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Carla Maria Pedrosa Ribeiro, PhD

Professor

***Noteworthy: A figure from a review article written by Dr. Ribeiro and Dr. Emily Hull-Ryde for Current Opinion in Pharmacology has been chosen for the cover of the 2022 Respiratory Issue. The article can be found . The cover for the 2022 Respiratory Issue, for which Dr. Ribeiro served with Dr. Martina Gentzsch as guest editors, can be previewed below.***

Cover of Current Opinion in Pharmacology, Volume 65

Specialty Areas:

Inflammation Mechanisms in CF, COPD, and Asthma

Chronology:

PhD: Duke University, 1992; Postdoctoral: NIH/NIEHS, 1993-1998; Research Associate, University of North Carolina, 1998-2001; Assistant Professor of Medicine, University of North Carolina, 2001-2010; Associate Professor of Medicine, University of North Carolina, 2010-present; Joint Associate Professor of Cell Biology and Physiology, University of North Carolina, July 2011-May 2021; Professor of Cell Biology and Physiology, University of North Carolina, May 2021-present.

Research Focus:

Research in the Ribeiro laboratory focuses on studying mechanisms of airway inflammatory responses relevant to the pathogenesis of airway diseases characterized by mucus obstruction, inflammation, and oxidative stress, such as cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD) and asthma. In particular, we study the functional roles of the endoplasmic reticulum (ER) and the mitochondria in the regulation of intracellular calcium (Ca2+i) signals and Ca2+i-mediated inflammation, and ER stress responses pertinent to the pathophysiology of these pulmonary diseases.

Techniques employed in the Ribeiro lab include:

  • Primary culturing of human and murine airway epithelia; culturing of a variety of immortalized cell lines including airway epithelial cell lines.
  • Bronchoalveolar lavages; isolation and culturing of murine and human alveolar macrophages.
  • DNA, RNA and protein extraction from cells and tissues; DNA, RNA and protein quantitation; DNA cloning; RNA purification; RNase Protection Assays; PCR and RT-PCR; RNA microarrays.
  • Northern and Southern blotting.
  • Agarose and polyacrylamide gel electrophoresis; Western blotting.
  • ELISA; immunocytochemistry; immunofluorescence; confocal microscopy.
  • Measurements of intracellular calcium signals (including ER and mitochondrial calcium mobilization) by microfluorimetry and confocal microscopy.
  • Assessment of intracellular reactive oxygen species.
  • Assays to evaluate airway mucin production and secretion.

I joined the 大象传媒 Cystic Fibrosis Center in 1998 with 1) a strong background in calcium signaling, acquired during my postdoctoral training at the National Institute of Environmental and Health Sciences (NIEHS/NIH), and 2) a solid understanding of renal epithelial biology and membrane transport from my studies at Baylor College of Medicine and during graduate school at Duke University. Hence, the research in my lab has combined these areas of expertise to create a new field aimed at addressing fundamental questions in human airway epithelial biology involving Ca2+i-dependent responses and their role in airway inflammation.

Our studies have revealed that Ca2+i responses to infectious/inflammatory stimuli are increased in CF epithelia due to an expansion of the endoplasmic reticulum (ER) Ca2+i stores. We have subsequently shown that the ER/Ca2+i store expansion contributes to airway hyperinflammation by amplifying Ca2+i-dependent inflammatory responses and increasing the ER cpaacity for the epithelial synthesis of inflammatory mediators. The initial findings in CF epithelia have been extended to other diseased epithelia, since we have also found that ER/Ca2+i stores are also expanded in inflamed, native primary ciliary diskynesia and COPD human airway epithelia.

