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Matthew Markovetz, PhD

Research Associate

Specialty Areas:

Mucus biophysics and liquid and ion transport that regulate mucus properties and clearance

Chronology:

BS, Chemical and Biological Engineering, University of Colorado at Boulder (2012).

PhD, Chemical Engineering, University of Pittsburgh (2016).

Postdoctoral Fellow, Cystic Fibrosis and Pulmonary Research Center, University of North Carolina at Chapel Hill (2017-2020).

Research Associate, Cystic Fibrosis and Pulmonary Research Center, University of North Carolina at Chapel Hill (2020-present).

Research Focus:

Mucus serves as a protective barrier at the interface of all “wet” epithelia. Whether in the reproductive and GI tracts, the eyes, or the respiratory system – including the lung, which is our primary organ of focus – mucus functions to protect the epithelium from harmful elements like toxins and pathogens. From a basic science perspective, mucus is a biopolymeric gel composed of thousands of different components, but the primary biopolymers that regulate its properties are a class of extraordinarily large and long proteins called mucins. In the lung specifically, mucus composed mostly of the mucin MUC5B traps inhaled pathogens and particulate matter, preventing their access to airway cells while the mucus is efficiently transported up and out of the airways by way of ciliary action. This mucociliary clearance (MCC) system is critical to health, and defects in any of its individual components can cause disease. For example, primary ciliary dyskinesia results from defective or absent ciliary action. With regard to our research in mucus, the airway pathology of cystic fibrosis (CF) is characterized by the accumulation of mucus that becomes abnormally sticky and viscous. In fact, CF has also been referred to historically as mucoviscidosis of the lung. Asthma and COPD are also noteworthy diseases that feature mucus abnormalities.

In the case of CF, mucus becomes hyperviscous because its components become hyperconcentrated due to the dysfunctional or absent chloride water secretion caused by a mutation in the cystic fibrosis transmembrane conductance regulator protein. In particular, levels of MUC5B and its inflammatory counterpart MUC5AC become elevated and proportionately more MUC5AC is produced. This induces a feedback cycle of inflammation and further mucus production, which in the absence of liquid secretion, leads to MCC failure and airway obstruction. In our lab, we characterize how these changes in mucus concentration and composition affect its biophysical properties through rheological studies at the macro and microscale. By studying the effect of concentration on viscoelasticity we are able to predict the extent to which hyperconcentration affects MCC negatively and propose and study therapeutic pathways that may decrease the mucus burden on the MCC system. Similarly, we are able to study how therapeutics that aim to break up the chemical linkages with the mucus gel may also affect the viscoelasticity and clearability of mucus. Furthermore, by applying fundamental mathematical and engineering perspectives toward the study of mucus, we are able to robustly characterize mucus despite the heterogeneities inherent to most mucus sample types and their means of acquisition. Ultimately we seek to provide translational knowledge regarding the fundamental behavior of mucus as polymer gel to how it affects human health and disease.

Selected Bibliography:

