Involvement of the ACE2/Ang-(1–7)/MasR Axis in Pulmonary Fibrosis: Implications for COVID-19

Pulmonary fibrosis is a chronic, fibrotic lung disease affecting 3 million people worldwide. The ACE2/Ang-(1–7)/MasR axis is of interest in pulmonary fibrosis due to evidence of its anti-fibrotic action. Current scientific evidence supports that inhibition of ACE2 causes enhanced fibrosis. ACE2 is also the primary receptor that facilitates the entry of SARS-CoV-2, the virus responsible for the current COVID-19 pandemic. COVID-19 is associated with a myriad of symptoms ranging from asymptomatic to severe pneumonia and acute respiratory distress syndrome (ARDS) leading to respiratory failure, mechanical ventilation, and often death. One of the potential complications in people who recover from COVID-19 is pulmonary fibrosis. Cigarette smoking is a risk factor for fibrotic lung diseases, including the idiopathic form of this disease (idiopathic pulmonary fibrosis), which has a prevalence of 41% to 83%. Cigarette smoke increases the expression of pulmonary ACE2 and is thought to alter susceptibility to COVID-19. Cannabis is another popular combustible product that shares some similarities with cigarette smoke, however, cannabis contains cannabinoids that may reduce inflammation and/or ACE2 levels. The role of cannabis smoke in the pathogenesis of pulmonary fibrosis remains unknown. This review aimed to characterize the ACE2-Ang-(1–7)-MasR Axis in the context of pulmonary fibrosis with an emphasis on risk factors, including the SARS-CoV-2 virus and exposure to environmental toxicants. In the context of the pandemic, there is a dire need for an understanding of pulmonary fibrotic events. More research is needed to understand the interplay between ACE2, pulmonary fibrosis, and susceptibility to coronavirus infection.

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The loss of IL-31 signaling attenuates bleomycin-induced pulmonary fibrosis

10.1101/2020.12.18.423450 ◽

2020 ◽

Author(s):

Dan JK Yombo ◽

Nishanth Gupta ◽

Anil G. Jegga ◽

Satish K Madala

Keyword(s):

T Cells ◽

Lung Function ◽

Pulmonary Fibrosis ◽

Gene Networks ◽

Pulmonary Inflammation ◽

Collagen Deposition ◽

Lung Function Decline ◽

Elevated Expression ◽

Fibrotic Lung Disease

AbstractIdiopathic Pulmonary Fibrosis (IPF) is a severe fibrotic lung disease characterized by excessive collagen deposition and progressive decline in lung function. Multiple Th2 T cell-derived cytokines including IL-4 and IL-13 have been shown to contribute to inflammation and fibrotic remodeling in multiple tissues. Interleukin-31 (IL-31) is a newly identified cytokine that is predominantly produced by CD4 TH2 T cells, but its signaling receptor called IL-31RA has been shown predominately expressed by non-hematopoietic cells. However, the potential role of the IL-31-IL31RA axis in pulmonary inflammation and fibrosis has remained largely unknown. To determine the role of IL-31 signaling in pulmonary fibrosis, wildtype, and IL-31RA knockout mice were treated with bleomycin and measured changes in collagen deposition and lung function. Notably, the loss of IL-31 signaling attenuated collagen deposition and lung function decline during bleomycin-induced pulmonary fibrosis. However, the loss of IL-31RA signaling did not affect inflammation in the lungs. The total lung transcriptome analysis showed a significant reduction in fibrosis-associated gene transcripts including ECM- and epithelial cell-associated gene networks. Furthermore, the lungs of IPF showed an elevated expression of IL-31 when compared to control subjects. In support, the percentage of IL-31 producing CD4+ T cells was greater in the lungs and PBMCs from IPF patients compared to healthy controls. Our findings suggest a pathogenic role for IL-31/IL-31RA signaling during bleomycin-induced pulmonary fibrosis. In summary, therapeutic targeting of the IL-31-IL-31RA axis could be beneficial in pulmonary fibrosis and has translational benefits specifically by preventing collagen deposition and improving lung function.

