Destruction Of Lung Architecture Research Articles

HDAC6 inhibitor promotes reactive oxygen species-meditated clearance of Staphylococcus aureus in macrophage.

Staphylococcus aureus (S. aureus) pneumonia has become an increasingly important public health problem. Recent evidence suggests that epigenetic modifications are critical in the host immune defence against pathogen infection. In this study, we found that S. aureus infection induces the expression of histone deacetylase 6 (HDAC6) in a dose-dependent manner. Furthermore, by using a S. aureus pneumonia mouse model, we showed that the HDAC6 inhibitor, tubastatin A, demonstrates a protective effect in S. aureus pneumonia, decreasing the mortality and destruction of lung architecture, reducing the bacterial burden in the lungs and inhibiting inflammatory responses. Mechanistic studies in primary bone marrow-derived macrophages demonstrated that the HDAC6 inhibitors, tubastatin A and tubacin, reduced the intracellular bacterial load by promoting bacterial clearance rather than regulating phagocytosis. Finally, N-acetyl-L- cysteine, a widely used reactive oxygen species (ROS) scavenger, antagonized ROS production and significantly inhibited tubastatin A-induced S. aureus clearance. These findings demonstrate that HDAC6 inhibitors promote the bactericidal activity of macrophages by inducing ROS, an important host factor for S. aureus clearance and production. Our study identified HDAC6 as a suitable epigenetic modification target for preventing S. aureus infection, and tubastatin A as a useful compound in treating S. aureus pneumonia.

Loss of SP-A in the Lung Exacerbates Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a devastating and common chronic lung disease that is pathologically characterized by the destruction of lung architecture and the accumulation of extracellular matrix in the lung. Previous studies have shown an association between lung surfactant protein (SP) and the pathogenesis of IPF, as demonstrated by mutations and the altered expression of SP in patients with IPF. However, the role of SP in the development of lung fibrosis is poorly understood. In this study, the role of surfactant protein A (SP-A) was explored in experimental lung fibrosis induced with a low or high dose of bleomycin (BLM) and CRISPR/Cas9-mediated genetic deletion of SP-A. Our results showed that lung SP-A deficiency in mice promoted the development of fibrotic damage and exacerbated inflammatory responses to the BLM challenge. In vitro experiments with murine lung epithelial LA-4 cells demonstrated that in response to transforming growth factor-β1 (TGF-β1), LA-4 cells had a decreased protein expression of SP-A. Furthermore, exogenous SP administration to LA-4 cells inhibited the TGF-β1-induced upregulation of fibrotic markers. Overall, these findings suggest a novel antifibrotic mechanism of SP-A in the development of lung fibrosis, which indicates the therapeutic potential of the lung SP-A in preventing the development of IPF.

Evaluation of Small Molecule Inhibitors of Pseudomonas Virulence factor LasB as Non‐Traditional Immunotherapeutics

Pseudomonas aeruginosa can cause severe opportunistic pulmonary infections associated with mechanical ventilation and the genetic disease cystic fibrosis. Due to its multidrug resistance, it is a priority pathogen for therapeutic development. Inflammation during such infections, which causes destruction of lung architecture and function, is activated in part through the maturation of IL‐1β by the virulence factor LasB. Previous results in mouse models suggest that matrix metalloprotease inhibitor drugs also inhibit LasB, preventing cell death and inflammation caused by caused by P. aeruginosa. We hypothesized that other inhibitors of matrix metalloproteases, including tetracycline‐family antibiotics, could be used to target LasB. We evaluated small molecule inhibitors against LasB activation during infections of macrophages, neutrophils, and monocytes and the synergy of these inhibitors with conventional antibiotics and anti‐inflammatories. We first optimized the drug concentration by testing the ability of the various drugs to inhibit LasB at various dilutions. Using an effective concentration, we then infected the various cell types with P. aeruginosa and analyzed the impact of the inhibitors on cell death and maturation of IL‐1β in infected cells. The results indicate that several tetracycline‐family compounds inhibit LasB during P. aeruginosa infections and decrease cell death. This was true for compounds that had no antimicrobial activity yet still inhibited LasB. In addition, the results suggest that the drugs target different cell types. Together, we find that tetracyclines may have therapeutic benefits, even against resistant bacteria, due to their ability to decrease inflammation. This may serve as an effective adjunctive therapy during infection to limit tissue damage and give the immune system and antibiotics more time to respond.

