Aberrant Multiciliogenesis in Idiopathic Pulmonary Fibrosis

Kim, Eunjoo; Mathai, Susan K.; Stancil, I.T.; Ma, Xiaoxun; Hernandez-Gutierrez, Ashley; Becerra, Jessica N; Marrero-Torres, Emilette; Hennessy, Corinne E.; Hatakka, Kristina L.; Wartchow, Eric P.; Estrella, A.M.; Huber, Jonathan; Cardwell, Jonathan; Burnham, Ellen L.; Zhang, Yingze; Evans, Christopher M.; Vladar, Eszter K.; Schwartz, David A.; Dobrinskikh, Evgenia; Yang, Ivana V.

doi:10.1165/rcmb.2021-0554oc

Cited by 12 publications

(15 citation statements)

References 49 publications

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“…This likely reflects the advancement of our spatial proteomic capability or that previously observed increases in ciliary gene expression represent a compensatory mechanism occurring in response to loss of ciliated epithelial cells in fibrosis. Structurally, transmission electron microscopy demonstrates that the UIP/IPF distal airways display defects in microtubule organization, which will have detrimental effect on cilia function [39]. In the context in cystic fibrosis, it is reported that airway epithelial also have decreased ciliated cells with enhanced mucin expression [63].…”

Section: Discussionmentioning

confidence: 99%

“…These data suggest that the loss of proteins associated with ciliogenesis within the fibrotic HC airways may be part of the mechanism of fibrosis progression. A previous study demonstrated that ciliary microtubules are morphologically disorganized in UIP/IPF, which will have profound effects on cilia structure and function [39]. To demonstrate that abnormal ciliogenesis is a potential mechanistic theme in the fibrotic HC airway cells, we immunostained for tubulin alpha 4a (TUBA4A; a marker of cilia) in 4 UIP specimens and 2 controls.…”

Section: Honeycomb Airway Cells Are Enriched In Proteins Involved In ...mentioning

confidence: 99%

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The UIP honeycomb airway cells are the site of mucin biogenesis with deranged cilia

Herrera

Dingle

Montero

et al. 2022

Preprint

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Honeycombing (HC) is a histological pattern consistent with Usual Interstitial Pneumonia (UIP). HC refers to cystic airways (HC airways) located at sites of dense fibrosis with marked mucus accumulation. Utilizing laser capture microdissection coupled mass spectrometry (LCM-MS), we interrogated the fibrotic HC airway cells and fibrotic uninvolved airway cells (distant from sites of UIP and morphologically intact) in 10 UIP specimens; 6 non-fibrotic airway cell specimens served as controls. Furthermore, we performed LCM-MS on the mucus plugs found in 6 UIP and 6 mucinous adenocarcinoma (MA) specimens. The mass spectrometry data were subject to both qualitative and quantitative analysis and validated by immunohistochemistry. Surprisingly, fibrotic uninvolved airway cells share a similar protein profile to HC airway cells, showing deregulation of SLITs and ROBO pathway as the strongest category. We find that BPIFB1 is the most significantly increased secretome-associated protein in UIP, whereas MUC5AC is the most significantly increased in MA. We conclude that spatial proteomics demonstrates that the fibrotic uninvolved airway cells are abnormal. In addition, fibrotic HC airway cells are enriched in mucin biogenesis proteins with a marked derangement in proteins essential for ciliogenesis. This unbiased spatial proteomic approach will generate novel and testable hypotheses to decipher fibrosis progression.

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Section: Discussionmentioning

confidence: 99%

Section: Honeycomb Airway Cells Are Enriched In Proteins Involved In ...mentioning

confidence: 99%

The UIP honeycomb airway cells are the site of mucin biogenesis with deranged cilia

Herrera

Dingle

Montero

et al. 2022

Preprint

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“…In this context, pulmonary fibrosis mechanisms relate to the altered biology of the bronchial secretory cell. MUC5B rs35705950 T risk allele carriership increases the expression of mucin5B in the distal lung, causes mucociliary dysfunction and ER stress, and triggers a vicious cycle of injury/repair and regeneration at the bronchoalveolar junction leading to fibrosis [ 233 , 234 , 235 , 236 , 237 , 238 , 239 , 240 , 241 ].…”

