Phytomedicine. 2021 May 21;89:153599. doi: 10.1016/j.phymed.2021.153599. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis is a chronic, progressive, fibrotic disease. Although the pathogenesis remains unclear, the effect of endoplasmic reticulum (ER) stress in type II alveolar epithelial cells (AEC IIs) is increasingly thought to be a critical mechanism.

PURPOSE: We investigated the effects of citrus alkaline extracts (CAE) on AEC IIs and elucidated the underlying mechanism for their possible use in ameliorating pulmonary fibrosis (PF).

METHODS: A bleomycin-induced mouse model of PF, and an in vitro tunicamycin (TM) -induced ER stress model in A549 cells were successfully established. Accumulation of collagen in lung tissues in vivo was assessed using histological analysis and western blotting. The expression levels of the ER-stress marker BiP and other related proteins were assessed by western blotting and immunofluorescence staining. Mitochondrial membrane potential was assessed to evaluate mitochondrial homeostasis.

RESULTS: CAE mitigated collagen deposition to ameliorate PF in vivo. CAE suppressed the bleomycin or TM-induced increases in ER-stress biomarker, BiP, and PERK pathway proteins, resulting in a decrease in ER stress in mouse lung tissues and A549 cells, respectively. Additionally, CAE treatment suppressed the bleomycin or TM-induced increase in the ER-stress downstream proteins, activating ATF3 and increased the levels of PINK1 in AEC IIs, both in vivo and in vitro. The reduced mitochondrial homeostasis induced by TM was restored by CAE-treatment in A549 cells. Furthermore, conditioned media from TM-treated A549 cells increased collagen deposition in MRC5 cells mainly via TGF-β1. The increased collagen deposition was not seen using conditioned media from CAE-treated A549 cells.

CONCLUSION: These results provide novel insights into the potential mechanism of CAE in inhibiting ER stress in AEC IIs, and suggests that it has great potential to ameliorate PF via the ATF3/PINK1 pathway.

PMID:34260993 | DOI:10.1016/j.phymed.2021.153599

Respir Med. 2021 Jul 7;186:106534. doi: 10.1016/j.rmed.2021.106534. Online ahead of print.

ABSTRACT

BACKGROUND: Acute exacerbation (AE) of interstitial lung disease (ILD) is an acute respiratory deterioration of unknown etiology, associated with high mortality. Currently, bronchoalveolar lavage (BAL) has been no longer required for the diagnosis of AE-ILD; however, the clinical utility of BAL fluid (BALF) cellular analysis in AE-ILD remains unclear.

METHODS: A retrospective study of 71 patients who underwent BAL at our institution between 2005 and 2019 and were diagnosed with AE-ILD was conducted. We performed BALF cellular analysis and evaluated its prognostic significance.

RESULTS: There were 26 patients with AE of idiopathic pulmonary fibrosis (IPF) and 45 with AE of non-IPF, including idiopathic interstitial pneumonias/non-IPF (n = 22), ILD associated with collagen tissue disease (n = 20) and fibrotic hypersensitivity pneumonia (n = 3). All patients were treated with high-dose corticosteroids, and the 90-day mortality after AE was 31%. Most patients showed a high percentage of lymphocytes and/or neutrophils in BALF regardless of the underlying ILD. There was a significant negative correlation between BALF neutrophils and the PaO2/FiO2 ratio, and patients with UIP pattern or diffuse AE pattern on HRCT had a significantly higher percentage of BALF neutrophils than those with other patterns. Multivariate analysis revealed that lower and higher percentage of lymphocytes and neutrophils, respectively, in BALF were independent poor prognostic factors for 90-day survival. BALF lymphocyte and neutrophil count ≥25% and <20%, respectively, predicted favorable survival after AE.

CONCLUSIONS: Cellular analysis of BALF in AE-ILD is a potential biomarker for predicting prognosis after AE.