  1. Rouillard KR, Esther CP, Kissner WJ, Plott LM, Bowman DW, Markovetz MR, Hill DB. Combination treatment to improve mucociliary transport of Pseudomonas aeruginosa biofilms. PLoS One. 2024 Feb 23;19(2):e0294120. doi: 10.1371/journal.pone.0294120. PMID: 38394229; PMCID: PMC10890754.
  2. Donoghue LJ, Markovetz MR, Morrison CB, Chen G, McFadden KM, Sadritabrizi T, Gutay MI, Kato T, Rogers TD, Snead JY, Livraghi-Butrico A, Button B, Ehre C, Grubb BR, Hill DB, Kelada SNP. BPIFB1 loss alters airway mucus properties and diminishes mucociliary clearance. Am J Physiol Lung Cell Mol Physiol. 2023 Dec 1;325(6):L765-L775. doi: 10.1152/ajplung.00390.2022. PMID: 37847709.
  3. Ozeri-Galai E, Friedman L, Barchad-Avitzur O, Markovetz MR, Boone W, Rouillard KR, Stampfer CD, Oren YS, Hill DB, Kerem B, Hart G. Delivery Characterization of SPL84 Inhaled Antisense Oligonucleotide Drug for 3849 + 10 kb C- > T Cystic Fibrosis Patients. Nucleic Acid Ther. 2023 Oct;33(5):306-318. doi: 10.1089/nat.2023.0015. PMID: 37643307.
  4. Markovetz MR, Hibbard JE, Plott LM, Bacudio LG, Kissner WJ, Ghio A, Kumar PA, Arora H, Hill DB. Normalizing salt content by mixing native human airway mucus samples normalizes sample rheology. Front Physiol. 2023 Mar 10;14:1111647. doi: 10.3389/fphys.2023.1111647. PMID: 36969580; PMCID: PMC10036356.
  5. Rouillard KR, Markovetz MR, Kissner WJ, Boone WL, Plott LM, Hill DB. Altering the viscoelastic properties of mucus-grown Pseudomonas aeruginosa biofilms affects antibiotic susceptibility. Biofilm. 2023 Jan 21;5:100104. doi: 10.1016/j.bioflm.2023.100104. PMID: 36711323; PMCID: PMC9880403.
  6. Markovetz MR, Garbarine IC, Morrison CB, Kissner WJ, Seim I, Forest MG, Papanikolas MJ, Freeman R, Ceppe A, Ghio A, Alexis NE, Stick SM, Ehre C, Boucher RC, Esther CR, Muhlebach MS, Hill DB. Mucus and mucus flake composition and abundance reflect inflammatory and infection status in cystic fibrosis. J Cyst Fibros. 2022 Nov;21(6):959-966. doi: 10.1016/j.jcf.2022.04.008. PMID: 35437233.
  7. Rouillard KR, Kissner WJ, Markovetz MR, Hill DB. Effects of Mucin and DNA Concentrations in Airway Mucus on Pseudomonas aeruginosa Biofilm Recalcitrance. mSphere. 2022 Aug 31;7(4):e0029122. doi: 10.1128/msphere.00291-22. PMID: 35968965; PMCID: PMC9429933.
  8. Wykoff JA, Shaffer KM, Araba KC, Markovetz MR, Patarin J, Robert de Saint Vincent M, Donaldson SH, Ehre C. Rapid Viscoelastic Characterization of Airway Mucus using a Benchtop Rheometer. J Vis Exp. 2022 Apr 21;(182). doi: 10.3791/63876. PMID: 35532240.
  9. Kato T, Radicioni G, Papanikolas MJ, Stoychev GV, Markovetz MR, Aoki K, Porterfield M, Okuda K, Barbosa Cardenas SM, Gilmore RC, Morrison CB, Ehre C, Burns KA, White KK, Brennan TA, Goodell HP, Thacker H, Loznev HT, Forsberg LJ, Nagase T, Rubinstein M, Randell SH, Tiemeyer M, Hill DB, Kesimer M, O’Neal WK, Ballard ST, Freeman R, Button B, Boucher RC. Mucus concentration-dependent biophysical abnormalities unify submucosal gland and superficial airway dysfunction in cystic fibrosis. Sci Adv. 2022 Apr;8(13):eabm9718. doi: 10.1126/sciadv.abm9718. PMID: 35363522.
  10. Morrison CB, Shaffer KM, Araba KC, Markovetz MR, Wykoff JA, Quinney NL, Hao S, Delion MF, Flen AL, Morton LC, Liao J, Hill DB, Drumm ML, O’Neal WK, Kesimer M, Gentzsch M, Ehre C. Treatment of cystic fibrosis airway cells with CFTR modulators reverses aberrant mucus properties via hydration. Eur Respir J. 2022 Feb 3;59(2):2100185. doi: 10.1183/13993003.00185-2021. PMID: 34172469. PMCID: PMC8859811.
  11. Ford AG, Cao XZ, Papanikolas MJ, Kato T, Boucher RC, Markovetz MR, Hill DB, Freeman R, Forest MG. Molecular Dynamics Simulations to Explore the Structure and Rheological Properties of Normal and Hyperconcentrated Airway Mucus. Stud Appl Math. 2021 Nov;147(4):1369-1387. doi: 10.1111/sapm.12433. PMID: 35221375; PMCID: PMC8871504.
  12. Sears PR, Bustamante-Marin XM, Gong H, Markovetz MR, Superfine R, Hill DB, Ostrowski LE. Induction of ciliary orientation by matrix patterning and characterization of mucociliary transport. Biophys J. 2021 Apr 20;120(8):1387-1395. doi: 10.1016/j.bpj.2021.01.041. PMID: 33705757. PMCID: PMC8105732.
