Age-Dependent Susceptibility to Pulmonary Fibrosis Is Associated with NLRP3 Inflammasome Activation

Stout‐Delgado, Heather; Cho, Soo Jung; Chu, Sarah G.; Mitzel, Dana N.; Villalba, Julian A.; El–Chemaly, Souheil; Ryter, Stefan W.; Choi, Augustine M.K.; Rosas, Iván O.

doi:10.1165/rcmb.2015-0222oc

Cited by 112 publications

(109 citation statements)

References 52 publications

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“…SASP provokes ER stress and reinforces senescence through autocrine activity rather than by spreading the senescence phenotype to healthy neighboring cells. Activation of the inflammasome has been shown to be relevant in development of lung fibrosis in aging mice, since deficiency of the inflammasome component NLRP3 diminishes bleomycin-induced lung injury in older animals (75). Another important component in the modulation of SASP is the abundance of caveolae and their components, which increases with senescence (76).…”

Section: Cellular Perturbations In the Ipf Lungmentioning

confidence: 99%

Mitochondria in the spotlight of aging and idiopathic pulmonary fibrosis

Mora¹,

Bueno²,

Rojas³

2017

Journal of Clinical Investigation

172

166

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One of the most remarkable medical accomplishments in the last century has been the increasing longevity of the human population. A decrease in birth rates, accompanied by a reduction in mortality among the elderly population, has collectively increased the percentage of the aged population, particularly in developed countries. Globally, it is estimated that the proportion of the population over the age of 60 will increase from 11% to 22% by 2050, and 28% by 2100. Currently, 18% of the US population is over 60 years of age (57 million), which is predicted to rise to 27% (107 million) in 2050 and up to 31% (149 million) by 2100 (1). The aging population has propelled an increase in the overall prevalence of chronic conditions. Several lung diseases, including acute lung injury and asthma, and some infectious diseases, such as pneumonia, increase in severity and mortality with age. Additionally, there has been a significant increase in incidence of chronic lung diseases -including chronic obstructive pulmonary disease, most forms of lung cancer, and idiopathic pulmonary fibrosis (IPF) -resulting in aging-related increases in prevalence.IPF is the most common form of idiopathic interstitial lung diseases. Its overall incidence in the US is 7 to 17 per 100,000 persons with a prevalence between 13.2 and 63 per 100,000 persons (2). A 1996 study initially demonstrated a higher incidence and prevalence of IPF in patients over 65 (3). These observations were confirmed more recently by Raghu et al. (4) and others, using both broad and narrow case-finding criteria for IPF diagnosis. These studies estimated that in the US, the prevalence of IPF increases with age, ranging from 4 per 100,000 for population aged between 18 and 34 years old to 227.2 per 100,000 among those 75 or older (4). This aging-related increase in cumulative incidence and prevalence of IPF has been corroborated by several studies that include populations in Europe and Asia (5-9). Accordingly, the median age at diagnosis of sporadic IPF ranges between 50 and 85 years old, and patients younger than 50 are more commonly associated with familial, rather than sporadic, forms of the disease (2). Mortality rates from IPF are steadily increasing worldwide, and a positive association has also been observed with advanced age (10). Examination of US government health insurance data for people aged 65 and older shows an increasing prevalence of IPF among older age groups (11). These studies confirm the growing concern that aging, and consequently age-related diseases, will drive up health care expenditures. As the elderly population in developed countries is expected to double in the next 25 years, there is an urgent need to understand the pathogenesis of IPF and develop interventions to attenuate or reverse lung fibrosis. The physiology of aging and the lungEvolutionary theories of aging include the concept of selection shadow that permits the accumulation of mutations with late deleterious effects, and the theory of antagonistic pleiotropy, which supports the sele...

