Front Immunol. 2021 Feb 18;12:613907. doi: 10.3389/fimmu.2021.613907. eCollection 2021.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is serious chronic lung disease with limited therapeutic approaches. Inflammation and immune disorders are considered as the main factors in the initiation and development of pulmonary fibrosis. Inspired by the key roles of macrophages during the processes of inflammation and immune disorders, here, we report a new method for direct drug delivery into the in-situ fibrotic tissue sites in vitro and in vivo. First, liposomes containing dexamethasone (Dex-L) are prepared and designed to entry into the macrophages in the early hours, forming the macrophages loaded Dex-L delivery system (Dex-L-MV). Chemokine and cytokine factors such as IL-6, IL-10, Arg-1 are measured to show the effect of Dex-L to the various subtypes of macrophages. Next, we mimic the inflammatory and anti-inflammatory microenvironment by co-culture of polarized/inactive macrophage and fibroblast cells to show the acute inflammation response of Dex-L-MV. Further, we confirm the targeted delivery of Dex-L-MV into the inflammatory sites in vivo, and surprisingly found that injected macrophage containing Dex can reduce the level of macrophage infiltration and expression of the markers of collagen deposition during the fibrotic stage, while causing little systematic toxicity. These data demonstrated the suitability and immune regulation effect of Dex-L-MV for the anti-pulmonary process. It is envisaged that these findings are a step forward toward endogenous immune targeting systems as a tool for clinical drug delivery.

PMID:33679754 | PMC:PMC7935565 | DOI:10.3389/fimmu.2021.613907

J Inflamm Res. 2021 Feb 26;14:611-619. doi: 10.2147/JIR.S296382. eCollection 2021.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive fibrosis disease caused by genetic susceptibility (causative) and other indirect risk factors such as smoking, micro-aspiration and air pollution. Repeated damage of lung epithelial cells can cause fibroblast activation and excessive collagen will lead the scar formation and severe fibrosis. It has been decades since drugs for the treatment of IPF were developed, but clinical choices were limited. Exchange Protein directly Activated by cAMP (EPAC), as a newly emerging cAMP (adenosine 3',5'-cyclic monophosphate) downstream molecule, plays a vital role in the cellular pathways of IPF such as inhibiting fibroblast proliferation, stress fiber formation and epithelium cell adhesion, so it may be a novel target for drug development and treatment for curbing IPF. Here, we hypothesize that EPAC may participate in the signaling pathways related to IPF in different cell types (fibroblasts; airway smooth muscle cells; vascular endothelial cells; lung epithelial cells; macrophages; mesenchymal stem cells; T cells), thereby playing a potentially therapeutic role in resisting the process of fibrosis. We summarize the current correlation between EPAC and IPF in these different cell types, and further insights into EPAC will help to optimize the pharmacological treatment for IPF.

PMID:33679138 | PMC:PMC7926039 | DOI:10.2147/JIR.S296382

Respir Investig. 2021 Mar 4:S2212-5345(21)00034-4. doi: 10.1016/j.resinv.2021.02.002. Online ahead of print.

NO ABSTRACT

PMID:33678586 | DOI:10.1016/j.resinv.2021.02.002

Respir Med. 2021 Feb 11;179:106333. doi: 10.1016/j.rmed.2021.106333. Online ahead of print.

ABSTRACT

BACKGROUND: Multidisciplinary discussion (MDD) is widely recommended for patients with interstitial lung disease (ILD), but published primary data from MDD has been scarce, and factors influencing MDD other than chest computed tomography (CT) and lung histopathology interpretations have not been well-described.

METHODS: Single institution MDD of 179 patients with ILD.

RESULTS: MDD consensus clinical diagnoses included autoimmune-related ILD, chronic hypersensitivity pneumonitis, smoking-related ILD, idiopathic pulmonary fibrosis, medication-induced ILD, occupation-related ILD, unclassifiable ILD, and a few less common pulmonary disorders. In 168 of 179 patients, one or more environmental exposures or pertinent features of the medical history were identified, including recreational/avocational, residential, and occupational exposures, systemic autoimmune disease, malignancy, medication use, and family history. The MDD process demonstrated the importance of comprehensively assessing these exposures and features, beyond merely noting their presence, for rendering consensus clinical diagnoses. Precise, well-defined chest CT and lung histopathology interpretations were rendered at MDD, including usual interstitial pneumonia, nonspecific interstitial pneumonia, and organizing pneumonia, but these interpretations were associated with a variety of MDD consensus clinical diagnoses, demonstrating their nonspecific nature in many instances. In 77 patients in which MDD consensus diagnosis differed from referring diagnosis, assessment of environmental exposures and medical history was found retrospectively to be the most impactful factor.