Because the ER/Ca2+i store expansion is a hallmark of several pulmonary diseases, we reasoned that it is an adaptive epithelial response that plays a key functional role in the pathophysiology of airway inflammation. We have addressed the mechanism responsible for the ER/Ca2+i store expansion during airway inflammation and found that it is mediated by activation of an ER stress response known as the unfolded protein response (UPR). In mammalian cells, activation of the UPR by increased levels of unfolded proteins in the lumen of the ER is sensed by 3 ER stress transducers, ATF6, IRE1 (a and b) and PERK. Activation of these UPR pathways results in downstream activation of signaling pathways relevant to the pathophysiology of airways diseases. (Fig. 1)

The UPR pathway responsible for the ER/Ca2+i stores is mediated by IRE1a-dependent mRNA splicing (activation) of the transcription factor X-box binding protein 1 (XBP-1). Indeed, native CF human airway epithelia exhibit up-regulation of IRE1a-dependent XBP-1 mRNA splicing coupled with up-regulation of ER/Ca2+i stores (Fig 2). Up-regulation of ER/Ca2+i stores is also a feature of native COPD human airway epithelia (Fig 2). Further studies in our lab have also implicated airway epithelia inflammation with the activation of an additional UPR pathway mediated by activating transcription factor 4 (ATF4). Activation of ATF4 is relevant to inflammatory responses, since ATF4 confers protection against oxidative stress, induces amino acid transport, and improves cellular metabolism and survival. Our current model for the roles of XBP-1 and ATF4 in airway epithelial inflammatory responses in shown in Figure 3.

The alterations in ER signaling resulting from activation of the UPR can have additional consequences for the cell biology of inflamed airway epithelia. For example, we have also reported that mitochondria are in close proximity to ER/Ca2+i stores and buffer ER/Ca2+i signals triggered by mucosal inflammatory mediators in human airway epithelia. Because mitochondrial respiration is a major source of intracellular reactive oxygen species (ROS), and mitochondrial ER/Ca2+i uptake stimulates mitochondrial respiration-dependent ROS production, we have addressed whether a direct correlation between the magnitude of ER/Ca2+i signals and the mitochondrial generation of ROS exists in inflamed airway epithelia. Our current findings suggest that the increased ER/Ca2+i signals resulting from ER/Ca2+i store expansion couple to a larger ER/Ca2+i mediated mitochondrial generation of ROS in inflamed airway epithelia. These alterations are relevant to oxidative stress responses of inflamed CF airways.

An important aspect of our research has been the development of a new model of CF airway epithelial inflammation, consisting of exposing normal airway epithelia to supernatant from mucopurulent material (SMM) from human CF airways. This model has been initially used to test the anti-inflammatory action of the macrolide antibiotic azithromycin, and has been subsequently used to test additional macrolides for anti-inflammatory effects. Please see below the additional studies we have initiated utilizing the SMM model.

A key feature of our research involving UPR activation and airway inflammation deals with a hallmark of chronic inflammation in CF, COPD and asthmatic airways, e.g., the overproduction of mucins (Fig 4). We have published in Mucosal Immunology that the IRE1 isoform, IRE1B, is specifically expressed in mucous cells (Fig. 5) and is required for airway mucin production. These findings offer the proof of concept that IRE1B is a novel therapeutic target for the mucus overproduction characteristic of CF, COPD and asthmatic airways.

Our latest published research has uncovered a key role for the IRE1a/XBP-1 pathway in mediating hyper-inflammatory responses of human CF alveolar macrophages.

We are currently investigating the functional role of additional branches of the UPR in other aspects of pulmonary inflammation, and in cigarette smoke-induced alterations in airway epithelial function. Our long-term goal is to establish the functional importance of UPR activation in airway inflammation by performing translational studies relevant to human airway diseases, including CF, COPD and asthma. These studies will likely lead to new therapies for these pulmonary diseases, based on targeting UPR pathways.