PMID:34260978 | DOI:10.1016/j.rmed.2021.106534

J Mol Med (Berl). 2021 Jul 13. doi: 10.1007/s00109-021-02113-y. Online ahead of print.

ABSTRACT

Pulmonary fibrosis is a chronic debilitating condition characterized by progressive deposition of connective tissue, leading to a steady restriction of lung elasticity, a decline in lung function, and a median survival of 4.5 years. The leading causes of pulmonary fibrosis are inhalation of foreign particles (such as silicosis and pneumoconiosis), infections (such as post COVID-19), autoimmune diseases (such as systemic autoimmune diseases of the connective tissue), and idiopathic pulmonary fibrosis. The therapeutics currently available for pulmonary fibrosis only modestly slow the progression of the disease. This review is centered on the interplay of damage-associated molecular pattern (DAMP) molecules, Toll-like receptor 4 (TLR4), and inflammatory cytokines (such as TNF-α, IL-1β, and IL-17) as they contribute to the pathogenesis of pulmonary fibrosis, and the possible avenues to develop effective therapeutics that disrupt this interplay.

PMID:34258628 | DOI:10.1007/s00109-021-02113-y

Dtsch Med Wochenschr. 2021 Jul;146(13-14):927-932. doi: 10.1055/a-1449-5158. Epub 2021 Jul 13.

ABSTRACT

Acute COVID-19 pneumonia may result in persistent changes with various imaging and histopathological patterns, including organizing pneumonia and pulmonary fibrosis. In addition, SARS-CoV-2 infection is associated with increased risk of pulmonary vascular endothelialitis and thrombosis. Herein, current findings on pulmonary consequences of COVID-19 with implications for clinical management are summarized based on a selective literature review.

PMID:34256411 | DOI:10.1055/a-1449-5158

Chest. 2021 Jul 9:S0012-3692(21)01317-9. doi: 10.1016/j.chest.2021.06.067. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is associated with a poor prognosis with variable clinical course. Early identification of patients at high risk for disease progression and death would lead to early therapeutic intervention and thereby improvement of outcomes. Cold-inducible RNA-binding protein (CIRBP) is produced in response to cellular stresses, which is implicated in multiple biological processes, including cell survival and proliferation.

RESEARCH QUESTION: Is CIRBP a useful biomarker for predicting the outcomes of patients with IPF?

STUDY DESIGN AND METHODS: This study included 95 and 93 patients with IPF from two independent hospitals (derivation and validation cohorts, respectively). The associations of serum CIRBP level upon IPF diagnosis with disease progression within 1 year after diagnosis (i.e. ≥10% relative decline in percent predicted forced vital capacity or death) and all-cause mortality were retrospectively analysed. Discrimination performances for predicting these outcomes were evaluated using the c-index.

RESULTS: Serum and lung tissue CIRBP levels were higher in patients with IPF than in control subjects. In the derivation cohort, the CIRBP high sub-group had significantly higher 1-year disease progression rates and lower cumulative survival rates than the CIRBP low sub-group, and the results were replicated in the validation cohort. In multivariate analyses, high serum CIRBP level was independently associated with higher 1-year disease progression and all-cause mortality rates in both cohorts. Combining the Gender-Age-Physiology and serum CIRBP models improved the c-indices for predicting 1-year disease progression and all-cause mortality compared with that of each model alone. The c-indices of serum CIRBP were particularly high in patients with Gender-Age-Physiology stage I.

INTERPRETATION: This study successfully validated that serum CIRBP level was an independent predictor of 1-year disease progression and all-cause mortality in IPF. CIRBP is a promising biomarker that can help identify high-risk patients with IPF, especially in the early stage.

PMID:34252438 | DOI:10.1016/j.chest.2021.06.067

J Int Med Res. 2021 Jul;49(7):3000605211029058. doi: 10.1177/03000605211029058.

ABSTRACT

OBJECTIVE: We aimed to assess the relationship between major air pollutants and the natural history and mortality of idiopathic pulmonary fibrosis (IPF).