  13. Rouillard KR, Markovetz MR, Bacudio LG, Hill DB, Schoenfisch MH. Pseudomonas aeruginosa Biofilm Eradication via Nitric Oxide-Releasing Cyclodextrins. ACS Infect Dis. 2020 Jul 10;6(7):1940-1950. doi: 10.1021/acsinfecdis.0c00246. PMID: 32510928.
  14. Morrison CB, Markovetz MR, Ehre C. Mucus, mucins, and cystic fibrosis. Pediatr Pulmonol. 2019 Nov;54 Suppl 3(Suppl 3):S84-S96. doi: 10.1002/ppul.24530. PMID: 31715083; PMCID: PMC6853602.
  15. Markovetz M, Subramani D, Kissner W, Morrison C, Garbarine I, Ghio A, Ramsey K, Arora H, Kumar P, Nix D, Kumagai T, Krunkosky T, KrauseD , Radicioni G, Alexis N, Kesimer M, Tiemeyer M, Boucher RC, Ehre C, Hill D. Endotracheal tube mucus as a source of airway mucus for rheological study. Am J Physiol Lung Cell Mol Physiol. 2019 Oct 1;317(4):L498-L509. doi: 10.1152/ajplung.00238.2019. PMID: 31389736. PMCID: PMC6842913.
  16. Esther CR Jr, Muhlebach MS, Ehre C, Hill DB, Wolfgang MC, Kesimer M, Ramsey KA, Markovetz MR, Garbarine IC, Forest MG, Seim I, Zorn B, Morrison CB, Delion MF, Thelin WR, Villalon D, Sabeter JR, Turkovic L, Ranganathan S, Stick SM, Boucher RC, on behalf of AREST CF. Mucus accumulation in the lungs precedes structural changes and infection in children with cystic fibrosis. Sci Transl Med. 2019 Apr 3;11(486). doi: 10.1126/scitranslmed.aav3488. PMID: 30944166. PMCID: PMC6566903.
  17. Ehre C, Rushton ZL, Wang B, Hothem LN, Morrison CB, Fontana NC, Markovetz MR, Delion MF, Kato T, Villalon D, Thelin WR, Esther CR Jr., Hill DB, Grubb BR, Livraghi-Butrico A, Donaldson SH, Boucher RC. An improved inhaled mucolytic to treat airway muco-obstructive diseases. Am J Respir Crit Care Med. 2019 Jan 15;199(2):171-180. doi: 10.1164/rccm.201802-0245OC. PMID: 30212240. PMCID: PMC6353008.
  18. Hancock LA, Hennessy CE, Solomon GM, Dobrinskikh E, Estrella A, Hara N, Hill DB, Kissner WJ, Markovetz MR, Grove Villalon DE, Voss ME, Tearney GJ, Carroll KS, Shi Y, Schwarz MI, Thelin WR, Rowe SM, Yang IV, Evans CM, Schwartz DA. Muc5b overexpression causes mucociliary dysfunction and enhances lung fibrosis in mice. Nat Commun. 2018 Dec 18;9(1):5363. doi: 10.1038/s41467-018-07768-9. PMID: 30560893; PMCID: PMC6299094.
  19. Hill DB, Long RF, Kissner WJ, Atieh E, Garbarine IC, Markovetz MR, Fontana NC, Christy M, Habibpour M, Tarran R, Forest MG, Boucher RC, Button B. Pathological Mucus and Impaired Mucus Clearance in Cystic Fibrosis Patients Results from Increased Concentration, not altered pH. Eur Respir J. 2018 Dec 6;52(6). doi: 10.1183/13993003.01297-2018. PMID: 30361244. PMCID: PMC6446239.
  20. Corcoran TE, Godovchik JE, Donn KH, Busick DR, Goralski J, Locke LW, Markovetz MR, Myerburg MM, Muthukrishnan A, Weber L, Lacy RT, Pilewski JM. Overnight delivery of hypertonic saline by nasal cannula aerosol for cystic fibrosis. Pediatr Pulmonol. 2017 Sep;52(9):1142-1149. doi: 10.1002/ppul.23749. PMID: 28737262; PMCID: PMC5561478.
  21. Locke LW, Myerburg MM, Weiner DJ, Markovetz MR, Parker RS, Muthukrishnan A, Weber L, Czachowski MR, Lacy RT, Pilewski JM, Corcoran TE. Pseudomonas infection and mucociliary and absorptive clearance in the cystic fibrosis lung. Eur Respir J. 2016 May;47(5):1392-401. doi: 10.1183/13993003.01880-2015. PMID: 27009167; PMCID: PMC5516211.
  22. Markovetz MR, Corcoran TE, Locke LW, Myerburg MM, Pilewski JM, Parker RS. A physiologically-motivated compartment-based model of the effect of inhaled hypertonic saline on mucociliary clearance and liquid transport in cystic fibrosis. PLoS One. 2014 Nov 10;9(11):e111972. doi: 10.1371/journal.pone.0111972. PMID: 25383714; PMCID: PMC4226497.
  23. Locke LW, Myerburg MM, Markovetz MR, Parker RS, Weber L, Czachowski MR, Harding TJ, Brown SL, Nero JA, Pilewski JM, Corcoran TE. Quantitative imaging of airway liquid absorption in cystic fibrosis. Eur Respir J. 2014 Sep;44(3):675-84. doi: 10.1183/09031936.00220513. PMID: 24743971; PMCID: PMC4150848.
Matthew Markovetz, PhD