SARCOIDOSIS WITH SUPERIMPOSED SARS-COV-2 LEADING TO HIGHER PREVALENCE OF CAPA?

TOPIC: Chest Infections TYPE: Fellow Case Reports INTRODUCTION: The recent SARS-CoV-2 pandemic has immensely affected individuals worldwide leading to a serious global emergency. It has the capability to end in post-infection complications and critical outcomes due to significant pro-inflammatory conditions. The role of SARS-CoV-2 in patients with immune disorders, such as sarcoidosis, and the specific interaction between these two diseases remains unclear. Here we present a case of a 65-year-old female with sarcoidosis who got infected with SARS-CoV-2 complicated by pulmonary embolism (PE) and COVID associated pulmonary aspergillosis (CAPA) CASE PRESENTATION: A 60-year-old African American female with a PMH of Sarcoidosis, Chronic thromboembolic pulmonary hypertension (CTEPH) on Riociguat, Macitentan, and Warfarin presented with cough, SOB, and fever for 1-week duration. Upon arrival to the ED, vital signs were significant for tachypnea and hypoxemia. COVID-19 PCR was positive. Initial chest CT revealed bilateral ground-glass opacities (GGOs) with multilobar chronic airspace disease. She was treated with Remdesivir and dexamethasone. During the hospital course, warfarin was held due to supratherapeutic INR. However, before discharge her respiratory parameters decompensated and she required HFNC to maintain her saturation. CT pulmonary angiogram revealed PE in the right distal segmental branch with significant bilateral patchy infiltrates more severe in the distribution of lower lobe suggestive of multilobar pneumonia with bilateral GGOs with crazy paving. Beta galactomannan came back positive and Voriconazole was started empirically with significant improvement in respiratory symptoms. Later fungal culture from sputum confirmed aspergillosis. DISCUSSION: SARS-CoV-2 activates the immune system which results in a release of inflammatory cytokines and leads to cytokine storms. But it remains unknown how the interaction differs in patients with an altered immune system, especially in cases of impairment of the T-cell immunity and granuloma formation, such as sarcoidosis. Some authors suggested that constitutional defects of the regulation of macroautophagy in sarcoidosis could lead to a more severe outcome from the novel SARS-CoV-2 infection. literature review showed that alveolar damage, dysfunctional mucociliary clearance, and altered immune system further facilitates fungal invasion. We, therefore, hypothesize that SARS-CoV-2 in a patient with underlying sarcoidosis may lead to increased risk for pulmonary aspergillosis. CONCLUSIONS: The role of infection from the novel coronavirus in patients having sarcoidosis is still largely unknown however clinicians should be aware that it has the risk of serious complications and clinical deterioration including further destruction of lung architecture, hypervascular response, hypercoagulability, and superinfection like CAPA. REFERENCE #1: https://www.lung.org/lung-health-diseases/lung-disease-lookup/sarcoidosis/learn-about-sarcoidosis REFERENCE #2: https://www.hopkinsmedicine.org/health/conditions-and-diseases/pulmonary-sarcoidosis REFERENCE #3: https://www.nature.com/articles/s41379-020-00661-1#citeas DISCLOSURES: No relevant relationships by Danilo Enriquez, source=Web Response No relevant relationships by SM Hossain, source=Web Response No relevant relationships by Tahmina Jahir, source=Web Response No relevant relationships by Ruby Risal, source=Web Response No relevant relationships by Marie Frances Schmidt, source=Web Response No relevant relationships by Binav Shrestha, source=Web Response No relevant relationships by Sabbena Uppal, source=Web Response

The influence of allopurinol and post-conditioning on lung injuries induced by lower-limb ischemia and reperfusion in Wistar rats.