Cartoon diagram depicting UPR pathways in mammalian cells
Figure 1. UPR pathways in mammalian cells. From Ribeiro and O鈥橬eal (2012): ER Stress in Chronic Obstructive Lung Diseases. Curr Mol Med. 12:872-82.
Microscopy images of human bronchial airway epithelia, more fully described in the figure caption
Figure 2. Native human CF and COPD bronchial airway epithelia exhibit up-regulation of ER Ca2+ stores. A: XBP-1 mRNA splicing in freshly isolated CF vs. normal bronchial epithelia. B: Expression of the ER Ca2+ store markers calreticulin and IP3 receptors in normal and CF native eptheilia. C: Calreticulin expression in normal and COPD epithelia. Modified from Ribeiro and O鈥橬eal (2012): ER Stress in Chronic Obstructive Lung Diseases. Curr Mol Med. 12:872-82.
A series of cartoon diagrams depicting the processes that are more fully described in the figure caption
Figure 3. Model linking airway epithelial infection/inflammation (step 1)-induced UPR activation and the resulting adaptive responses (step 2) mediated by XBP-1 and ATF4 that are relevant for airway epithelial inflammatory responses. From Ribeiro and Boucher (2010): Role of endoplasmic reticulum stress in cystic fibrosis-related airway inflammatory responses. Proc. Am. Thorac. Soc. 7:387-94.
Immunofluorescent image of human COPD bronchial airway epithelia,more fully described in the figure caption
Figure 4. Native human COPD bronchial airway epithelia exhibiting mucous cell metaplasia. The immunofluorescent stains of MUC5AC and the ER marker calreticulin are depicted in green and red, respectively. Image from C. Ribeiro.
Microscopy images of inflamed CF human bronchial epithelia, more fully described in the figure caption
Figure 5. IRE1尾 expression is up-regulated in mucous cells from native inflamed CF human bronchial epithelia. IRE1尾 immunostain in normal and CF human bronchial epithelia. From Martino et al (2013): The ER Stress Transducer IRE1尾 is Required for Airway Epithelial Mucin Production. Mucosal Immunol. 6(3):639-54.

Selected Bibliography:

  1. Gentzsch M, Esther CR Jr, Ribeiro CMP. . Lancet Respir Med. 2024 Nov;12(11):e67. doi: 10.1016/S2213-2600(24)00305-9. PMID: 39395437.
  2. Asakura T, Okuda K, Chen G, Dang H, Kato T, Mikami Y, Schworer SA, Gilmore RC, Radicioni G, Hawkins P, Barbosa Cardenas SM, Saito M, Cawley AM, De la Cruz G, Chua M, Alexis NE, Masugi Y, Noone PG, Ribeiro CMP, Kesimer M, Olivier KN, Hasegawa N, Randell SH, O’Neal WK, Boucher RC. . Am J Respir Crit Care Med.2024 Feb 15;209(4):374-389. doi: 10.1164/rccm.202306-1093OC. PMID: 38016030. PMCID: PMC10878387.
  3. Gentzsch M, Baker B, Cholon DM, Kam CW, McKinzie CJ, Despotes KA, Boyles SE, Quinney NL, Esther CR Jr, Ribeiro CMP. . ERJ Open Res. 2024 Jan 15;10(1):00746-2023. doi: 10.1183/23120541.00746-2023. PMID: 38226069; PMCID: PMC10789252.
  4. Cholon DM, Greenwald MA, Higgs MG, Quinney NL, Boyles SE, Meinig SL, Minges JT, Chaubal A, Tarran R, Ribeiro CMP, Wolfgang MC, Gentzsch M. . Cells. 2023 Nov 13;12(22):2618. doi: 10.3390/cells12222618. PMID: 37998353; PMCID: PMC10670530.
  5. Ribeiro CMP, Higgs MG, Muhlebach MS, Wolfgang MC, Borgatti M, Lampronti I, Cabrini G. . Int J Mol Sci. 2023 Mar 5;24(5):5010. doi: 10.3390/ijms24055010. PMID: 36902441; PMCID: PMC10003689.
  6. Ribeiro CMP, Gentzsch M. . Curr Opin Pharmacol. 2022 Dec;67:102289. doi: 10.1016/j.coph.2022.102289. PMID: 36152600.
  7. Figueira MF, Ribeiro CMP, Button B. . Curr Opin Pharmacol. 2022 Aug;65:102248. doi: 10.1016/j.coph.2022.102248. PMID: 35689870. PMCID: PMC9891491.
  8. Ribeiro CMP, Hull-Ryde EA. . Curr Opin Pharmacol. 2022 Aug;65:102258. doi: 10.1016/j.coph.2022.102258. PMID: 35749907.
  9. Davis ES, Ghosh A, Coakley RD, Wrennall JA, Lubamba BA, Rowell TR, Dang H, Pawlak EA, Li Q, Alexis NE, Ribeiro CMP, Tarran R. . Nicotine Tob Res. 2022 Feb 14;24(3):395-399. doi: 10.1093/ntr/ntab186. PMID: 34519792; PMCID: PMC8842413.
  10. Ribeiro CMP, Gentzsch M. . Cells. 2021 Nov 22;10(11):3260. doi: 10.3390/cells10113260. PMID: 34831482; PMCID: PMC8619863.
  11. Ribeiro CMP, McElvaney NG, Cabrini G. . Front Pharmacol. 2021 Nov 4;12:794854. doi: 10.3389/fphar.2021.794854. PMID: 34867428; PMCID: PMC8632627.
  12. Gentzsch M, Cholon DM, Quinney NL, Martino MEB, Minges JT, Boyles SE, Guhr Lee TN, Esther CR Jr, Ribeiro CMP. . Front Pharmacol. 2021 Mar 30;12:628722. doi: 10.3389/fphar.2021.628722. PMID: 33859562; PMCID: PMC8042279.
  13. Hull-Ryde EA, Minges JT, Martino MEB, Kato T, Norris-Drouin JL, Ribeiro CMP. . Int J Mol Sci. 2021 Mar 17;22(6):3063. doi: 10.3390/ijms22063063. PMID: 33802742; PMCID: PMC8002512.
  14. Rimessi A, Pozzato C, Carparelli L, Rossi A, Ranucci S, De Fino I, Cigana C, Talarico A, Wieckowski MR, Ribeiro CMP, Trapella C, Rossi G, Cabrini G, Bragonzi A, Pinton P. . Sci Adv. 2020 May 6;6(19):eaax9093. doi: 10.1126/sciadv.aax9093. PMID: 32494695; PMCID: PMC7202873.
  15. Amatngalim GD, Ribeiro CMP. . Eur Respir J. 2020 Apr 16;55(4):2000466. doi: 10.1183/13993003.00466-2020. PMID: 32300022.
  16. O’Neal WK, Ribeiro CMP. . Am J Respir Cell Mol Biol. 2020 Mar;62(3):279-280. doi: 10.1165/rcmb.2019-0360ED. PMID: 31633992; PMCID: PMC7055690.
  17. Murphy SV, Ribeiro CMP. Am J Respir Cell Mol Biol. 2019 Sep;61(3):273-274. doi: 10.1165/rcmb.2019-0107ED. PMID: 30951377; PMCID: PMC6839932.