METHODS: We conducted a retrospective cohort study from 2013 to 2019 among 52 patients with IPF from the pneumology department of a tertiary hospital. According to their geocoded residential address, each patient was assigned a mean concentration of carbon monoxide (CO), nitrogen dioxide, particulate matter 2.5 and 10, ozone, and sulfur dioxide, as measured at a single surveillance station in central Madrid, Spain. We analyzed forced vital capacity (FVC), CO diffusing capacity, 6-minute walking test, degree of dyspnea, radiologic pattern, and signs of pulmonary hypertension in all patients.

RESULTS: Patients' mean age was 66 ± 10 years, and 79% were men. The mean predicted FVC was 78.9 ± 0.5%. Forty-two patients met the criteria for severe disease, and 18 patients died. Mortality was significantly associated with increased CO exposure (for each 0.1 mg/m2 increase: odds ratio 2.45, 95% confidence interval 1.39-4.56). We observed no association between any of the other investigated contaminants and IPF mortality or severity.

CONCLUSIONS: Air pollution, specifically that caused by carbon monoxide, can increase mortality in patients with IPF.

PMID:34251275 | DOI:10.1177/03000605211029058

J Med Chem. 2021 Jul 12. doi: 10.1021/acs.jmedchem.1c00184. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease characterized by a progressive-fibrosing phenotype. IPF has been associated with aberrant HDAC activities confirmed by our immunohistochemistry studies on HDAC6 overexpression in IPF lung tissues. We herein developed a series of novel hHDAC6 inhibitors, having low inhibitory potency over hHDAC1 and hHDAC8, as potential pharmacological tools for IPF treatment. Their inhibitory potency was combined with low in vitro and in vivo toxicity. Structural analysis of 6h and structure-activity relationship studies contributed to the optimization of the binding mode of the new molecules. The best-performing analogues were tested for their efficacy in inhibiting fibrotic sphere formation and cell viability, proving their capability in reverting the IPF phenotype. The efficacy of analogue 6h was also determined in a validated human lung model of TGF-β1-dependent fibrogenesis. The results highlighted in this manuscript may pave the way for the identification of first-in-class molecules for the treatment of IPF.

PMID:34251197 | DOI:10.1021/acs.jmedchem.1c00184

Front Physiol. 2021 Jun 24;12:691227. doi: 10.3389/fphys.2021.691227. eCollection 2021.

ABSTRACT

Mucosal surfaces are lined by epithelial cells, which provide a complex and adaptive module that ensures first-line defense against external toxics, irritants, antigens, and pathogens. The underlying mechanisms of host protection encompass multiple physical, chemical, and immune pathways. In the lung, inhaled agents continually challenge the airway epithelial barrier, which is altered in chronic diseases such as chronic obstructive pulmonary disease, asthma, cystic fibrosis, or pulmonary fibrosis. In this review, we describe the epithelial barrier abnormalities that are observed in such disorders and summarize current knowledge on the mechanisms driving impaired barrier function, which could represent targets of future therapeutic approaches.

PMID:34248677 | PMC:PMC8264588 | DOI:10.3389/fphys.2021.691227

BMC Pulm Med. 2021 Jul 12;21(1):221. doi: 10.1186/s12890-021-01587-3.

ABSTRACT

BACKGROUND: Currently, there are two antifibrotics used to treat idiopathic pulmonary fibrosis (IPF): pirfenidone and nintedanib. Antifibrotics slow disease progression by reducing the annual decline of forced vital capacity (FVC), which possibly improves outcomes in IPF patients. During treatment, patients occasionally switch antifibrotic treatments. However, prognostic implication of changing antifibrotics has not yet been evaluated.

METHODS: This multi-center retrospective cohort study examined 262 consecutive IPF patients who received antifibrotic therapy. Antifibrotic agents were switched in 37 patients (14.1%). The prognoses were compared between the patient cohort that switched antifibrotics (Switch-IPF) and those without (Non-Switch-IPF) using propensity-score matched analyses.