To analyze the effects of allopurinol and of post-conditioning on lung injuries induced by lower-limb ischemia and reperfusion. Thirty rats were used. They were divided in 5 groups: (1) group A: abdominal aortic dissection only, (2) group B: ischemia and reperfusion, (3) group C: administered allopurinol (100mg/Kg) a few hours before procedure, (4) group D: post-conditioned and (5) group E: administered allopurinol and post-conditioned. With the exception of group A, all groups were submitted to infrarenal aortic ischemia for 2 hours, and reperfusion for 72 hours. After euthanasia, lungs were removed for histological analysis. They were graded under two scores: pulmonary injury (neutrophil infiltration, interstitial edema, vascular congestion, and destruction of lung architecture) and lymphocytic score (neutrophil infiltration, lymphoid aggregate and secondary follicle). On the pulmonary injury score, the degree of injury was smaller than in groups D and E, when compared to group B, p<0.05. Group C did not obtain the same result (p>0,05). On the lymphocytic score, there was no statistic difference among groups, p>0.05. Both post-conditioning and the combination of allopurinol and post-conditioning were effective in remote lung protection induced by lower-limbs I/R. When used in isolation, allopurinol showed no protective effect.

P123 &lt;break /&gt; Mechanisms of treatment response to Pirfenidone of idiopathic pulmonary fibrosis (IPF) patients

Objectives: IPF is a progressive fibro-proliferative lung disease that causes destruction of lung architecture. Pirfenidone is the first licensed therapy for IPF. The aim of this prospective study is to characterise specific molecular and cellular mechanisms of patient response to Pirfenidone. We also wished to evaluate cryoprobe assisted transbronchial lung biopsy …

Toll-like receptors in the pathogenesis of pulmonary fibrosis

Pulmonary fibrosis (PF) constitutes the end stage of a broad range of heterogeneous interstitial lung diseases, characterized by the destruction of the pulmonary parenchyma, deposition of extracellular matrix and dramatic changes in the phenotype of both fibroblasts and alveolar epithelial cells. More than 200 causes of pulmonary fibrosis have been identified so far, yet the most common form is idiopathic pulmonary fibrosis (IPF). IPF is a lethal lung disorder of unknown etiology with a gradually increasing worldwide incidence and a median survival of 3–5 years from the time of diagnosis. Despite intense research efforts, the pathogenesis remains elusive and no effective treatment is available. Accumulating body of evidence suggests an abnormal wound healing response followed by extracellular matrix deposition, destruction of lung architecture, ultimately leading to respiratory failure. The contribution of immune system in lung fibrogenesis had been largely underscored due to the absence of response to immunosuppressive agents; however, the premise that lung fibrosis has an immunologic background has been recently revived. Toll-like receptors (TLRs) are pattern recognition receptors (PRRs), which link innate and adaptive immune response and regulate wound healing. TLRs promote tissue repair or fibrosis in many disease settings including lung fibrosis, albeit with profound differences depending on the cellular microenvironment. This review summarizes the current state of knowledge regarding the mechanistic implications between TLRs and lung fibrosis and highlights the therapeutic potential of targeting TLR signaling at the ligand or receptor level.

Antiflammin-1 attenuates bleomycin-induced pulmonary fibrosis in mice

BackgroundAntiflammin-1 (AF-1), a derivative of uteroglobin (UG), is a synthetic nonapeptide with diverse biological functions. In the present study, we investigated whether AF-1 has a protective effect against bleomycin-induced pulmonary fibrosis.MethodsC57BL/6 mice were injected with bleomycin intratracheally to create an animal model of bleomycin-induced pulmonary fibrosis. On Day 7 and Day 28, we examined the anti-inflammatory effect and antifibrotic effect, respectively, of AF-1 on the bleomycin-treated mice. The effects of AF-1 on the transforming growth factor-beta 1 (TGF-β1)-induced proliferation of murine lung fibroblasts (NIH3T3) were examined by a bromodeoxycytidine (BrdU) incorporation assay and cell cycle analysis.ResultsSevere lung inflammation and fibrosis were observed in the bleomycin-treated mice on Day 7 and Day 28, respectively. Administration of AF-1 significantly reduced the number of neutrophils in the bronchoalveolar lavage fluid (BALF) and the levels of tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) in the lung homogenates on Day 7. Histological examination revealed that AF-1 markedly reduced the number of infiltrating cells on Day 7 and attenuated the collagen deposition and destruction of lung architecture on Day 28. The hydroxyproline (HYP) content was significantly decreased in the AF-1-treated mice. In vitro, AF-1 inhibited the TGF-β1-induced proliferation of NIH3T3 cells, which was mediated by the UG receptor.ConclusionsAF-1 has anti-inflammatory and antifibrotic actions in bleomycin-induced lung injury. We propose that the antifibrotic effect of AF-1 might be related to its suppression of fibroblast growth in bleomycin-treated lungs and that AF-1 has potential as a new therapeutic tool for pulmonary fibrosis.