CONCLUSIONS: A comprehensive assessment of environmental exposures and pertinent features of the medical history guided MDD. In addition to rendering consensus clinical diagnoses, MDD presented clinicians with opportunities to initiate environmental remediation, behavior modification, or medication alteration likely to benefit individual patients with ILD.

PMID:33676119 | DOI:10.1016/j.rmed.2021.106333

Molecules. 2021 Feb 20;26(4):1123. doi: 10.3390/molecules26041123.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a lethal, agnogenic interstitial lung disease with limited therapeutic options. To investigate vital genes involved in the development of IPF, we integrated and compared four expression profiles (GSE110147, GSE53845, GSE24206, and GSE10667), including 87 IPF samples and 40 normal samples. By reanalyzing these datasets, we managed to identify 62 upregulated genes and 20 downregulated genes in IPF samples compared with normal samples. Differentially expressed genes (DEGs) were analyzed by gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis to illustrate relevant pathways of IPF, biological processes, molecular function, and cell components. The DEGs were then subjected to protein-protein interaction (PPI) for network analysis, serving to find 11 key candidate genes (ANXA3, STX11, THBS2, MMP1, MMP9, MMP7, MMP10, SPP1, COL1A1, ITGB8, IGF1). The result of RT-qPCR and immunohistochemical staining verified our finding as well. In summary, we identified 11 key candidate genes related to the process of IPF, which may contribute to novel treatments of IPF.

PMID:33672678 | DOI:10.3390/molecules26041123

Int J Mol Sci. 2021 Feb 23;22(4):2228. doi: 10.3390/ijms22042228.

ABSTRACT

Endotoxin removal therapy with polymyxin B immobilized fiber column (PMX) has been clinically applied for sepsis and septic shock patients since 1994. The effectiveness and usefulness of this therapy have been demonstrated for more than a quarter of a century. However, a documented survival benefit has not yet been demonstrable in a large, multicenter, randomized and controlled trial. Following the findings derived from a large sepsis clinical trial with PMX in North America, a new trial is ongoing to determine if PMX has a long-term survival benefit when administered to septic patients. Another approach to support a survival benefit from intervention with PMX is to utilize a detailed analysis available from a large clinical data base. The endotoxin adsorption capacity of PMX columns in vitro and the effectiveness of PMX columns can be further demonstrable in animal models. The capability of PMX and details of its mechanism of action to intervene in the sepsis cascade and impede organ dysfunction in septic patients is not fully understood. The surface antigen expression in monocytes and neutrophils are improved after PMX therapy. Immunomodulatory effects as a result of endotoxin removal and/or other mechanisms of action have been suggested. These effects and other potential immune effects may explain some of the improved effects upon organ dysfunction of sepsis and septic shock patients. Endotoxemia may be involved in the pathophysiology of other diseases than sepsis. A rapid diagnostic method to detect and target endotoxemia could allow us to practice precision medicine and expand the clinical indications of endotoxin removal therapy.

PMID:33672437 | DOI:10.3390/ijms22042228

Int J Mol Sci. 2021 Feb 17;22(4):1985. doi: 10.3390/ijms22041985.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a fatal and age-related pulmonary disease. Nintedanib is a receptor tyrosine kinase inhibitor, and one of the only two listed drugs against IPF. Regorafenib is a novel, orally active, multi-kinase inhibitor that has similar targets to nintedanib and is applied to treat colorectal cancer and gastrointestinal stromal tumors in patients. In this study, we first identified that regorafenib could alleviate bleomycin-induced pulmonary fibrosis in mice. The in vivo experiments indicated that regorafenib suppresses collagen accumulation and myofibroblast activation. Further in vitro mechanism studies showed that regorafenib inhibits the activation and migration of myofibroblasts and extracellular matrix production, mainly through suppressing the transforming growth factor (TGF)-β1/Smad and non-Smad signaling pathways. In vitro studies have also indicated that regorafenib could augment autophagy in myofibroblasts by suppressing TGF-β1/mTOR (mechanistic target of rapamycin) signaling, and could promote apoptosis in myofibroblasts. In conclusion, regorafenib attenuates bleomycin-induced pulmonary fibrosis by suppressing the TGF-β1 signaling pathway.

