scholarly journals The Pathogenic Role of Smooth Muscle Cell-Derived Wnt5a in a Murine Model of Lung Fibrosis

2021 ◽  
Vol 14 (8) ◽  
pp. 755
Author(s):  
André Carmo-Fernandes ◽  
Michelle Puschkarow ◽  
Karin Peters ◽  
Stefanie Gnipp ◽  
Marcus Peters
Keyword(s):  
Smooth Muscle ◽  
Lung Fibrosis ◽  
Lung Parenchyma ◽  
Wnt5a Expression ◽  
Inflammatory Processes ◽  
Clinical Conditions ◽  
Precise Role ◽  
Deficient Mice ◽  
Gene Deficient Mouse

Idiopathic pulmonary fibrosis (IPF) is a disease characterized by extensive fibrosis of the lung tissue. Wnt5a expression was observed to be upregulated in IPF and suggested to be involved in the progression of the disease. Interestingly, smooth muscle cells (SMC) are a major source of Wnt5a in IPF patients. However, no study has been conducted until now to investigate the precise role of smooth muscle-derived Wnt5a in IPF. Here, we used the bleomycin-induced lung fibrosis model in a conditional gene-deficient mouse, where the Wnt5a gene was excised from SMC. We show here that the excision of the Wnt5a gene in SMC led to significantly improved health conditions with minimized weight loss and improved lung function. This improvement was based on a significantly lower deposition of collagen in the lung with a reduced number of fibrotic foci in lung parenchyma. Furthermore, the bleomycin-induced cellular infiltration into the airways was not altered in the gene-deficient mice compared with wild-type mice. Thus, we demonstrate that the Wnt5a expression of SMC of the airways leads to aggravated fibrosis of the lung with poor clinical conditions. This aggravation was not an influence in the bleomycin-induced inflammatory processes but on the development of fibrotic foci in lung parenchyma and the deposition of collagen.

Role of diagnostic imaging in diagnosis by Covid-19

2020 ◽  
Author(s):  
Coda Marco ◽  
Sica Federica ◽  
Finelli Mirko ◽  
Ungaro Gaetano ◽  
Sica Alfonso Marco
Keyword(s):  
Differential Diagnosis ◽  
Lung Parenchyma ◽  
Chest Ct ◽  
Initial Assessment ◽  
X Rays ◽  
Radiological Imaging ◽  
Laboratory Examinations ◽  
Clinical Conditions

The diagnosis from Covid-19 provides the set of several examinations such as: clinical examinations, laboratory examinations, radiographic examinations. Using radiological imaging, RX and chest CT, it is possible to evaluate the impairment of lung function and thanks to this aspect it is possible to define the severity and clinical conditions of the patient. In this way, it allows timely therapeutic intervention especially if the patient shows a mild condition in such a way as to avoid the onset of further complications. Chest X-rays allow both an initial assessment of patients and the possibility to perform a differential diagnosis towards other possible causes of lung parenchyma involvement. The CT scan, which highlights the peculiar characteristics of COVID pneumonia, is performed both as diagnostic confirmation and in the patient’s follow-up.

scholarly journals Serotonin 5-HT2receptor activation prevents allergic asthma in a mouse model

2015 ◽  
Vol 308 (2) ◽  
pp. L191-L198 ◽  
Author(s):  
Felix Nau ◽  
Justin Miller ◽  
Jordy Saravia ◽  
Terry Ahlert ◽  
Bangning Yu ◽  
...  
Keyword(s):  
Mouse Model ◽  
Allergic Asthma ◽  
Small Molecule ◽  
Primary Cultures ◽  
Allergic Inflammation ◽  
Inflammatory Processes ◽  
Inhaled Glucocorticoids ◽  
Precise Role ◽  
Airways Inflammation

