scholarly journals DRP1-Mediated Mitochondrial Fission Regulates the Lung Epithelial Response to Allergen

Author(s):  
Sierra Bruno ◽  
Amit Kumar ◽  
Zoe Mark ◽  
Ravishankar Chandrasekaran ◽  
Emily Nakada ◽  
...  

Abstract Background: Mitochondria regulate a myriad of cellular needs and functions. Dysregulation of mitochondrial control within airway epithelial cells has been implicated in the pro-inflammatory response to allergens in asthmatics. Because of their multifaceted nature, mitochondrial structure needs to be tightly regulated through fission and fusion. Dynamin Related Protein 1 (DRP1), a cytosolic GTPase, is a key driver of mitochondrial fission. During allergic asthma, airway epithelial mitochondria appear smaller and structurally altered. The role of DRP1-mediated mitochondrial fission, however, has not been fully elucidated in allergic airway disease. Methods: We used a Human Bronchial Epithelial Cell line (HBECs), primary Mouse Tracheal Epithelial Cells (MTECs), and conditional ablation of DRP1 in lung epithelial cells to investigate mitochondrial fission and its impact on the pro-inflammatory response to House Dust Mite (HDM) in vitro and in vivo. Results: Our data suggest that, following HDM challenge, mitochondrial fission is rapidly upregulated in airway epithelial cells and precedes production of pro-inflammatory cytokines and chemokines. Further, deletion of DRP1 in lung epithelial cells lead to decreased mitochondrial fission and enhanced pro-inflammatory signaling in response to HDM. Analysis of lung epithelial specific DRP1 deletion in mice demonstrated enhanced Airway Hyper Responsiveness (AHR), inflammation, differential mucin transcription, and epithelial cell death. Conclusions: Mitochondrial fission is rapidly upregulated in airway epithelial cells following HDM exposure, prior to epithelial release of pro-inflammatory cytokines and chemokines. Deletion of DRP1, a necessary pro- fission protein, reduces fission and enhances the pro-inflammatory epithelial response to HDM, exacerbating the allergic response.

2007 ◽  
Vol 293 (5) ◽  
pp. L1208-L1218 ◽  
Author(s):  
Ewa Ostrowska ◽  
Elena Sokolova ◽  
Georg Reiser

Protease-activated receptors (PARs) are involved in the contribution of airway epithelial cells to the development of inflammation by release of pro- and anti-inflammatory mediators. Here, we evaluated in epithelial cells the influence of LPS and continuous PAR activation on PAR expression level and the release of the proinflammatory chemokine IL-8. We studied primary human small airway epithelial cells and two airway epithelial cell lines, A549 and HBE cells. LPS specifically upregulated expression of PAR-2 but not of PAR-1. Exposure of epithelial cells to PAR-1 or PAR-2 agonists increased the PAR-1 expression level. The PAR-2 agonist exhibited higher potency than PAR-1 activators. However, the combined exposure of epithelial cells to LPS and PAR agonists abrogated the PAR-1 upregulation. The PAR-2 expression level was also upregulated after exposure to PAR-1 or PAR-2 agonists. This elevation was higher than the effect of PAR agonists on the PAR-1 level. In contrast to the PAR-1 level, the PAR-2 level remained elevated under concomitant stimulation with LPS and PAR-2 agonist. Furthermore, activation of PAR-2, but not of PAR-1, caused production of IL-8 from the epithelial cells. Interestingly, both in the epithelial cell line and in primary epithelial cells, there was a potentiation of the stimulation of the IL-8 synthesis and release by PAR-2 agonist together with LPS. In summary, these results underline the important role of PAR-2 in human lung epithelial cells. Moreover, our study shows an intricate interplay between LPS and PAR agonists in affecting PAR regulation and IL-8 production.


2008 ◽  
Vol 294 (3) ◽  
pp. L478-L488 ◽  
Author(s):  
Aruna Kode ◽  
Saravanan Rajendrasozhan ◽  
Samuel Caito ◽  
Se-Ran Yang ◽  
Ian L. Megson ◽  
...  