PMID:33671452 | DOI:10.3390/ijms22041985

J Clin Med. 2021 Feb 24;10(5):895. doi: 10.3390/jcm10050895.

ABSTRACT

The pathogenesis of pleuroparenchymal fibroelastosis (PPFE), a rare interstitial lung disease, remains unclear. Based on previous reports and our experience, we hypothesized that alveolar epithelial denudation (AED) was involved in the pathogenesis of PPFE. This multicenter retrospective study investigated the percentage of AED and the features of the denudated areas in 26 PPFE cases, 30 idiopathic pulmonary fibrosis (IPF) cases, and 29 controls. PPFE patients had lower forced vital capacities and higher residual volume/total lung capacities in pulmonary function tests compared to IPF and control patients. Histopathologically, subpleural fibroelastosis was observed in PPFE, and AED was observed in 12.01% of cases in the subpleural or interlobular septa regardless of fibroelastosis. The percentage of AED in the PPFE group was significantly higher than that in the IPF group (6.84%; p = 0.03) and the normal group (1.19%; p < 0.001). In the IPF group, the percentage of AED and the presence of PPFE-like lesions in the upper lobes were examined radiologically, but no correlation was found. We showed that AED frequently occurred in PPFE. AED was less frequent in IPF, which, in combination with imaging data, suggests that PPFE may have a different pathogenesis from IPF.

PMID:33668178 | DOI:10.3390/jcm10050895

Rev Med Inst Mex Seguro Soc. 2021 Feb 2;59(1):55-64. doi: 10.24875/RMIMSS.M21000052.

ABSTRACT

Background: Interstitial lung disease (ILD) corresponds to a heterogeneous group of pathologies that differ in etiology with common clinical and radiological manifestations. In Latin America and Mexico, reports are scarce and the need for studies to understand the scenario is emphasized. Objective: To analyze a multidimensional profile in patients with interstitial lung disease in Yucatan. Method: This is an observational, prospective, analytic, descriptive study including consecutive patients diagnosed with ILD over a 4-year period. Demographic and clinical data, lung function tests, chest imaging, serum immunological profile, and echocardiographic findings were recorded. Differences between subgroups were analyzed performing a one-way analysis of variance (ANOVA). Results: 110 patients were included. The median age was 60 years and women were most affected. The main cause of ILD was related with connective tissue diseases (CTD). A group subanalysis revealed that Idiopathic pulmonary fibrosis (IPF) was common in males with a history of smoking and an imaging pattern of usual interstitial pneumonia. Lung function tests showed a moderate-to-severe pulmonary restriction (FVC 55%p) and mild hypoxemia (PaO2 79mmHg). Positive antinuclear antibodies are less likely in cases with IPF (20 vs. 65%; p = 0.006). Conclusion: In Southeastern Mexico, ILD occurs in women in their seventh decade of life; the most common cause is related with CTD. Our results support that ILD has a heterogeneous expression and is relevant the need for subsequent studies characterizing each ILD.

PMID:33667044 | DOI:10.24875/RMIMSS.M21000052

Int Med Case Rep J. 2021 Feb 26;14:133-138. doi: 10.2147/IMCRJ.S295099. eCollection 2021.

ABSTRACT

BACKGROUND: Fournier's gangrene (FG) is a rare but deadly form of necrotizing fasciitis involving the genital, perineal, and anorectal region. Risk factors include diabetes mellitus, immunosuppression, and alcohol misuse. Because multisystem organ failure can rapidly develop, early diagnosis is critical. Treatment includes fluid resuscitation, broad-spectrum antibiotics, and surgical debridement. Uncommonly, extension of perineal infection into adjacent organs can necessitate multivisceral resection, which can make reconstruction a challenge. Even with swift diagnosis and optimal treatment, morbidity and mortality are high.