Pathogenesis and New Diagnosis Guideline of Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal fibrotic lung disease in many patients. In spite of extensive research for many decades, the exact pathogenesis of IPF is unknown. At recent, the role of alveolar epithelial cells has been focused in the initiation of IPF in terms of epithelial-mesenchymal transition, dysregulated Wnt signaling, and activation of transforming growth factor-β (TGF-β). The resulting excess collagen deposition and destruction of lung architecture by myofibroblasts and fibroblastic foci leads to the development of IPF. IPF can be diagnosed by typical high resolution chest tomogram (HRCT) or by multidisciplinary discussion based on the new guideline published on 2010. (Korean J Med 2013;84:481-488)

Nitric oxide attenuates epithelial-mesenchymal transition in alveolar epithelial cells

Patients with interstitial lung diseases, such as idiopathic pulmonary fibrosis (IPF) and bronchopulmonary dysplasia (BPD), suffer from lung fibrosis secondary to myofibroblast-mediated excessive ECM deposition and destruction of lung architecture. Transforming growth factor (TGF)-beta1 induces epithelial-mesenchymal transition (EMT) of alveolar epithelial cells (AEC) to myofibroblasts both in vitro and in vivo. Inhaled nitric oxide (NO) attenuates ECM accumulation, enhances lung growth, and decreases alveolar myofibroblast number in experimental models. We therefore hypothesized that NO attenuates TGF-beta1-induced EMT in cultured AEC. Studies of the capacity for endogenous NO production in AEC revealed that endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) are expressed and active in AEC. Total NOS activity was 1.3 pmol x mg protein(-1) x min(-1) with 67% derived from eNOS. TGF-beta1 (50 pM) suppressed eNOS expression by more than 60% and activity by 83% but did not affect iNOS expression or activity. Inhibition of endogenous NOS with l-NAME led to spontaneous EMT, manifested by increased alpha-smooth muscle actin (alpha-SMA) expression and a fibroblast-like morphology. Provision of exogenous NO to TGF-beta1-treated AEC decreased stress fiber-associated alpha-SMA expression and decreased collagen I expression by 80%. NO-treated AEC also retained an epithelial morphology and expressed increased lamellar protein, E-cadherin, and pro-surfactant protein B compared with those treated with TGF-beta alone. These findings indicate that NO serves a critical role in preserving an epithelial phenotype and in attenuating EMT in AEC. NO-mediated regulation of AEC fate may have important implications in the pathophysiology and treatment of diseases such as IPF and BPD.

Organizing Pneumonia Presenting as a Solitary Nodular Shadow on a Chest Radiograph

Background: The role of infection as a cause of focal organizing pneumonia (OP) is not fully understood. Objectives: This study aimed to determine the clinical, radiological and pathological characteristics of patients with OP presenting a solitary nodular shadow on a chest radiograph. Methods: Fourteen patients who presented with a solitary nodular shadow on a chest radiograph, pathologically diagnosed as OP after surgical resection, were allocated into two groups according to the histological findings. The first had OP with aggregates of neutrophils in airways and/or pulmonary parenchyma with or without necrosis or destruction of lung architecture (group 1: OP with neutrophilic infiltration; n = 10). The second consisted of patients with OP presenting neither neutrophilic infiltration, necrosis nor destruction of lung architecture (group 2: OP without neutrophilic infiltration; n = 4). Results: Cough, sputum, and chest pain were the common symptoms in both groups of patients. Computed tomography (CT) revealed that all nodules in both groups were located in the peripheral lung parenchyma and had irregular margins, and their shapes varied from round to wedge-shaped. Haemophilus influenzae was isolated from sputum or transbronchial aspirates from 3 patients in group 1. Conclusions: The specimens resected from patients with focal OP mostly show small aggregates of neutrophils. However, the dominant histological feature is OP and neutrophilic infiltration, suggesting infection was a minor histological component in all cases. Clinical symptoms and chest CT findings did not clearly distinguish these two groups of patients. It is thus reasonable to place these OPs in the same category and to treat them in the same way. Surgical excision appears to be the only method for a precise diagnosis.