RESULTS: The median period between the initiation of antifibrotic therapy and the drug switch was 25.8 (12.7-35.3) months. The most common reasons for the switch were disease progression (n = 17) followed by gastrointestinal disorders (n = 12). Of the 37 patients that switched antifibrotics, only eight patients disrupted switched antifibrotics by their adverse reactions. The overall prognosis of the Switch-IPF cohort was significantly better than the Non-Switch-IPF cohort (median periods: 67.2 vs. 27.1 months, p < 0.0001). In propensity-score matched analyses that were adjusted to age, sex, FVC (%), history of acute exacerbation, and usage of long-term oxygen therapy, the Switch-IPF cohort had significantly longer survival times than the Non-Switch-IPF group (median 67.2 vs. 41.3 months, p = 0.0219). The second-line antifibrotic therapy showed similar survival probabilities than those in first-line antifibrotic therapy in multistate model analyses.

CONCLUSION: Switching antifibrotics is feasible and may improve prognosis in patients with IPF. A further prospective study will be required to confirm clinical implication of switching the antifibrotics.

PMID:34247593 | DOI:10.1186/s12890-021-01587-3

Respiration. 2021 Jul 9:1-7. doi: 10.1159/000517030. Online ahead of print.

ABSTRACT

BACKGROUND: Although physical activity is associated with mortality in patients with idiopathic pulmonary fibrosis (IPF), reference values to interpret levels of physical activity are lacking.

OBJECTIVES: This study aimed to investigate the prognostic significance of physical activity assessed by step count and its cutoff points for all-cause mortality.

METHODS: We measured physical activity (steps per day) using an accelerometer in patients with IPF at the time of diagnosis. Relationships among physical activity and mortality, as well as cutoff points of daily step count to predict all-cause mortality were examined.

RESULTS: Eighty-seven patients (73 males) were enrolled. Forty-four patients (50.1%) died during the follow-up (median 54 months). In analysis adjusting for Gender-Age-Physiology stage and 6-min walk distance, daily step count was an independent predictor of all-cause mortality (hazard ratio (HR) = 0.820, 95% confidence interval (CI) = 0.694-0.968, p = 0.019). The optimal cutoff point (receiving operating characteristic analysis) for 1-year mortality was 3,473 steps per day (sensitivity = 0.818 and specificity = 0.724). Mortality was significantly lower in patients with a daily step count exceeding 3,473 steps than in those whose count was 3,473 or less (HR = 0.395, 95% CI = 0.218-0.715, p = 0.002).

CONCLUSIONS: Step count, an easily interpretable measurement, was a significant predictor of all-cause mortality in patients with IPF. At the time of diagnosis, a count that exceeded the cutoff point of 3,473 steps/day more than halved mortality. These findings highlight the importance of assessing physical activity in this patient population.

PMID:34247176 | DOI:10.1159/000517030

BMC Pulm Med. 2021 Jul 10;21(1):218. doi: 10.1186/s12890-021-01595-3.

ABSTRACT

BACKGROUND: Although antifibrotic drugs, including nintedanib and pirfenidone, slow the progression of idiopathic pulmonary fibrosis (IPF), there is little data about the timing of start of antifibrotic treatment in real-world clinical practice. The present study aimed to clarify the efficacy of nintedanib and pirfenidone in patients with early-stage IPF.

METHODS: We compared survival and disease progression between patients with IPF with Japanese Respiratory Society (JRS) disease severity system stage I with and without oxygen desaturation on the 6-min walk test (6MWT) and increased the gender-age-physiology (GAP) staging. We examined the efficacy of antifibrotic drugs in patients with early-stage IPF.