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The role of macrophage-derived TGF-β1 on SiO2-induced pulmonary fibrosis: A review

Toxicology and Industrial Health ◽

10.1177/0748233721989896 ◽

2021 ◽

pp. 074823372198989

Author(s):

Zhao-qiang Zhang ◽

Hai-tao Tian ◽

Hu Liu ◽

Ruining Xie

Keyword(s):

Pulmonary Fibrosis ◽

Molecular Mechanisms ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β1 ◽

Silica Dust ◽

Molecular Events ◽

Fibrotic Lung Disease ◽

Different Sources ◽

Tgf Β1

Silicosis is an occupational fibrotic lung disease caused by inhaling large amounts of crystalline silica dust. Transforming growth factor-β1 (TGF-β1), which is secreted from macrophages, has an important role in the development of this disease. Macrophages can recognize and capture silicon dust, undergo M2 polarization, synthesize TGF-β1 precursors, and secrete them out of the cell where they are activated. Activated TGF-β1 induces cells from different sources, transforming them into myofibroblasts through autocrine and paracrine mechanisms, ultimately causing silicosis. These processes involve complex molecular events, which are not yet fully understood. This systematic summary may further elucidate the location and development of pulmonary fibrosis in the formation of silicosis. In this review, we discussed the proposed cellular and molecular mechanisms of production, secretion, activation of TGF-β1, as well as the mechanisms through which TGF-β1 induces cells from three different sources into myofibroblasts during the pathogenesis of silicosis. This study furthers the medical understanding of the pathogenesis and theoretical basis for diagnosing silicosis, thereby promoting silicosis prevention and treatment.

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Lost after translation: insights from pulmonary surfactant for understanding the role of alveolar epithelial dysfunction and cellular quality control in fibrotic lung disease

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00139.2015 ◽

2015 ◽

Vol 309 (6) ◽

pp. L507-L525 ◽

Cited By ~ 52

Author(s):

Surafel Mulugeta ◽

Shin-Ichi Nureki ◽

Michael F. Beers

Keyword(s):

Quality Control ◽

Pulmonary Fibrosis ◽

Er Stress ◽

Lung Disease ◽

Pulmonary Surfactant ◽

Model Systems ◽

Cell Dysfunction ◽

Fibrotic Lung Disease ◽

Epithelial Dysfunction

Dating back nearly 35 years ago to the Witschi hypothesis, epithelial cell dysfunction and abnormal wound healing have reemerged as central concepts in the pathophysiology of idiopathic pulmonary fibrosis (IPF) in adults and in interstitial lung disease in children. Alveolar type 2 (AT2) cells represent a metabolically active compartment in the distal air spaces responsible for pulmonary surfactant biosynthesis and function as a progenitor population required for maintenance of alveolar integrity. Rare mutations in surfactant system components have provided new clues to understanding broader questions regarding the role of AT2 cell dysfunction in the pathophysiology of fibrotic lung diseases. Drawing on data generated from a variety of model systems expressing disease-related surfactant component mutations [surfactant proteins A and C (SP-A and SP-C); the lipid transporter ABCA3], this review will examine the concept of epithelial dysfunction in fibrotic lung disease, provide an update on AT2 cell and surfactant biology, summarize cellular responses to mutant surfactant components [including endoplasmic reticulum (ER) stress, mitochondrial dysfunction, and intrinsic apoptosis], and examine quality control pathways (unfolded protein response, the ubiquitin-proteasome system, macroautophagy) that can be utilized to restore AT2 homeostasis. This integrated response and its derangement will be placed in the context of cell stress and quality control signatures found in patients with familial or sporadic IPF as well as non-surfactant-related AT2 cell dysfunction syndromes associated with a fibrotic lung phenotype. Finally, the need for targeted therapeutic strategies for pulmonary fibrosis that address epithelial ER stress, its downstream signaling, and cell quality control are discussed.