Section: Common Variants In Ipf and Muc5b Rs35705950mentioning

confidence: 99%

Genetics in Idiopathic Pulmonary Fibrosis: A Clinical Perspective

et al. 2022

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Background: Unraveling the genetic background in a significant proportion of patients with both sporadic and familial IPF provided new insights into the pathogenic pathways of pulmonary fibrosis. Aim: The aim of the present study is to overview the clinical significance of genetics in IPF. Perspective: It is fascinating to realize the so-far underestimated but dynamically increasing impact that genetics has on aspects related to the pathophysiology, accurate and early diagnosis, and treatment and prevention of this devastating disease. Genetics in IPF have contributed as no other in unchaining the disease from the dogma of a “a sporadic entity of the elderly, limited to the lungs” and allowed all scientists, but mostly clinicians, all over the world to consider its many aspects and “faces” in all age groups, including its co-existence with several extra pulmonary conditions from cutaneous albinism to bone-marrow and liver failure. Conclusion: By providing additional evidence for unsuspected characteristics such as immunodeficiency, impaired mucus, and surfactant and telomere maintenance that very often co-exist through the interaction of common and rare genetic variants in the same patient, genetics have created a generous and pluralistic yet unifying platform that could lead to the understanding of the injurious and pro-fibrotic effects of many seemingly unrelated extrinsic and intrinsic offending factors. The same platform constantly instructs us about our limitations as well as about the heritability, the knowledge and the wisdom that is still missing.

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“…Accumulating evidence show that ciliary proteins are implicated in the development or disease condition of other organs, for example, bone development and blood pressure control (8)(9)(10)(11). Recent studies showed that ciliary proteins are also involved in organ fibrosis (6,12). Although polycystins have been revealed to be up-regulated in kidneys following ischemic or toxic acute injury (13,14), their roles in injury-induced renal tubulointerstitial fibrosis remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Tubular obstruction induced polycystin upregulation is pro-fibrotic and induced a severe cystic phenotype in adult mice with autosomal dominant polycystic kidney disease: the coexistence of polycystin loss and gain function in ADPKD

Wang

Jing³

et al. 2021

Preprint

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Mutations in PKD2 gene, which encodes polycystin-2, cause autosomal polycystic kidney disease (ADPKD). Development of ADPKD is associated with progression of renal fibrosis. Whether renal fibrosis in ADPKD is a direct effect of polycystin-2 mutation or a consequence of cyst growth induced tubular obstruction is currently unknown. Polycystin-2 has been identified as a direct target of triptolide, and we used triptolide as a probe to study the role of polycystin-2 in renal fibrosis. To study the expression of polycystin-2, we established unilateral ureteral obstruction (UUO), unilateral ischemia-reperfusion injury (UIRI) and aristolochic acid nephropathy mouse models. Here we showed that polycystin-2 is up-regulated in these three mouse models and tightly correlated with the expression of collagen-I in a time dependent manner. Treatment with triptolide inhibited the expression of polycystin-2 and pro-fibrotic markers in UUO and UIRI models. Moreover, triptolide dose-dependently inhibited the expression of polycystin-2 and pro-fibrotic markers in rat renal fibroblasts or in TGF-β stimulated human renal epithelial (HK2) cells. Knockdown of PKD2 reduced the expression of pro-fibrotic markers in TGF-β stimulated or unstimulated HK2 cells. Finally, we showed that knockdown of PKD2 attenuated the inhibitory effect of triptolide on the expression of pro-fibrotic markers in TGF-β stimulated HK2 cells.In conclusion, polycystin-2 is a pro-fibrotic protein suggesting that renal fibrosis in ADPKD kidneys is not a direct effect of PKD2 mutation.

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Aberrant Multiciliogenesis in Idiopathic Pulmonary Fibrosis

Cited by 12 publications

References 49 publications

The UIP honeycomb airway cells are the site of mucin biogenesis with deranged cilia

The UIP honeycomb airway cells are the site of mucin biogenesis with deranged cilia

Genetics in Idiopathic Pulmonary Fibrosis: A Clinical Perspective

Tubular obstruction induced polycystin upregulation is pro-fibrotic and induced a severe cystic phenotype in adult mice with autosomal dominant polycystic kidney disease: the coexistence of polycystin loss and gain function in ADPKD

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