RESULTS: The severity of stage I IPF (n = 179) according to the JRS criteria consisted of the following GAP staging criteria: stage I, 111 cases; stage II, 58 cases; stage III, 10 cases. The duration from the initial visit to disease progression and survival time was significantly shorter in JRS stage I patients with oxygen desaturation on the 6MWT or with increased GAP staging (unfavorable group) compared with patients without those factors. In the unfavorable group, the relative decline in percentage predicted forced vital capacity (%FVC) over 6 months was significantly lower in patients undergoing antifibrotic treatment compared with non-treated patients.

CONCLUSION: Antifibrotic drugs have a beneficial effect on the decline in %FVC in Japanese patients with early-stage IPF who have oxygen desaturation on the 6MWT or increased GAP staging.

PMID:34246227 | DOI:10.1186/s12890-021-01595-3

Biomed Pharmacother. 2021 Jul;139:111633. doi: 10.1016/j.biopha.2021.111633. Epub 2021 May 8.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is the most common and most deadly form of interstitial lung disease. Osteopontin (OPN), a matricellular protein with proinflammatory and profibrotic properties, plays a major role in several fibrotic diseases, including IPF; OPN is highly upregulated in patients' lung samples. In this study, we knocked down OPN in a bleomycin (BLM)-induced pulmonary fibrosis (PF) mouse model using small interfering RNA (siRNA) to determine whether the use of OPN siRNA is an effective therapeutic strategy for IPF. We found that fibrosing areas were significantly smaller in specimens from OPN siRNA-treated mice. The number of alveolar macrophages, neutrophils, and lymphocytes in bronchoalveolar lavage fluid was also reduced in OPN siRNA-treated mice. Regarding the expression of epithelial-mesenchymal transition (EMT)-related proteins, the administration of OPN-siRNA to BLM-treated mice upregulated E-cadherin expression and downregulated vimentin expression. Moreover, in vitro, we incubated the human alveolar adenocarcinoma cell line A549 with transforming growth factor (TGF)-β1 and subsequently transfected the cells with OPN siRNA. We found a significant upregulation of Col1A1, fibronectin, and vimentin after TGF-β1 stimulation in A549 cells. In contrast, a downregulation of Col1A1, fibronectin, and vimentin mRNA levels was observed in TGF-β1-stimulated OPN knockdown A549 cells. Therefore, the downregulation of OPN effectively reduced pulmonary fibrotic and EMT changes both in vitro and in vivo. Altogether, our results indicate that OPN siRNA exerts a protective effect on BLM-induced PF in mice. Our results provide a basis for the development of novel targeted therapeutic strategies for IPF.

PMID:34243624 | DOI:10.1016/j.biopha.2021.111633

J Infect Public Health. 2021 Jun 27;14(8):1075-1086. doi: 10.1016/j.jiph.2021.06.013. Online ahead of print.

ABSTRACT

The development of remdesivir has been a breakthrough for COVID-19 treatment. It has been approved in about 50 countries, including Saudi Arabia, since 2020. The generic structure of remdesivir was first disclosed in 2009. This patent review summarizes the remdesivir based inventions to treat/prevent COVID-19 and other disorders from 2009 to May 16, 2021, emphasizing the patents related to medical and pharmaceutical sciences. The primary patents/patent applications of remdesivir are related to its compositions, new combinations with other therapeutic agents, delivery systems, and new indications. The inventive combinations have displayed synergistic effects against COVID-19, whereas the delivery systems/compositions have improved patient compliance. The inventions related to new indications of remdesivir to treat Ebola, hepatitis, idiopathic pulmonary fibrosis, diabetic nephropathy, and cardiovascular complications enhance its therapeutic area. Many new innovative combinations and delivery systems of remdesivir are anticipated to provide better treatment for COVID-19.

PMID:34243049 | DOI:10.1016/j.jiph.2021.06.013

Ageing Res Rev. 2021 Jul 6:101405. doi: 10.1016/j.arr.2021.101405. Online ahead of print.