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Eicosanoids: mediators and therapeutic targets in fibrotic lung disease

Clinical Science ◽

10.1042/cs20050012 ◽

2005 ◽

Vol 108 (6) ◽

pp. 479-491 ◽

Cited By ~ 54

Author(s):

Ryan P. CHARBENEAU ◽

Marc PETERS-GOLDEN

Keyword(s):

Prostaglandin E2 ◽

Lung Disease ◽

Lung Diseases ◽

Lipid Mediators ◽

Therapeutic Approaches ◽

Chronic Lung Diseases ◽

Fibrotic Lung Diseases ◽

Fibrotic Lung Disease ◽

End Stage

Fibrosis is a common end-stage sequella of a number of acute and chronic lung diseases. Current concepts of pathogenesis implicate dysregulated interactions between epithelial cells and mesenchymal cells. Although investigative efforts have documented important roles for cytokines and growth factors in the pathogenesis of fibrotic lung diseases, these observations have not as yet been translated into efficacious therapies, and there is a pressing need for new pathogenetic insights and therapeutic approaches for these devastating disorders. Eicosanoids are lipid mediators derived from arachidonic acid, the most studied of which are the prostaglandins and leukotrienes. Although they are primarily known for their roles in asthma, pain, fever and vascular responses, present evidence indicates that eicosanoids exert relevant effects on immune/inflammatory, as well as structural, cells pertinent to fibrogenesis. In general, leukotrienes promote, whereas prostaglandin E2 opposes, fibrogenic responses. An imbalance of eicosanoids also exists in pulmonary fibrosis, which favours the production of leukotrienes over prostaglandin E2. This review highlights the role of this imbalance in the evolution of fibrotic lung disease, discusses the mechanisms by which it may arise and considers approaches for therapeutic targeting of eicosanoids in these conditions.

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The Role of Zinc in Thyroid Hormones Metabolism

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831/a000262 ◽

2019 ◽

Vol 89 (1-2) ◽

pp. 80-88 ◽

Cited By ~ 6

Author(s):

Juliana Soares Severo ◽

Jennifer Beatriz Silva Morais ◽

Taynáh Emannuelle Coelho de Freitas ◽

Ana Letícia Pereira Andrade ◽

Mayara Monte Feitosa ◽

...

Keyword(s):

Thyroid Hormones ◽

Scientific Evidence ◽

Thyroid Stimulating Hormone ◽

Zinc Transporters ◽

Serum Concentrations ◽

Metabolic Adaptations ◽

Serum T3 ◽

Regulatory Effects ◽

Shed Light

Abstract. Thyroid hormones play an important role in body homeostasis by facilitating metabolism of lipids and glucose, regulating metabolic adaptations, responding to changes in energy intake, and controlling thermogenesis. Proper metabolism and action of these hormones requires the participation of various nutrients. Among them is zinc, whose interaction with thyroid hormones is complex. It is known to regulate both the synthesis and mechanism of action of these hormones. In the present review, we aim to shed light on the regulatory effects of zinc on thyroid hormones. Scientific evidence shows that zinc plays a key role in the metabolism of thyroid hormones, specifically by regulating deiodinases enzymes activity, thyrotropin releasing hormone (TRH) and thyroid stimulating hormone (TSH) synthesis, as well as by modulating the structures of essential transcription factors involved in the synthesis of thyroid hormones. Serum concentrations of zinc also appear to influence the levels of serum T3, T4 and TSH. In addition, studies have shown that Zinc transporters (ZnTs) are present in the hypothalamus, pituitary and thyroid, but their functions remain unknown. Therefore, it is important to further investigate the roles of zinc in regulation of thyroid hormones metabolism, and their importance in the treatment of several diseases associated with thyroid gland dysfunction.

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