Nuclear erythroid-related factor 2 (Nrf2), a redox-sensitive transcription factor, is involved in transcriptional regulation of many antioxidant genes, including glutamate-cysteine ligase (GCL). Cigarette smoke (CS) is known to cause oxidative stress and deplete glutathione (GSH) levels in alveolar epithelial cells. We hypothesized that resveratrol, a polyphenolic phytoalexin, has antioxidant signaling properties by inducing GSH biosynthesis via the activation of Nrf2 and protects lung epithelial cells against CS-mediated oxidative stress. Treatment of human primary small airway epithelial and human alveolar epithelial (A549) cells with CS extract (CSE) dose dependently decreased GSH levels and GCL activity, effects that were associated with enhanced production of reactive oxygen species. Resveratrol restored CSE-depleted GSH levels by upregulation of GCL via activation of Nrf2 and also quenched CSE-induced release of reactive oxygen species. Interestingly, CSE failed to induce nuclear translocation of Nrf2 in A549 and small airway epithelial cells. On the contrary, Nrf2 was localized in the cytosol of alveolar and airway epithelial cells due to CSE-mediated posttranslational modifications such as aldehyde/carbonyl adduct formation and nitration. On the other hand, resveratrol attenuated CSE-mediated Nrf2 modifications, thereby inducing its nuclear translocation associated with GCL gene transcription, as demonstrated by GCL-promoter reporter and Nrf2 small interfering RNA approaches. Thus resveratrol attenuates CSE-mediated GSH depletion by inducing GSH synthesis and protects epithelial cells by reversing CSE-induced posttranslational modifications of Nrf2. These data may have implications in dietary modulation of antioxidants in treatment of chronic obstructive pulmonary disease.


2021 ◽  
Author(s):  
Shahanshah Khan ◽  
Mahnoush S. Shafiei ◽  
Christopher Longoria ◽  
John Schoggins ◽  
Rashmin C. Savani ◽  
...  

Pathogenesis of COVID-19 is associated with a hyperinflammatory response; however, the precise mechanism of SARS-CoV-2-induced inflammation is poorly understood. Here we investigated direct inflammatory functions of major structural proteins of SARS-CoV-2. We observed that spike (S) protein potently induces inflammatory cytokines and chemokines including IL-6, IL-1b, TNFa, CXCL1, CXCL2, and CCL2, but not IFNs in human and mouse macrophages. No such inflammatory response was observed in response to membrane (M), envelope (E), and neucleocapsid (N) proteins. When stimulated with extracellular S protein, human lung epithelial cells A549 also produce inflammatory cytokines and chemokines. Interestingly, epithelial cells expressing S protein intracellularly are non-inflammatory, but elicit an inflammatory response in macrophages when co-cultured. Biochemical studies revealed that S protein triggers inflammation via activation of the NF-kB pathway in a MyD88-dependent manner. Further, such an activation of the NF-kB pathway is abrogated in Tlr2-deficient macrophages. Consistently, administration of S protein induces IL-6, TNF-a, and IL-1b in wild-type, but not Tlr2-deficient mice. Together these data reveal a mechanism for the cytokine storm during SARS-CoV-2 infection and suggest that TLR2 could be a potential therapeutic target for COVID-19.


2015 ◽  
Vol 309 (1) ◽  
pp. L27-L36 ◽  
Author(s):  
Thomas E. Sussan ◽  
Sachin Gajghate ◽  
Samit Chatterjee ◽  
Pooja Mandke ◽  
Sarah McCormick ◽  
...  

Asthma development and pathogenesis are influenced by the interactions of airway epithelial cells and innate and adaptive immune cells in response to allergens. Oxidative stress is an important mediator of asthmatic phenotypes in these cell types. Nuclear erythroid 2-related factor 2 ( Nrf2) is a redox-sensitive transcription factor that is the key regulator of the response to oxidative and environmental stress. We previously demonstrated that Nrf2-deficient mice have heightened susceptibility to asthma, including elevated oxidative stress, inflammation, mucus, and airway hyperresponsiveness (AHR) (Rangasamy T, Guo J, Mitzner WA, Roman J, Singh A, Fryer AD, Yamamoto M, Kensler TW, Tuder RM, Georas SN, Biswal S. J Exp Med 202: 47–59, 2005). Here we dissected the role of Nrf2 in lung epithelial cells and tested whether genetic or pharmacological activation of Nrf2 reduces allergic asthma in mice. Cell-specific activation of Nrf2 in club cells of the airway epithelium significantly reduced allergen-induced AHR, inflammation, mucus, Th2 cytokine secretion, oxidative stress, and airway leakiness and increased airway levels of tight junction proteins zonula occludens-1 and E-cadherin. In isolated airway epithelial cells, Nrf2 enhanced epithelial barrier function and increased localization of zonula occludens-1 to the cell surface. Pharmacological activation of Nrf2 by 2-trifluoromethyl-2′-methoxychalone during the allergen challenge was sufficient to reduce allergic inflammation and AHR. New therapeutic options are needed for asthma, and this study demonstrates that activation of Nrf2 in lung epithelial cells is a novel potential therapeutic target to reduce asthma susceptibility.