ABSTRACT

Age is a major risk factor for chronic respiratory diseases such as idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) and certain phenotypes of asthma. The recent COVID-19 pandemic also highlights the increased susceptibility of the elderly to acute respiratory distress syndrome (ARDS), a diffuse inflammatory lung injury with often long-term effects (ie parenchymal fibrosis). Collectively, these lung conditions are characterized by a pathogenic reparative process that, rather than restoring organ function, contributes to structural and functional tissue decline. In the ageing lung, the homeostatic control of wound healing following challenge or injury has an increased likelihood of being perturbed, increasing susceptibility to disease. This loss of fidelity is a consequence of a diverse range of underlying ageing mechanisms including senescence, mitochondrial dysfunction, proteostatic stress and diminished autophagy that occur within the lung, as well as in other tissues, organs and systems of the body. These ageing pathways are highly interconnected, involving localized and systemic increases in inflammatory mediators and damage associated molecular patterns (DAMPS); along with corresponding changes in immune cell function, metabolism and composition of the pulmonary and gut microbiomes. Here we comprehensively review the roles of ageing mechanisms in the tissue remodeling of lung disease.

PMID:34242806 | DOI:10.1016/j.arr.2021.101405

Ann Am Thorac Soc. 2021 Jul;18(7):1115-1116. doi: 10.1513/AnnalsATS.202102-123ED.

NO ABSTRACT

PMID:34242150 | DOI:10.1513/AnnalsATS.202102-123ED

Cureus. 2021 May 31;13(5):e15360. doi: 10.7759/cureus.15360. eCollection 2021 May.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrosing interstitial pneumonia of unknown cause, occurring in adults and limited to the lungs. In the past, treatment was aimed at minimizing inflammation and slowing the progression of inflammation to fibrosis. However, the underlying lesion in IPF may be more fibrotic than inflammatory, explaining why few patients respond to anti-inflammatory therapies and the prognosis remains poor. In this review of literature, we will be focusing on main lines of treatment including current medications, supportive care, lung transplantation evaluation, and potential future strategies of treatment.

PMID:34239792 | PMC:PMC8245298 | DOI:10.7759/cureus.15360

Pulm Med. 2021 Jun 18;2021:5488591. doi: 10.1155/2021/5488591. eCollection 2021.

ABSTRACT

The S100 protein family consists of over 20 members in humans that are involved in many intracellular and extracellular processes, including proliferation, differentiation, apoptosis, Ca2 + homeostasis, energy metabolism, inflammation, tissue repair, and migration/invasion. Although there are structural similarities between each member, they are not functionally interchangeable. The S100 proteins function both as intracellular Ca2+ sensors and as extracellular factors. Dysregulated responses of multiple members of the S100 family are observed in several diseases, including the lungs (asthma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, cystic fibrosis, pulmonary hypertension, and lung cancer). To this degree, extensive research was undertaken to identify their roles in pulmonary disease pathogenesis and the identification of inhibitors for several S100 family members that have progressed to clinical trials in patients for nonpulmonary conditions. This review outlines the potential role of each S100 protein in pulmonary diseases, details the possible mechanisms observed in diseases, and outlines potential therapeutic strategies for treatment.

PMID:34239729 | PMC:PMC8214497 | DOI:10.1155/2021/5488591

Aging (Albany NY). 2021 Jul 8;13. doi: 10.18632/aging.203291. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is an age-related disorder that carries a universally poor prognosis and is thought to arise from repetitive micro injuries to the alveolar epithelium. To date, a major factor limiting our understanding of IPF is a deficiency of disease models, particularly in vitro models that can recapitulate the full complement of molecular attributes in the human condition. In this study, we aimed to develop a model that more closely resembles the aberrant IPF lung epithelium. By exposing mouse alveolar epithelial cells to repeated, low doses of bleomycin, instead of usual one-time exposures, we uncovered changes strikingly similar to those in the IPF lung epithelium. This included the acquisition of multiple phenotypic and functional characteristics of senescent cells and the adoption of previously described changes in mitochondrial homeostasis, including alterations in redox balance, energy production and activity of the mitochondrial unfolded protein response. We also uncovered dramatic changes in cellular metabolism and detected a profound loss of proteostasis, as characterized by the accumulation of cytoplasmic protein aggregates, dysregulated expression of chaperone proteins and decreased activity of the ubiquitin proteasome system. In summary, we describe an in vitro model that closely resembles the aberrant lung epithelium in IPF. We propose that this simple yet powerful tool could help uncover new biological mechanisms and assist in developing new pharmacological tools to treat the disease.