CASE PRESENTATION: A 66-year-old male with a history of diabetes mellitus presented to the emergency department with progressive scrotal pain, swelling, and perineal skin changes. Examination revealed necrosis of the scrotal soft tissues with involvement of the anal canal and rectum. The patient was initiated on intravenous fluids and broad-spectrum antibiotics, then brought immediately to the operating room where surgical care was provided by a urologist, colorectal surgeon, and general surgeon with expertise in complex mesh repair. Extension of necrotic changes travelling proximally through the full thickness of the rectum was noted. The patient underwent extensive scrotal and perineal debridement, laparotomy, abdominoperineal resection (APR), end colostomy, and polyglactin mesh repair of the resultant pelvic floor defect. The patient had appropriate return of bowel function and satisfactory healing of the perineum postoperatively but ultimately died after a ventricular fibrillation-related cardiac arrest precipitated by a flare of idiopathic pulmonary fibrosis.

CONCLUSION: Early diagnosis and referral to the appropriate specialists are essential elements of managing FG. Here we present a case with extension of necrotizing soft tissue infection into the rectum, requiring pelvic dissection and APR as well as absorbable mesh use to aid in perineal closure. Despite expedient treatment, poor outcomes with this condition are unfortunately common.

PMID:33664599 | PMC:PMC7924126 | DOI:10.2147/IMCRJ.S295099

Clin Lung Cancer. 2021 Feb 4:S1525-7304(21)00017-6. doi: 10.1016/j.cllc.2021.01.014. Online ahead of print.

ABSTRACT

BACKGROUND: Immune checkpoint inhibitors (ICIs), such as programmed cell death 1 (PD-1) inhibitors, are used to treat multiple cancers. Limited data exist as to the use of ICIs in patients with coexistent interstitial lung disease (ILD). We conducted a retrospective case series to assess clinical and radiologic outcomes of patients with ILD treated with PD-1 inhibitors.

METHODS: Eligible patients were 18 years of age or older, treated with pembrolizumab or nivolumab for oncologic indications, and had evidence of ILD on chest computed tomography scan not attributable to radiotherapy before initiation of ICI therapy. Outcomes of interest included mortality, hospitalizations for respiratory-related causes, development of pneumonitis, and radiologic change in ILD over a 1-year follow-up period.

RESULTS: We included 41 patients in the analysis. At 1 year, 17 patients (41.5%) were alive, 23 had died (56.1%), and 1 (2.4%) was lost to follow-up. Of 23 deaths, 16 (69.6%) were due to cancer, 4 (17.4%) to causes excluding cancer and ILD, and 3 (13.0%) to hypoxemic respiratory failure from ILD- or ICI-induced pneumonitis. Three patients (7.3%) required hospitalization owing to ILD, including drug-induced pneumonitis, and 3 (7.3%) developed pneumonitis attributable to anti-PD-1 therapy. On follow-up computed tomography scans, 32 patients (78.0%) had stable or improved ILD and 9 (22.0%) had progression.

CONCLUSION: Patients with ILD receiving PD-1 inhibitors more frequently died of cancer-related causes than from ILD. Further research is needed to determine the safety of ICIs in patients with ILD and if ILD subtype may help to refine ICI-associated risks.

PMID:33663958 | DOI:10.1016/j.cllc.2021.01.014

Mol Med. 2021 Mar 4;27(1):22. doi: 10.1186/s10020-021-00283-6.

ABSTRACT

BACKGROUND: Although the morbidity and mortality rates associated with idiopathic pulmonary fibrosis (IPF) are high, there is still lack of powerful and precise therapeutic options for IPF.

OBJECT: Through in vitro model, this study sought to determine whether binding of acetylated CCAAT/enhancer binding protein β (C/EBPβ) to alpha-smooth muscle actin (α-SMA) promoter could affect the activity of the latter as well as assess if it is essential for epithelial-to-mesenchymal transition (EMT) and extracellular matrix deposition in IPF.

METHODS: The expression of EMT and C/EBPβ in A549 cells treated with transforming growth factor-beta (TGF-β) as pulmonary fibrotic model was detected by western blotting and qPCR. Collagen-I expression using ELISA was performed. The luciferase activity was used to examine the activity of C/EBPβ. Knockdown of C/EBPβ was performed by siRNA. We also investigated the effect of deacetylation of C/EBPβ on EMT using sirtuin 1 (SIRT1). The binding ability of C/EBPβ with α-SMA promoter was affirmed via chromatin immunoprecipitation (ChIP) and electrophoresis mobility shift assay (EMSA). The relationship between α-SMA and acetylated C/EBPβ was determined with co-immunoprecipitation (Co-IP). SiRNA-mediated knockdown of C/EBPβ in A549 cells attenuated TGF-β1-induced myofibroblast differentiation and ECM deposition. The extent of association between acetylated C/EBPβ and α-SMA promoter was dynamically monitored.