Asthma is an inflammatory disease of the lung characterized by airways hyper-responsiveness (AHR), inflammation, and mucus hyperproduction. Current mainstream therapies include bronchodilators that relieve bronchoconstriction and inhaled glucocorticoids to reduce inflammation. The small molecule hormone and neurotransmitter serotonin has long been known to be involved in inflammatory processes; however, its precise role in asthma is unknown. We have previously established that activation of serotonin 5-hydroxytryptamine (5-HT)2Areceptors has potent anti-inflammatory activity in primary cultures of vascular tissues and in the whole animal in vasculature and gut tissues. The 5-HT2Areceptor agonist, ( R)-2,5-dimethoxy-4-iodoamphetamine [( R)-DOI] is especially potent. In this work, we have examined the effect of ( R)-DOI in an established mouse model of allergic asthma. In the ovalbumin mouse model of allergic inflammation, we demonstrate that inhalation of ( R)-DOI prevents the development of many key features of allergic asthma, including AHR, mucus hyperproduction, airways inflammation, and pulmonary eosinophil recruitment. Our results highlight a likely role of the 5-HT2receptors in allergic airways disease and suggest that 5-HT2receptor agonists may represent an effective and novel small molecule-based therapy for asthma.

scholarly journals A Brief History of Airway Smooth Muscle’s Role in Airway Hyperresponsiveness

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
C. D. Pascoe ◽  
L. Wang ◽  
H. T. Syyong ◽  
P. D. Paré
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Airway Hyperresponsiveness ◽  
Plastic Behavior ◽  
Phenotypic Changes ◽  
History Of Research ◽  
History Of ◽  
Cardiac Muscles ◽  
Precise Role

A link between airway smooth muscle (ASM) and airway hyperresponsiveness (AHR) in asthma was first postulated in the midnineteenth century, and the suspected link has garnered ever increasing interest over the years. AHR is characterized by excessive narrowing of airways in response to nonspecific stimuli, and it is the ASM that drives this narrowing. The stimuli that can be used to demonstrate AHR vary widely, as do the potential mechanisms by which phenotypic changes in ASM or nonmuscle factors can contribute to AHR. In this paper, we review the history of research on airway smooth muscle’s role in airway hyperresponsiveness. This research has ranged from analyzing the quantity of ASM in the airways to testing for alterations in the plastic behavior of smooth muscle, which distinguishes it from skeletal and cardiac muscles. This long history of research and the continued interest in this topic mean that the precise role of ASM in airway responsiveness remains elusive, which makes it a pertinent topic for this collection of articles.

scholarly journals Delayed resolution of bleomycin-induced pulmonary fibrosis in absence of MMP13 (collagenase 3)

2019 ◽  
Vol 316 (5) ◽  
pp. L961-L976 ◽  
Author(s):  
Sandra Cabrera ◽  
Mariana Maciel ◽  
Daniel Hernández-Barrientos ◽  
Jazmín Calyeca ◽  
Miguel Gaxiola ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Lung Injury ◽  
Lung Fibrosis ◽  
Intratracheal Instillation ◽  
Lavage Fluid ◽  
Collagenolytic Activity ◽  
Tissue Integrity ◽  
Two Stages ◽  
Deficient Mice

Matrix metalloprotease 13 (MMP13) deficiency in pulmonary fibrosis has described contradictory phenotypes on inflammatory and fibrotic responses after lung injury, and its role during lung fibrosis resolution is still undefined. MMP13 has been considered the main collagenase in rodents, and the remodeling of fibrillar collagen is widely attributed to the action of this enzyme. In this study we aimed to explore the role of MMP13 during lung fibrosis progression and resolution. Lung fibrosis was induced by intratracheal instillation, and inflammatory, fibrotic, and resolution stages were evaluated in Mmp13-null and wild-type (WT) mice. Bronchoalveolar lavage fluid was taken for cytokine array analysis and activity of gelatinases. Our results showed that MMP13 is upregulated mainly during two stages after lung injury, inflammation and resolution of fibrosis, and it is mainly expressed by alveolar and interstitial macrophages. Mmp13-null mice exhibited more extensive inflammation at 7 days after bleomycin treatment, and it was characterized by increased macrophage infiltration and significant alterations in proinflammatory cytokines. We also documented that Mmp13-deficient mice experienced more severe and prolonged lung fibrosis compared with WT mice. Delayed resolution in Mmp13-deficient lungs was characterized by a decreased overall collagenolytic activity and persistent fibrotic foci associated with emphysema-like areas. Together, our findings indicate that MMP13 plays an antifibrotic role and its activity is crucial in lung repair and restoration of tissue integrity during fibrosis resolution.

