IL‐17A deficiency mitigates bleomycin‐induced complement activation during lung fibrosis

Cipolla, Ellyse; Fisher, Amanda; Gu, Hongmei; Mickler, Elizabeth A.; Agarwal, Manisha; Wilke, Carol A.; Kim, Kevin K.; Moore, Bethany B.; Vittal, Ragini

doi:10.1096/fj.201700289r

Cited by 53 publications

(44 citation statements)

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“…We then mimicked the clinical setting wherein IPF patients present themselves with lung fibrosis and used a therapeutic strategy (Figures 1A-1F) as reported previously [3,4,16,17]. At two weeks after the onset of fibrosis, we then silenced the gene expression of C3ar or C5ar using oropharyngeal instillation of naked siRNA.…”

Section: Resultsmentioning

confidence: 99%

“…We have also observed a suppression of these complement components due to bleomycin injury in IL-17A deficient mice [3]. Furthermore, we had reported that IL-17A-mediates epithelial injury via TGF-β during bronchiolitis obliterans [1].…”

Section: Resultsmentioning

confidence: 99%

“…ALK5, effectively prevents the loss of membrane-bound cellular DAF at 24 h. We next investigated this effect in normal primary human alveolar type II epithelial cells (hAECs). Our prior studies show that IL-17A mediates loss of cellular DAF within 4 h in hAECs [3]. We therefore investigated the loss of cellular DAF with blockade of receptors of C3a ( C3aR A) and TGF-β (ALK5 In) in parallel to assess the extent of protection.…”

Section: Resultsmentioning

confidence: 99%

“…Antibodies used were against C3aR [3], and C5aR [3] were purchased from Novus Biologicals, Littleton, CO. CD46 [2] and DAF [3] antibodies were purchased from Santa Cruz Biotechnology. Densitometric analyses were performed with ImageJ 1.32j (NIH, Bethesda, MD).…”

Section: Methodsmentioning

confidence: 99%

“…IL-17A [1] and the complement cascade [2] which trigger TGF-β-related signaling pathways. Our recent report also suggests that IL-17A may drive fibrosis via the complement cascade [3]. Signaling interactions between these pro-fibrotic pathways may shed significant insights on the specific drivers of epithelial injury and dysregulated tissue repair.…”

Section: Introductionmentioning

confidence: 99%

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Potential Mechanisms Underlying TGF-β-mediated Complement Activation in Lung Fibrosis

Fisher¹,

Cipolla²,

Varre³

et al. 2017

Cell Mol Med

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While our previous studies suggest that limiting bleomycin-induced complement activation suppresses TGF-β signaling, the specific hierarchical interactions between TGF-β and complement in lung fibrosis are unclear. Herein, we investigated the mechanisms underlying TGF-β-induced complement activation in the pathogenesis of lung fibrosis. C57-BL6 mice were given intratracheal instillations of adenoviral vectors overexpressing TGF-β (Ad-TGFβ) or the firefly gene-luciferase (Ad-Luc; control). Two weeks later, mice with fibrotic lungs were instilled RNAi specific to receptors for C3a or C5a-C3ar or C5ar, and sacrificed at day 28. Histopathological analyses revealed that genetic silencing of C3ar or C5ar arrested the progression of TGF-β-induced lung fibrosis, collagen deposition and content (hydroxyproline, col1a1/2); and significantly suppressed local complement activation. With genetic silencing of either C3ar or C5ar, in Ad-TGFβ-injured lungs: we detected the recovery of Smad7 (TGF-β inhibitor) and diminished local release of DAF (membrane-bound complement inhibitor); in vitro: TGF-β-mediated loss of DAF was prevented. Conversely, blockade of the TGF-β receptor prevented C3a-mediated loss of DAF in both normal primary human alveolar and small airway epithelial cells. Of the 52 miRNAs analyzed as part of the Affymetrix array, normal primary human SAECs exposed to C3a, C5a or TGF-β caused discrete and overlapping miRNA regulation related to epithelial proliferation or apoptosis (miR-891A, miR-4442, miR-548, miR-4633), cellular contractility (miR-1197) and lung fibrosis . Our studies present potential mechanisms by which TGF-β activates complement and promotes lung fibrosis.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Potential Mechanisms Underlying TGF-β-mediated Complement Activation in Lung Fibrosis

Fisher¹,

Cipolla²,

Varre³

et al. 2017

Cell Mol Med

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Regeneration and repair in the healing lung

2020

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The lung achieves an efficient gas exchange between a complex non‐sterile atmosphere and the body via a delicate and extensive epithelial surface, with high efficiency because of elastic deformation allowing for an increase and decrease in volume during the process of breathing and because of an extensive vasculature which aids rapid gas diffusion. The lungs’ large surface area exposes the organ to a continual risk of damage from pathogens, toxins or irritants; however, lung damage can be rapidly healed via regenerative processes that restore its structure and function. In response to sustained and extensive damage, the lung is healed via a non‐regenerative process resulting in scar tissue which locally stiffens its structure, which over time leads to a serious loss of lung function and to increasing morbidities. This review discusses what is known about the factors which influence whether a lung is healed by regeneration or repair and what potential new therapeutic approaches may positively influence lung healing.

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Evaluation of common protein biomarkers involved in the pathogenesis of respiratory diseases with proteomic methods: A systematic review

Rezaeeyan,

Arabfard,

Rasouli

et al. 2023

Immunity Inflam & Disease

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AimRespiratory disease (RD) is one of the most common diseases characterized by lung dysfunction. Many diagnostic mechanisms have been used to identify the pathogenic agents of responsible for RD. Among these, proteomics emerges as a valuable diagnostic method for pinpointing the specific proteins involved in RD pathogenesis. Therefore, in this study, for the first time, we examined the protein markers involved in the pathogenesis of chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), asthma, bronchiolitis obliterans (BO), and chemical warfare victims exposed to mustard gas, using the proteomics method as a systematic study.Materials and MethodsA systematic search was performed up to September 2023 on several databases, including PubMed, Scopus, ISI Web of Science, and Cochrane. In total, selected 4246 articles were for evaluation according to the criteria. Finally, 119 studies were selected for this systematic review.ResultsA total of 13,806 proteins were identified, 6471 in COPD, 1603 in Asthma, 5638 in IPF, three in BO, and 91 in mustard gas exposed victims. Alterations in the expression of these proteins were observed in the respective diseases. After evaluation, the results showed that 31 proteins were found to be shared among all five diseases.ConclusionAlthough these 31 proteins regulate different factors and molecular pathways in all five diseases, they ultimately lead to the regulation of inflammatory pathways. In other words, the expression of some proteins in COPD and mustard‐exposed patients increases inflammatory reactions, while in IPF, they cause lung fibrosis. Asthma, causes allergic reactions due to T‐cell differentiation toward Th2.

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IL‐17A deficiency mitigates bleomycin‐induced complement activation during lung fibrosis

Cited by 53 publications

References 54 publications

Potential Mechanisms Underlying TGF-β-mediated Complement Activation in Lung Fibrosis

Potential Mechanisms Underlying TGF-β-mediated Complement Activation in Lung Fibrosis

Regeneration and repair in the healing lung

Evaluation of common protein biomarkers involved in the pathogenesis of respiratory diseases with proteomic methods: A systematic review

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