RESULTS: It was confirmed that deacetylation of C/EBPβ in A549 cells successfully ameliorated TGF-β1-induced EMT, as shown by reduction in α-SMA expression and excessive collagen-I accumulation.

CONCLUSION: The EMT and fibrotic effect of TGF-β1 is dependent on acetylated C/EBPβ-mediated regulation of α-SMA gene activity. Thus, C/EBPβ acetylation may play a central role in pulmonary fibrosis.

PMID:33663392 | DOI:10.1186/s10020-021-00283-6

Adv Respir Med. 2021;89(1):49-54. doi: 10.5603/ARM.a2020.0193.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a specific form of chronic fibrosing interstitial pneumonia that has an unknown etiology. The natural history of the disease is characterized by a progressive decline in pulmonary function and overall health and well-being. The median survival time is between 2-3 years; however, the disease course is variable and unpredictable. The twelve-minute walking test (12MWT) and six-minute walking test (6MWT) are two fixed time tests that are commonly used in clinical practice. Our short and clinically oriented narrative review attempted to summarize current evidence supporting the use of fixed time, self-paced walking tests in predicting the outcome of patients diagnosed with IPF. A number of studies have justified that the 6MWT is a simple, cost-effective, well documented, fixed time, and self-paced walking test which is a valid and reliable measure of disease status and can also be used as a prognostic tool in patients with IPF. However, there is a need for dedicated and validated reference equations for this population of patients. It is also necessary to fill the knowledge gap about the role of the 12MWT. We hypothesize that it would be useful in evaluating patients that are in the early stages of the disease.

PMID:33660248 | DOI:10.5603/ARM.a2020.0193

Environ Sci Pollut Res Int. 2021 Mar 4. doi: 10.1007/s11356-021-13208-x. Online ahead of print.

ABSTRACT

There is increasing interest in understanding the role of air pollution as one of the greatest threats to human health worldwide. Nine of 10 individuals breathe air with polluted compounds that have a great impact on lung tissue. The nature of the relationship is complex, and new or updated data are constantly being reported in the literature. The goal of our review was to summarize the most important air pollutants and their impact on the main respiratory diseases (chronic obstructive pulmonary disease, asthma, lung cancer, idiopathic pulmonary fibrosis, respiratory infections, bronchiectasis, tuberculosis) to reduce both short- and the long-term exposure consequences. We considered the most important air pollutants, including sulfur dioxide, nitrogen dioxide, carbon monoxide, volatile organic compounds, ozone, particulate matter and biomass smoke, and observed their impact on pulmonary pathologies. We focused on respiratory pathologies, because air pollution potentiates the increase in respiratory diseases, and the evidence that air pollutants have a detrimental effect is growing. It is imperative to constantly improve policy initiatives on air quality in both high- and low-income countries.

PMID:33660184 | DOI:10.1007/s11356-021-13208-x

Front Med (Lausanne). 2021 Feb 15;8:607962. doi: 10.3389/fmed.2021.607962. eCollection 2021.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic disease that is characterized by the excessive deposition of scar tissue in the lungs. As currently available treatments are unable to restore lung function in patients, there is an urgent medical need for more effective drugs. Developing such drugs, however, is challenging because IPF has a complex pathogenesis. Emerging evidence indicates that heat shock protein 47 (HSP47), which is encoded by the gene Serpinh1, may be a suitable therapeutic target as it is required for collagen synthesis. Pharmacological inhibition or knockdown of HSP47 could therefore be a promising approach to treat fibrosis. The objective of this study was to assess the therapeutic potential of Serpinh1-targeting small interfering RNA (siRNA) in fibrogenic precision-cut lung slices prepared from murine tissue. To enhance fibrogenesis, slices were cultured for up to 144 h with transforming growth factor β1. Self-deliverable siRNA was used to knockdown mRNA and protein expression, without affecting the viability and morphology of slices. After silencing HSP47, only the secretion of fibronectin was reduced while other aspects of fibrogenesis remained unaffected (e.g., myofibroblast differentiation as well as collagen secretion and deposition). These observations are surprising as others have shown that Serpinh1-targeting siRNA suppressed collagen deposition in animals. Further studies are therefore warranted to elucidate downstream effects on fibrosis upon silencing HSP47.