scholarly journals Role of the 5-Lipoxygenase–activating Protein (FLAP) in Murine Acute Inflammatory Responses

1997 ◽  
Vol 185 (6) ◽  
pp. 1065-1076 ◽  
Author(s):  
Robert S. Byrum ◽  
Jennifer L. Goulet ◽  
Richard J. Griffiths ◽  
Beverly H. Koller
Keyword(s):  
Membrane Protein ◽  
Inflammatory Responses ◽  
Platelet Activating Factor ◽  
Inflammatory Reactions ◽  
Inflammatory Processes ◽  
Ige Mediated ◽  
Relationship Of ◽  
Deficient Mice

Leukotrienes are potent inflammatory mediators synthesized from arachidonic acid (AA) predominately by cells of myeloid origin. The synthesis of these lipids is believed to be dependent not only on the expression of the enzyme 5-lipoxygenase (5-LO), which catalyzes the first steps in the synthesis of leukotrienes, but also on expression of a nuclear membrane protein termed the 5-LO–activating protein (FLAP). To study the relationship of these two proteins in mediating the production of leukotrienes in vivo and to determine whether the membrane protein FLAP has additional functions in various inflammatory processes, we have generated a mouse line deficient in this protein. FLAP-deficient mice develop normally and are healthy. However, an array of assays comparing inflammatory reactions in FLAP-deficient mice and in normal controls revealed that FLAP plays a role in a subset of these reactions. Although examination of DTH and IgE-mediated passive anaphylaxis showed no difference between wild-type and FLAP-deficient animals, mice without FLAP possessed a blunted inflammatory response to topical AA and had increased resistance to platelet-activating factor–induced shock compared to controls. Also, edema associated with Zymosan A–induced peritonitis was markedly reduced in animals lacking FLAP. To determine whether these differences relate solely to a deficit in leukotriene production, or whether they reflect an additional role for FLAP in inflammation, we compared the FLAP-deficient mice to 5-LO–deficient animals. Evaluation of mice lacking FLAP and 5-LO indicated that production of leukotrienes during inflammatory responses is dependent upon the availability of FLAP and did not support additional functions for FLAP beyond its role in leukotriene production.

scholarly journals Multifaceted Role of PARP-1 in DNA Repair and Inflammation: Pathological and Therapeutic Implications in Cancer and Non-Cancer Diseases

Cells ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 41 ◽  
Author(s):  
Simonetta Pazzaglia ◽  
Claudio Pioli
Keyword(s):  
Dna Repair ◽  
Inflammatory Responses ◽  
Parp Inhibitors ◽  
Protective Role ◽  
Therapeutic Implications ◽  
Inflammatory Processes ◽  
Clinical Conditions ◽  
Cancer And Inflammation ◽  
Parp 1

PARP-1 (poly(ADP-ribose)-polymerase 1), mainly known for its protective role in DNA repair, also regulates inflammatory processes. Notably, defects in DNA repair and chronic inflammation may both predispose to cancer development. On the other hand, inhibition of DNA repair and inflammatory responses can be beneficial in cancer therapy and PARP inhibitors are currently used for their lethal effects on tumor cells. Furthermore, excess of PARP-1 activity has been associated with many tumors and inflammation-related clinical conditions, including asthma, sepsis, arthritis, atherosclerosis, and neurodegenerative diseases, to name a few. Activation and inhibition of PARP represent, therefore, a double-edged sword that can be exploited for therapeutic purposes. In our review, we will discuss recent findings highlighting the composite multifaceted role of PARP-1 in cancer and inflammation-related diseases.

scholarly journals Inhibition of PDIA3 in club cells attenuates osteopontin production and lung fibrosis