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Section: Cellular Perturbations In the Ipf Lungmentioning

confidence: 99%

Mitochondria in the spotlight of aging and idiopathic pulmonary fibrosis

Mora¹,

Bueno²,

Rojas³

2017

Journal of Clinical Investigation

172

166

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“…Immunoblotting was performed as described previously (5). Anti-b-actin (4,967), -a-tubulin (2,144), -AMPKa (5,831), -phospho-AMPKa (2,535), -Smad3 (9,513), -phospho-Smad3 (9,520) antibodies and a glycolytic sampler kit (8,337) were obtained from Cell Signaling (Danvers, MA).…”

Section: Immunoblot Analysismentioning

confidence: 99%

“…Quantitative reverse transcriptasepolymerase chain reaction was performed as described in our previous study (5).…”

Section: Quantitative Reverse Transcriptase-polymerase Chain Reactionmentioning

confidence: 99%

“…Fibrosis is characterized by the accumulation of extracellular matrix (ECM) proteins, activated myofibroblasts, and inflammatory cells (4). We and other groups have reported recently that aged mice, compared with their younger counterparts, have greater lung injury and fibrosis (5,6). Glycolytic reprogramming has been shown to play an important role in the pathogenesis of lung fibrosis (7).…”

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confidence: 99%

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Glucose Transporter 1–Dependent Glycolysis Is Increased during Aging-Related Lung Fibrosis, and Phloretin Inhibits Lung Fibrosis

Cho

Moon

Lee

et al. 2017

Am J Respir Cell Mol Biol

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100

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Aging is associated with metabolic diseases such as type 2 diabetes mellitus, cardiovascular disease, cancer, and neurodegeneration. Aging contributes to common processes including metabolic dysfunction, DNA damage, and reactive oxygen species generation. Although glycolysis has been linked to cell growth and proliferation, the mechanisms by which the activation of glycolysis by aging regulates fibrogenesis in the lung remain unclear. The objective of this study was to determine if glucose transporter 1 (GLUT1)-induced glycolysis regulates age-dependent fibrogenesis of the lung. Mouse and human lung tissues were analyzed for GLUT1 and glycolytic markers using immunoblotting. Glycolytic function was measured using a Seahorse apparatus. To study the effect of GLUT1, genetic inhibition of GLUT1 was performed by short hairpin RNA transduction, and phloretin was used for pharmacologic inhibition of GLUT1. GLUT1-dependent glycolysis is activated in aged lung. Genetic and pharmacologic inhibition of GLUT1 suppressed the protein expression of a-smooth muscle actin, a key cytoskeletal component of activated fibroblasts, in mouse primary lung fibroblast cells. Moreover, we demonstrated that the activation of AMPactivated protein kinase, which is regulated by GLUT1-dependent glycolysis, represents a critical metabolic pathway for fibroblast activation. Furthermore, we demonstrated that phloretin, a potent inhibitor of GLUT1, significantly inhibited bleomycin-induced lung fibrosis in vivo. These results suggest that GLUT1-dependent glycolysis regulates fibrogenesis in aged lung and that inhibition of GLUT1 provides a potential target of therapy of age-related lung fibrosis.

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“…23 The NLRP3 inflammasome has also been shown to promote fibroblast activation in response to oxidant injury 22 and NRLP3 À/À mice are protected from bleomycininduced fibrosis. 23 Thus, ageing may predispose mice to worse fibrotic outcomes because they have a lower threshold for inflammasome activation.…”

Section: The Inflammasome In Lung Fibrosismentioning

confidence: 99%

A pathologic two‐way street: how innate immunity impacts lung fibrosis and fibrosis impacts lung immunity

2019

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Lung fibrosis is characterised by the accumulation of extracellular matrix within the lung and is secondary to both known and unknown aetiologies. This accumulation of scar tissue limits gas exchange causing respiratory insufficiency. The pathogenesis of lung fibrosis is poorly understood, but immunologic‐based treatments have been largely ineffective. Despite this, accumulating evidence suggests that innate immune cells and receptors play important modulatory roles in the initiation and propagation of the disease. Paradoxically, while innate immune signalling may be important for the pathogenesis of fibrosis, there is also evidence to suggest that innate immune function against pathogens may be impaired, leading to dysregulated and/or impaired host defence. This review summarises the evidence for this pathologic two‐way street, highlights new concepts of pathogenesis and recommends future directions for research emphasis.

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Age-Dependent Susceptibility to Pulmonary Fibrosis Is Associated with NLRP3 Inflammasome Activation

Cited by 112 publications

References 52 publications

Mitochondria in the spotlight of aging and idiopathic pulmonary fibrosis

Mitochondria in the spotlight of aging and idiopathic pulmonary fibrosis

Glucose Transporter 1–Dependent Glycolysis Is Increased during Aging-Related Lung Fibrosis, and Phloretin Inhibits Lung Fibrosis

A pathologic two‐way street: how innate immunity impacts lung fibrosis and fibrosis impacts lung immunity

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