  18. Chen G, Ribeiro CMP, Sun L, Okuda K, Kato T, Gilmore RC, Martino MB, Dang H, Abzhanova A, Lin JM, Hull-Ryde EA, Volmer AS, Randell SH, Livraghi-Butrico A, Deng Y, Scherer PE, Stripp BR, O’Neal WK, Boucher RC. . Am J Respir Crit Care Med. 2019 Jul 15;200(2):220-234. doi: 10.1164/rccm.201810-1972OC. Erratum in: Am J Respir Crit Care Med. 2019 Oct 15;200(8):1074. PMID: 30973754; PMCID: PMC6635783.
  19. Gentzsch M, Cholon DM, Quinney NL, Boyles SE, Martino MEB, Ribeiro CMP. . Eur Respir J. 2018 Dec 20;52(6):1801133. doi: 10.1183/13993003.01133-2018. PMID: 30287473; PMCID: PMC6482470.
  20. Webster MJ, Reidel B, Tan CD, Ghosh A, Alexis NE, Donaldson SH, Kesimer M, Ribeiro CMP, Tarran R. . Eur Respir J. 2018 Oct 4;52(4):1800668. doi: 10.1183/13993003.00668-2018. PMID: 30190268; PMCID: PMC6547379.
  21. Rimessi A, Bezzerri V, Salvatori F, Tamanini A, Nigro F, Dechecchi MC, Santangelo A, Prandini P, Munari S, Provezza L, Garreau de Loubresse N, Muller J, Ribeiro CMP, Lippi G, Gambari R, Pinton P, Cabrini G. . Am J Respir Cell Mol Biol. 2018 Oct;59(4):428-436. doi: 10.1165/rcmb.2017-0267OC. PMID: 29668297.
  22. Abdullah LH, Coakley R, Webster MJ, Zhu Y, Tarran R, Radicioni G, Kesimer M, Boucher RC, Davis CW, Ribeiro CMP. . Am J Respir Crit Care Med. 2018 Feb 15;197(4):481-491. doi: 10.1164/rccm.201706-1139OC. PMID: 29099608; PMCID: PMC5821906.
  23. Ribeiro CM, Lubamba BA. . Int J Mol Sci. 2017 Jan 9;18(1):118. doi: 10.3390/ijms18010118. PMID: 28075361; PMCID: PMC5297752.
  24. Lubamba BA, Jones LC, O’Neal WK, Boucher RC, Ribeiro CM. . Am J Respir Crit Care Med. 2015 Dec 15;192(12):1449-61. doi: 10.1164/rccm.201504-0657OC. PMID: 26331676; PMCID: PMC4731720.
  25. Zhu Y, Abdullah LH, Doyle SP, Nguyen K, Ribeiro CM, Vasquez PA, Forest MG, Lethem MI, Dickey BF, Davis CW. . PLoS One. 2015 May 29;10(5):e0127267. doi: 10.1371/journal.pone.0127267. PMID: 26024524; PMCID: PMC4449158.
  26. Okada SF, Ribeiro CM, Sesma JI, Seminario-Vidal L, Abdullah LH, van Heusden C, Lazarowski ER, Boucher RC. . Am J Respir Cell Mol Biol. 2013 Nov;49(5):814-20. doi: 10.1165/rcmb.2012-0493OC. PMID: 23763446; PMCID: PMC3931099.
  27. Martino MB, Jones L, Brighton B, Ehre C, Abdulah L, Davis CW, Ron D, O’Neal WK, Ribeiro CM. . Mucosal Immunol. 2013 May;6(3):639-54. doi: 10.1038/mi.2012.105. PMID: 23168839; PMCID: PMC4031691.
  28. Ribeiro CM, O’Neal WK. . Curr Mol Med. 2012 Aug;12(7):872-82. doi: 10.2174/156652412801318791. PMID: 22697344.
  29. Ribeiro CM, Boucher RC. . Proc Am Thorac Soc. 2010 Nov;7(6):387-94. doi: 10.1513/pats.201001-017AW. PMID: 21030518; PMCID: PMC3136959.
  30. Ribeiro CM, Hurd H, Wu Y, Martino ME, Jones L, Brighton B, Boucher RC, O’Neal WK. . PLoS One. 2009 Jun 5;4(6):e5806. doi: 10.1371/journal.pone.0005806. PMID: 19503797; PMCID: PMC2688381.
  31. Martino ME, Olsen JC, Fulcher NB, Wolfgang MC, O’Neal WK, Ribeiro CM. . J Biol Chem. 2009 May 29;284(22):14904-13. doi: 10.1074/jbc.M809180200. PMID: 19321437; PMCID: PMC2685672.
  32. Livraghi A, Mall M, Paradiso AM, Boucher RC, Ribeiro CM. M. Am J Respir Cell Mol Biol. 2008 Apr;38(4):423-34. doi: 10.1165/rcmb.2007-0177OC. PMID: 17989361; PMCID: PMC2274946.
  33. Ribeiro CM, Paradiso AM, Schwab U, Perez-Vilar J, Jones L, O’neal W, Boucher RC. . J Biol Chem. 2005 May 6;280(18):17798-806. doi: 10.1074/jbc.M410618200. PMID: 15746099.
  34. Ribeiro CM, Paradiso AM, Carew MA, Shears SB, Boucher RC. . J Biol Chem. 2005 Mar 18;280(11):10202-9. doi: 10.1074/jbc.M410617200. PMID: 15647273.
Headshot of Carla Maria Pedrosa Ribeiro