Biomolecules ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1148
Author(s):  
Trevor Teafatiller ◽  
Sudhanshu Agrawal ◽  
Gabriela De Robles ◽  
Farah Rahmatpanah ◽  
Veedamali S. Subramanian ◽  
...  

Vitamin C is well documented to have antiviral functions; however, there is limited information about its effect on airway epithelial cells—the first cells to encounter infections. Here, we examined the effect of vitamin C on human bronchial epithelium transformed with Ad12-SV40 2B (BEAS-2B) cells, and observed that sodium-dependent vitamin C transporter 2 (SVCT2) was the primary vitamin C transporter. Transcriptomic analysis revealed that treating BEAS-2B cells with vitamin C led to a significant upregulation of several metabolic pathways and interferon-stimulated genes (ISGs) along with a downregulation of pathways involved in lung injury and inflammation. Remarkably, vitamin C also enhanced the expression of the viral-sensing receptors retinoic acid-inducible gene 1 (RIG-1) and melanoma differentiation-associated protein 5 (MDA-5), which was confirmed at the protein and functional levels. In addition, the lungs of l-gulono-γ-lactone oxidase knockout (GULO-KO) mice also displayed a marked decrease in these genes compared to wild-type controls. Collectively, our findings indicate that vitamin C acts at multiple levels to exert its antiviral and protective functions in the lungs.


2010 ◽  
Vol 298 (3) ◽  
pp. L290-L296 ◽  
Author(s):  
Naibing Gu ◽  
Guannan Kang ◽  
Chang'E Jin ◽  
Yongjian Xu ◽  
Zhenxiang Zhang ◽  
...  

Asthma is characterized by airway inflammation, mucus overproduction, airway hyperreactivity, and peribronchial fibrosis. Intelectin has been shown to be increased in airway epithelium of asthmatics. However, the role of intelectin in the pathogenesis of asthma is unknown. Airway epithelial cells can secrete chemokines such as monocyte chemotactic protein (MCP)-1 and -3 that play crucial roles in asthmatic airway inflammation. We hypothesized that intelectin plays a role in allergic airway inflammation by regulating chemokine expression. In a mouse allergic asthma model, we found that mRNA expression of intelectin-2 as well as MCP-1 and -3 in mouse lung was increased very early (within 2 h) after allergen challenge. Expression of intelectin protein was localized to mucous cells in airway epithelium. Treatment of MLE12 mouse lung epithelial cells with interleukin IL-13, a critical mediator of allergic airway disease, induced expression of intelectin-1 and -2 as well as MCP-1 and -3. When IL-13-induced intelectin-1 and -2 expression was inhibited by RNA interference, IL-13-induced extracellular signal-regulated kinase 1/2 phosphorylation and MCP-1 and -3 production by MLE12 cells was inhibited. Furthermore, inhibition of intelectin expression by airway transfection with shRNA targeting intelectin-1 and -2 attenuated allergen-induced airway inflammation. We conclude that intelectin, a molecule expressed by airway epithelial cells and upregulated in asthma, is required for IL-13-induced MCP-1 and -3 production in mouse lung epithelial cells and contributes to allergic airway inflammation.