PMID:34238764 | DOI:10.18632/aging.203291

Small. 2021 Jul 8:e2101861. doi: 10.1002/smll.202101861. Online ahead of print.

ABSTRACT

Gold nanoparticles (AuNPs) pose a great challenge in the development of nanotracers that can self-adaptively alter their properties in response to certain cellular environments for long-term stem cell tracking. Herein, pH-sensitive Au nanotracers (CPP-PSD@Au) are fabricated by sequential coupling of AuNPs with sulfonamide-based polymer (PSD) and cell-penetrating peptide (CPP), which can be efficiently internalized by mesenchymal stem cells (MSCs) and undergo pH-induced self-assembly in endosomes, facilitating long-term computed tomography (CT) imaging tracking MSCs in a murine model of idiopathic pulmonary fibrosis (IPF). Using the CPP-PSD@Au, the transplanted MSCs for the first time can be monitored with CT imaging for up to 35 days after transplantation into the lung of IPF mice, clearly elucidating the migration process of MSCs in vivo. Moreover, we preliminarily explored the mechanism of the CPP-PSD@Au labeled MSCs in the alleviation of IPF, including recovery of alveolar integrity, decrease of collagen deposition, as well as down-regulation of relevant cytokine level. This work facilitates our understanding of the behavior and effect of MSCs in the therapy of IPF, thereby providing an important insight into the stem cell-based treatment of lung diseases.

PMID:34235846 | DOI:10.1002/smll.202101861

Front Mol Biosci. 2021 Jun 21;8:633054. doi: 10.3389/fmolb.2021.633054. eCollection 2021.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is mainly characterized by aberrant extracellular matrix deposition, consequent to epithelial lung injury and myofibroblast activation, and inflammatory response. Glycogen synthase kinase 3 (GSK-3) is a serine-threonine kinase involved in several pathways, and its inhibition has been already suggested as a therapeutic strategy for IPF patients. There is evidence that GSK-3 is able to induce matrix metalloproteinase (MMP) expression and that its inhibition modulates MMP expression in the tissues. The aim of our study was to investigate the role of GSK-3 and its inhibition in the modulation of MMP-9 and -2 in an in vivo mouse model of lung fibrosis and in vitro using different cell lines exposed to pro-inflammatory or pro-fibrotic stimuli. We found that GSK-3 inhibition down-modulates gene expression and protein levels of MMP-9, MMP-2, and their inhibitors TIMP-1 and TIMP-2 in inflammatory cells harvested from bronchoalveolar lavage fluid (BALF) of mice treated with bleomycin as well as in interstitial alveolar macrophages and cuboidalized epithelial alveolar cells. To the same extent, GSK-3 inhibition blunted the increased MMP-9 and MMP-2 activity induced by pro-fibrotic stimuli in a human lung fibroblast cell line. Moreover, the αSMA protein level, a marker of fibroblast-to-myofibroblast transition involved in fibrosis, was decreased in primary fibroblasts treated with TGFβ following GSK-3 inhibition. Our results confirm the implication of GSK-3 in lung inflammation and fibrosis, suggesting that it might play its role by modulating MMP expression and activity but also pushing fibroblasts toward a myofibroblast phenotype and therefore enhancing extracellular matrix deposition. Thus, its inhibition could represent a possible therapeutic strategy.

PMID:34235177 | PMC:PMC8255387 | DOI:10.3389/fmolb.2021.633054