Thorax ◽  
2021 ◽  
pp. thoraxjnl-2021-216882
Author(s):  
Amit Kumar ◽  
Evan Elko ◽  
Sierra R Bruno ◽  
Zoe F Mark ◽  
Nicolas Chamberlain ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Lung Fibrosis ◽  
Therapeutic Potential ◽  
Lung Parenchyma ◽  
Secretory Protein ◽  
Club Cell ◽  
Club Cells ◽  
Research Consortium ◽  
Related Proteins

BackgroundThe role of club cells in the pathology of idiopathic pulmonary fibrosis (IPF) is not well understood. Protein disulfide isomerase A3 (PDIA3), an endoplasmic reticulum-based redox chaperone required for the functions of various fibrosis-related proteins; however, the mechanisms of action of PDIA3 in pulmonary fibrosis are not fully elucidated.ObjectivesTo examine the role of club cells and PDIA3 in the pathology of pulmonary fibrosis and the therapeutic potential of inhibition of PDIA3 in lung fibrosis.MethodsRole of PDIA3 and aberrant club cells in lung fibrosis was studied by analyses of human transcriptome dataset from Lung Genomics Research Consortium, other public resources, the specific deletion or inhibition of PDIA3 in club cells and blocking SPP1 downstream of PDIA3 in mice.ResultsPDIA3 and club cell secretory protein (SCGB1A1) signatures are upregulated in IPF compared with control patients. PDIA3 or SCGB1A1 increases also correlate with a decrease in lung function in patients with IPF. The bleomycin (BLM) model of lung fibrosis showed increases in PDIA3 in SCGB1A1 cells in the lung parenchyma. Ablation of Pdia3, specifically in SCGB1A1 cells, decreases parenchymal SCGB1A1 cells along with fibrosis in mice. The administration of a PDI inhibitor LOC14 reversed the BLM-induced parenchymal SCGB1A1 cells and fibrosis in mice. Evaluation of PDIA3 partners revealed that SPP1 is a major interactor in fibrosis. Blocking SPP1 attenuated the development of lung fibrosis in mice.ConclusionsOur study reveals a new relationship with distally localised club cells, PDIA3 and SPP1 in lung fibrosis and inhibition of PDIA3 or SPP1 attenuates lung fibrosis.

scholarly journals Vascular smooth muscle–derived tissue factor is critical for arterial thrombosis after ferric chloride–induced injury

Blood ◽  
2009 ◽  
Vol 113 (3) ◽  
pp. 705-713 ◽  
Author(s):  
Li Wang ◽  
Christine Miller ◽  
Robert F. Swarthout ◽  
Mohan Rao ◽  
Nigel Mackman ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Tissue Factor ◽  
Ferric Chloride ◽  
Arterial Thrombosis ◽  
Critical Role ◽  
Arterial Injury ◽  
Aortic Media ◽  
Deficient Mice

Abstract Tissue factor (TF) initiates coagulation, regulates hemostasis, and plays a critical role in mediating arterial thrombosis. TF is up-regulated in vascular smooth muscle cells (VSMCs) in atherosclerosis and arterial injury. To examine the biologic role of VSMC-derived TF, we crossed TFflox/flox mice with SM22αCre+/− mice. TF mRNA and activity were decreased in the aortic media of TF-deficient mice by 96% and 94.8%, respectively. There were no differences in TF activity measured in plasma or concentrated microparticles. TF-deficient mice were generated with the expected frequency, showed no evidence of bleeding or increased mortality, and had similar activated partial thromboplastin and tail vein bleeding times. Thrombus-mediated flow reduction in response to ferric chloride injury of the carotid arteries was significantly attenuated in VSMC-specific TF-deficient. Stable occlusion was seen in 11 of 12 wild-type mice, but in only 6 of 16 VSMC-specific TF-deficient mice (P = .001). These data suggest that VSMC-derived TF is critical in a macrovascular model of arterial thrombosis. This mouse model should be valuable in determining the contribution of VSMC-derived TF in other TF-mediated phenomena, such as restenosis.

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