2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Yasuhiro Matsumura

Protease activity is a characteristic common to many allergens. Allergen source-derived proteases interact with lung epithelial cells, which are now thought to play vital roles in both innate and adaptive immune responses. Allergen source-derived proteases act on airway epithelial cells to induce disruption of the tight junctions between epithelial cells, activation of protease-activated receptor-2, and the production of thymic stromal lymphopoietin. These facilitate allergen delivery across epithelial layers and enhance allergenicity or directly activate the immune system through a nonallergic mechanism. Furthermore, they cleave regulatory cell surface molecules involved in allergic reactions. Thus, allergen source-derived proteases are a potentially critical factor in the development of allergic sensitization and appear to be strongly associated with heightened allergenicity.


2015 ◽  
Vol 309 (11) ◽  
pp. L1229-L1238 ◽  
Author(s):  
Sadis Matalon ◽  
Rafal Bartoszewski ◽  
James F. Collawn

In utero, fetal lung epithelial cells actively secrete Cl− ions into the lung air spaces while Na+ ions follow passively to maintain electroneutrality. This process, driven by an electrochemical gradient generated by the Na+-K+-ATPase, is responsible for the secretion of fetal fluid that is essential for normal lung development. Shortly before birth, a significant upregulation of amiloride-sensitive epithelial channels (ENaCs) on the apical side of the lung epithelial cells results in upregulation of active Na+ transport. This process is critical for the reabsorption of fetal lung fluid and the establishment of optimum gas exchange. In the adult lung, active Na+ reabsorption across distal lung epithelial cells limits the degree of alveolar edema in patients with acute lung injury and cardiogenic edema. Cl− ions are transported either paracellularly or transcellularly to preserve electroneutrality. An increase in Cl− secretion across the distal lung epithelium has been reported following an acute increase in left atrial pressure and may result in pulmonary edema. In contrast, airway epithelial cells secrete Cl− through apical cystic fibrosis transmembrane conductance regulator and Ca2+-activated Cl− channels and absorb Na+. Thus the coordinated action of Cl− secretion and Na+ absorption is essential for maintenance of the volume of epithelial lining fluid that, in turn, maximizes mucociliary clearance and facilitates clearance of bacteria and debris from the lungs. Any factor that interferes with Na+ or Cl− transport or dramatically upregulates ENaC activity in airway epithelial cells has been associated with lung diseases such as cystic fibrosis or chronic obstructive lung disease. In this review we focus on the role of the ENaC, the mechanisms involved in ENaC regulation, and how ENaC dysregulation can lead to lung pathology.


2019 ◽  
Author(s):  
Ram P. Naikawadi ◽  
Gary Green ◽  
Kirk D. Jones ◽  
Natalia Achtar-Zadeh ◽  
Julia E. Mieleszko ◽  
...  

ABSTRACTRationaleTelomere dysfunction is associated with multiple fibrotic lung processes, including chronic lung allograft dysfunction (CLAD) which is a major limitation to long-term survival following lung transplantation. Although shorter donor telomere lengths are associated with an increased risk of CLAD, it is unknown whether short telomeres are a cause or consequence of CLAD pathology.ObjectiveOur objective was to test whether telomere dysfunction contributes to pathologic changes seen in CLAD.Methods and ResultsHistopathologic and molecular analysis of human CLAD lungs demonstrated shortened telomeres in lung epithelial cells quantified by teloFISH, increased numbers of surfactant protein C immunoreactive type II alveolar epithelial cells (AECs), and increased expression of senescence markers (beta-galactosidase, p16, p53 and p21) in lung epithelial cells. Telomere repeat binding factor 1 flox/flox (TRF1F/F) mice were crossed with tamoxifen inducible SCGB1a1-cre mice to generate SCGB1a1-creTRF1 F/F mice. Following 9 months of tamoxifen-induced deletion of TRF1 in club cells, mice developed mixed obstructive and restrictive lung physiology, small airway obliteration on micro-computed tomography, a 4-fold decrease in telomere length in airway epithelial cells, collagen deposition around bronchioles and adjacent lung parenchyma, increased type II AEC numbers, expression of senescence-associated beta-galactosidase in epithelial cells and decreased SCGB1a1 expression in airway epithelial cells.ConclusionsThese findings demonstrate that telomere dysfunction isolated to club cells leads to airway-centric lung remodeling and fibrosis similar to that observed in patients with CLAD and suggest that lung epithelial cell telomere dysfunction may be a molecular driver of CLAD.


Sign in / Sign up

Export Citation Format

Share Document