a PF mouse model via bleomycin (BLM) intratracheal instillation. We found that Gal-3 expression was significantly increased both in vitro and in vivo. Knockdown of Gal-3 in HFL1 cells markedly attenuated TGF-β1-induced FMD process and ROS accumulation. In TGF-β1-treated HFL1 cells, pretreatment with NRF2-specific inhibitor ML385 (5 μM) significantly increased the levels of Gal-3, α-SMA and ROS, suggesting that the expression of Gal-3 was regulated by NRF2. Treatment with NRF2-activator MT (250 μM) blocked α-SMA and ROS accumulation accompanied by reduced Gal-3 expression. In BLM-induced PF model, administration of MT (5 mg·kg·d, ip for 14 or 28 days) significantly attenuated the progression of lung fibrosis through up-regulating NRF2 and down-regulating Gal-3 expression in lung tissues. These results suggest that Gal-3 regulates TGF-β1-induced pro-fibrogenic responses and ROS production in FMD, and MT activates NRF2 to block FMD process by down-regulating Gal-3 expression. This study provides a useful clue for a clinical strategy to prevent PF. Graphic abstract of the mechanisms. MT attenuated BLM-induced PF via activating NRF2 and inhibiting Gal-3 expression.
Topics: Animals; Humans; Mice; Bleomycin; Fibroblasts; Galectin 3; Lung; Melatonin; NF-E2-Related Factor 2; Pulmonary Fibrosis; Reactive Oxygen Species; Transforming Growth Factor beta1
PubMed: 36333557
DOI: 10.1038/s41401-022-01018-x -
Archives of Pharmacal Research May 2021In 2019, an unprecedented disease named coronavirus disease 2019 (COVID-19) emerged and spread across the globe. Although the rapid transmission of COVID-19 has resulted... (Review)
Review
In 2019, an unprecedented disease named coronavirus disease 2019 (COVID-19) emerged and spread across the globe. Although the rapid transmission of COVID-19 has resulted in thousands of deaths and severe lung damage, conclusive treatment is not available. However, three COVID-19 vaccines have been authorized, and two more will be approved soon, according to a World Health Organization report on December 12, 2020. Many COVID-19 patients show symptoms of acute lung injury that eventually leads to pulmonary fibrosis. Our aim in this article is to present the relationship between pulmonary fibrosis and COVID-19, with a focus on angiotensin converting enzyme-2. We also evaluate the radiological imaging methods computed tomography (CT) and chest X-ray (CXR) for visualization of patient lung condition. Moreover, we review possible therapeutics for COVID-19 using four categories: treatments related and unrelated to lung disease and treatments that have and have not entered clinical trials. Although many treatments have started clinical trials, they have some drawbacks, such as short-term and small-group testing, that need to be addressed as soon as possible.
Topics: Angiotensin-Converting Enzyme 2; Antiviral Agents; COVID-19; Drug Development; Drug Repositioning; Humans; Pulmonary Fibrosis; Radiography, Thoracic; Tomography, X-Ray Computed; COVID-19 Drug Treatment
PubMed: 34047940
DOI: 10.1007/s12272-021-01331-9 -
Medicina (Kaunas, Lithuania) Sep 2019Combined pulmonary fibrosis and emphysema (CPFE) has been increasingly recognized over the past 10-15 years as a clinical entity characterized by rather severe imaging... (Review)
Review
Combined pulmonary fibrosis and emphysema (CPFE) has been increasingly recognized over the past 10-15 years as a clinical entity characterized by rather severe imaging and gas exchange abnormalities, but often only mild impairment in spirometric and lung volume indices. In this review, we explore the gas exchange and mechanical pathophysiologic abnormalities of pulmonary emphysema, pulmonary fibrosis, and combined emphysema and fibrosis with the goal of understanding how individual pathophysiologic observations in emphysema and fibrosis alone may impact clinical observations on pulmonary function testing (PFT) patterns in patients with CPFE. Lung elastance and lung compliance in patients with CPFE are likely intermediate between those of patients with emphysema and fibrosis alone, suggesting a counter-balancing effect of each individual process. The outcome of combined emphysema and fibrosis results in higher lung volumes overall on PFTs compared to patients with pulmonary fibrosis alone, and the forced expiratory volume in one second (FEV)/forced vital capacity (FVC) ratio in CPFE patients is generally preserved despite the presence of emphysema on chest computed tomography (CT) imaging. Conversely, there appears to be an additive deleterious effect on gas exchange properties of the lungs, reflecting a loss of normally functioning alveolar capillary units and effective surface area available for gas exchange, and manifested by a uniformly observed severe reduction in the diffusing capacity for carbon monoxide (DCO). Despite normal or only mildly impaired spirometric and lung volume indices, patients with CPFE are often severely functionally impaired with an overall rather poor prognosis. As chest CT imaging continues to be a frequent imaging modality in patients with cardiopulmonary disease, we expect that patients with a combination of pulmonary emphysema and pulmonary fibrosis will continue to be observed. Understanding the pathophysiology of this combined process and the abnormalities that manifest on PFT testing will likely be helpful to clinicians involved with the care of patients with CPFE.
Topics: Humans; Pulmonary Emphysema; Pulmonary Fibrosis; Respiratory Function Tests
PubMed: 31509942
DOI: 10.3390/medicina55090580 -
Journal of Cellular and Molecular... Dec 2023To investigate the effect and mechanism of polydatin on bleomycin (BLM)-induced pulmonary fibrosis in a mouse model. The lung fibrosis model was induced by BLM. The...
To investigate the effect and mechanism of polydatin on bleomycin (BLM)-induced pulmonary fibrosis in a mouse model. The lung fibrosis model was induced by BLM. The contents of TNF-α, LPS, IL-6 and IL-1β in lung tissue, intestine and serum were detected by ELISA. Gut microbiota diversity was detected by 16S rDNA sequencing; R language was used to analyse species composition, α-diversity, β-diversity, species differences and marker species. Mice were fed drinking water mixed with four antibiotics (ampicillin, neomycin, metronidazole, vancomycin; antibiotics, ABx) to build a mouse model of ABx-induced bacterial depletion; and faecal microbiota from different groups were transplanted into BLM-treated or untreated ABx mice. The histopathological changes and collagen I and α-SMA expression were determined. Polydatin effectively reduced the degree of fibrosis in a BLM-induced pulmonary fibrosis mouse model; BLM and/or polydatin affected the abundance of the dominant gut microbiota in mice. Moreover, faecal microbiota transplantation (FMT) from polydatin-treated BLM mice effectively alleviated lung fibrosis in BLM-treated ABx mice compared with FMT from BLM mice. Polydatin can reduce fibrosis and inflammation in a BLM-induced mouse pulmonary fibrosis model. The alteration of gut microbiota by polydatin may be involved in the therapeutic effect.
Topics: Mice; Animals; Pulmonary Fibrosis; Bleomycin; Gastrointestinal Microbiome; Lung; Fibrosis; Anti-Bacterial Agents; Mice, Inbred C57BL
PubMed: 37665061
DOI: 10.1111/jcmm.17937