PMID:33659262 | PMC:PMC7917123 | DOI:10.3389/fmed.2021.607962

Front Cell Dev Biol. 2021 Feb 15;9:600711. doi: 10.3389/fcell.2021.600711. eCollection 2021.

ABSTRACT

Extracellular vesicles (EVs) have emerged as a potential therapy for several diseases. These plasma membrane-derived fragments are released constitutively by virtually all cell types-including mesenchymal stromal cells (MSCs)-under stimulation or following cell-to-cell interaction, which leads to activation or inhibition of distinct signaling pathways. Based on their size, intracellular origin, and secretion pathway, EVs have been grouped into three main populations: exosomes, microvesicles (or microparticles), and apoptotic bodies. Several molecules can be found inside MSC-derived EVs, including proteins, lipids, mRNA, microRNAs, DNAs, as well as organelles that can be transferred to damaged recipient cells, thus contributing to the reparative process and promoting relevant anti-inflammatory/resolutive actions. Indeed, the paracrine/endocrine actions induced by MSC-derived EVs have demonstrated therapeutic potential to mitigate or even reverse tissue damage, thus raising interest in the regenerative medicine field, particularly for lung diseases. In this review, we summarize the main features of EVs and the current understanding of the mechanisms of action of MSC-derived EVs in several lung diseases, such as chronic obstructive pulmonary disease (COPD), pulmonary infections [including coronavirus disease 2019 (COVID-19)], asthma, acute respiratory distress syndrome (ARDS), idiopathic pulmonary fibrosis (IPF), and cystic fibrosis (CF), among others. Finally, we list a number of limitations associated with this therapeutic strategy that must be overcome in order to translate effective EV-based therapies into clinical practice.

PMID:33659247 | PMC:PMC7917181 | DOI:10.3389/fcell.2021.600711

Int J Tuberc Lung Dis. 2021 Feb 1;25(2):106-112. doi: 10.5588/ijtld.20.0622.

ABSTRACT

In addition to chronic obstructive pulmonary disease (COPD) and bronchogenic carcinoma, smoking can also cause interstitial lung diseases (ILDs) such as respiratory bronchiolitis (RB), RB with ILD (RB-ILD), desquamative interstitial pneumonia (DIP), Langerhans cell granulomatosis (LCG) and idiopathic pulmonary fibrosis-usual interstitial pneumonia (IPF-UIP). However, smoking seems to have a protective effect against hypersensitivity pneumonitis (HP), sarcoidosis and organising pneumonia (OP). High-resolution computed tomography (HRCT) has a pivotal role in the differential diagnosis. RB is extremely frequent in smokers, and is considered a marker for smoking exposure. It has no clinical relevance in itself since most patients with RB are asymptomatic. It is frequent to observe the association of RB with other smoking-related diseases, such as LCG or pulmonary neoplasms. In RB-ILD, HRCT features are more conspicuous and diffuse than in RB, but there is no definite cut-off between the two entities and any distinction can only be made by integrating imaging and clinical data. RB, RB-ILD and DIP may represent different degrees of the same pathological process, consisting in a bronchiolar and alveolar inflammatory reaction to smoking. Smoking is also a well-known risk factor for pulmonary fibrosis. Multidisciplinary discussion and follow-up can generally solve even the most difficult cases.

PMID:33656421 | DOI:10.5588/ijtld.20.0622

Am J Physiol Lung Cell Mol Physiol. 2021 Mar 3. doi: 10.1152/ajplung.00505.2020. Online ahead of print.

ABSTRACT

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a deadly condition characterized by progressive respiratory dysfunction. Exacerbations due to airway infections are believed to promote disease progression, and presence of Streptococcus in the lung microbiome has been associated with progression of IPF and mortality. The aim of this study was to analyze the effect of lung fibrosis on susceptibility to pneumococcal pneumonia and bacteremia.

