Overexpression of Decay Accelerating Factor Mitigates Fibrotic Responses to Lung Injury

Vittal, Ragini; Fisher, Amanda; Thompson, Eric L.; Cipolla, Ellyse; Gu, Hongmei; Mickler, Elizabeth A.; Varre, Ananya; Agarwal, Manisha; Kim, Kevin K.; Vasko, Michael R.; Moore, Bethany B.; Lama, Vibha N.

doi:10.1165/rcmb.2021-0463oc

Cited by 9 publications

(7 citation statements)

References 49 publications

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“…For example, airway epithelial cells and alveolar (type 1 and type 2) epithelial cells also express C3aR, C5, C5aR1, and C5aR2, in addition to C3 and FB ( 22 , 56 , 57 ). C3aR activation on alveolar type 2 epithelial cells has recently been implicated in promoting endoplasmic reticulum stress and exacerbating bleomycin-induced lung injury, cellular apoptosis, and inflammation, which was suppressed by decay-accelerating factor (CD55) induction, a membrane-associated complement regulator ( 58 ). These observations create a precedent for complement modulating certain cellular processes in a stimuli-specific and cell-specific manner and accordingly targeting therapies on the basis of the desired effect.…”

Section: Discussionmentioning

confidence: 99%

Lung epithelial cell–derived C3 protects against pneumonia-induced lung injury

et al. 2023

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The complement component C3 is a fundamental plasma protein for host defense, produced largely by the liver. However, recent work has demonstrated the critical importance of tissue-specific C3 expression in cell survival. Here, we analyzed the effects of local versus peripheral sources of C3 expression in a model of acute bacterial pneumonia induced by Pseudomonas aeruginosa . Whereas mice with global C3 deficiency had severe pneumonia-induced lung injury, those deficient only in liver-derived C3 remained protected, comparable to wild-type mice. Human lung transcriptome analysis showed that secretory epithelial cells, such as club cells, express high levels of C3 mRNA. Mice with tamoxifen-induced C3 gene ablation from club cells in the lung had worse pulmonary injury compared with similarly treated controls, despite maintaining normal circulating C3 levels. Last, in both the mouse pneumonia model and cultured primary human airway epithelial cells, we showed that stress-induced death associated with C3 deficiency parallels that seen in Factor B deficiency rather than C3a receptor deficiency. Moreover, C3-mediated reduction in epithelial cell death requires alternative pathway component Factor B. Thus, our findings suggest that a pathway reliant on locally derived C3 and Factor B protects the lung mucosal barrier.

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Section: Discussionmentioning

confidence: 99%

Lung epithelial cell–derived C3 protects against pneumonia-induced lung injury

et al. 2023

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“…MAC was also observed deposited in inflamed or sclerotic areas during the development of chronic nephritis, and stimulates collagen synthesis in human glomerular mesangial cells and glomerular epithelial cells 74,75 . Previous studies revealed that C5a and C3a promoted the expression of collagen and fibronectin which were the major components of ECM in renal fibrosis and subretinal fibrosis, 76,77 while DAF diminished the level of collagen in vivo and in vitro 71 . Furthermore, in human macrophages, C5a induced the expression of matrix metalloproteinase (MMP)‐1 and MMP‐9 which were identified to promote the degradation of elastin 78 .…”

Section: The Role Of Complement System In Vcmentioning

confidence: 94%

“…What is more, is that, the MAC was identified as a key regulatory in ER stress, which induced damage to the membrane of the ER with the increased expression of glucose‐regulated protein 78 and glucose‐regulated protein 94 in glomerular epithelial cells 66 . In addition, soluble DAF abrogated tunicamycin‐induced the expression of ATF6 and glucose‐regulated protein 78 during ER stress in alveolar type II epithelial cells 71 . Taken together, abnormal increase or activation of complement system leads to ER stress, thus affecting VC.…”

Section: The Role Of Complement System In Vcmentioning

confidence: 99%

“… 66 In addition, soluble DAF abrogated tunicamycin‐induced the expression of ATF6 and glucose‐regulated protein 78 during ER stress in alveolar type II epithelial cells. 71 Taken together, abnormal increase or activation of complement system leads to ER stress, thus affecting VC.…”

Section: The Role Of Complement System In Vcmentioning

confidence: 99%

“…74 , 75 Previous studies revealed that C5a and C3a promoted the expression of collagen and fibronectin which were the major components of ECM in renal fibrosis and subretinal fibrosis, 76 , 77 while DAF diminished the level of collagen in vivo and in vitro . 71 Furthermore, in human macrophages, C5a induced the expression of matrix metalloproteinase (MMP)‐1 and MMP‐9 which were identified to promote the degradation of elastin. 78 The above evidences indicate that complement system may act through regulate ECM remodelling in VC.…”

Section: The Role Of Complement System In Vcmentioning

confidence: 99%

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New insight of complement system in the process of vascular calcification

Liu

Luo

Huang

2023

J Cellular Molecular Medi

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The complement system defences against pathogenic microbes and modulates immune homeostasis by interacting with the innate and adaptive immune systems. Dysregulation, impairment or inadvertent activation of complement system contributes to the pathogenesis of some autoimmune diseases and cardiovascular diseases (CVD). Vascular calcification is the pivotal pathological basis of CVD, and contributes to the high morbidity and mortality of CVD. Increasing evidences indicate that the complement system plays a key role in chronic kidney diseases, atherosclerosis, diabetes mellitus and aging‐related diseases, which are closely related with vascular calcification. However, the effect of complement system on vascular calcification is still unclear. In this review, we summarize current evidences about the activation of complement system in vascular calcification. We also describe the complex network of complement system and vascular smooth muscle cells osteogenic transdifferentiation, systemic inflammation, endoplasmic reticulum stress, extracellular matrix remodelling, oxidative stress, apoptosis in vascular calcification. Hence, providing a better understanding of the potential relationship between complement system and vascular calcification, so as to provide a direction for slowing the progression of this burgeoning health concern.

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