METHODS: The effects of subclinical (low dose) infection with Streptococcus pneumoniae were studied in a well characterized fos-related antigen-2 (Fra-2) transgenic (TG) mouse model of spontaneous, progressive pulmonary fibrosis. Forty-eight hours after transnasal infection with Streptococcus pneumoniae, bacterial load was assessed in lung tissue, bronchoalveolar lavage (BAL), blood and spleen. Leukocyte subsets and cytokine levels were analyzed in BAL and blood. Lung compliance and arterial blood gases were assessed.

RESULTS: In contrast to wildtype mice, low dose lung infection with Streptococcus pneumoniae in Fra-2 TG mice resulted in substantial pneumonia including weight loss, increased lung bacterial load and bacteremia. BAL alveolar macrophages were reduced in Fra-2 TG mice compared to the corresponding WT mice. Proinflammatory cytokines and chemokines (IL-1β, IL-6, TNF-α, CXCL1) were elevated upon infection in BAL supernatant and plasma of Fra-2 TG mice. Lung compliance was decreased in Fra-2 TG mice following low dose infection with Streptococcus pneumoniae.

CONCLUSIONS: Pulmonary fibrosis increases susceptibility to pneumococcal pneumonia and bacteremia possibly via impaired alveolar bacterial clearance.

PMID:33655757 | DOI:10.1152/ajplung.00505.2020

Acta Pharmacol Sin. 2021 Mar 2. doi: 10.1038/s41401-021-00618-3. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is an aging-associated disease with a poor prognosis. Emerging evidence has revealed that targeting senescent cells may be a potential treatment for IPF. In this study, we aimed to explore whether roxithromycin (RXM) can improve lung fibrosis by targeting senescent cells. First, we confirmed the ability of RXM to selectively kill senescent cells by inducing apoptosis and inhibiting the expression of senescence-associated secretory phenotype (SASP) factors, suggesting the potential role of RXM as a "senolytic" and "senomorphic" drug. Next, we observed that TGF-β- and senescent cell-induced lung fibroblast activation was inhibited by RXM treatment, which prompted us to further investigate its effect in vivo. In a mouse model of bleomycin (BLM)-induced pulmonary fibrosis, RXM was shown to attenuate lung injury, inflammation, and fibrosis. Furthermore, the senescent phenotype of lung tissues induced by BLM was significantly diminished after RXM administration, indicating the potential of RXM as an antifibrotic and antisenescent agent. Interestingly, NADPH oxidase 4 (NOX4), implicated in lung fibrosis and cell senescence, was shown to be inhibited by RXM treatments. The antifibroblast activation and antisenescent effects of RXM were abolished in NOX4 knockdown cells, demonstrating that RXM may ameliorate BLM-induced pulmonary fibrosis by targeting senescent cells mediated by the NOX4 pathway. Collectively, these data demonstrated that RXM may be a potential clinical agent for IPF and further supported the notion that targeting cellular senescence is a promising treatment for progressive age-related disease.

PMID:33654217 | DOI:10.1038/s41401-021-00618-3

Sci Rep. 2021 Mar 2;11(1):4318. doi: 10.1038/s41598-021-81591-z.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrosing interstitial lung disease of unknown cause. It has a high risk of rapid progression and mortality. We conducted a systematic review and meta-analysis to evaluate the risk factor of IPF. We searched Medline, Embase, and the Cochrane library from the earliest record to March, 2020. Case-control studies on occupational and environmental risk factors or on jobs with a risk of IPF were searched for. From 2490 relevant records, 12 studies were included. Any occupational or environmental exposure to metal dust (OR 1.83, 95% CI 1.15-2.91, I2 = 54%), wood dust (OR 1.62 5% CI 1.04-2.53, I2 = 5%) and pesticide (OR 2.07, 95% CI 1.24-3.45, I2 = 0%) were associated with an increased risk of IPF. Farming or agricultural work (OR 1.88, 95% CI 1.17-3.04, I2 = 67%) was also associated with an increased risk of IPF. Moreover, smoking increased IPF risk with an odds ratio of 1.39 (95% CI 1.01-1.91, I2 = 29%). In conclusion, metal dust, wood dust, pesticide, occupational history of farming or agriculture and ever smoking increased the risk of IPF.

PMID:33654111 | DOI:10.1038/s41598-021-81591-z