There are more than 130 therapeutic proteins or peptides that are used to treat a broad range of illnesses. One of these proteins, tissue plasminogen activator (tPA), has been used to treat myocardial infarction and stroke. Professor Kathleen Stringer's laboratory has determined that in addition to its proteolytic function, tPA has anti-inflammatory activity. The combination of these two properties could make tPA a viable therapeutic candidate for treating inflammatory-fibrotic lung diseases, such as acute respiratory distress syndrome (ARDS), idiopathic pulmonary fibrosis (IPF), and plastic bronchitis (PB), a rare, typically pediatric, disease. To this end, the Stringer laboratory has developed a formulation of tPA (pf-tPA) for targeted pulmonary delivery and is focused on three main areas of research: pulmonary delivery of therapeutic proteins, pathogenesis of inflammatory-fibrin lung diseases, and mechanisms and disposition of therapeutic proteins in inflammatory lung disease.
- Pulmonary Delivery of Therapeutic Proteins
Candidate therapeutic proteins are formulated for pulmonary delivery using a range of assays to assess protein stability. Aerodynamic particle size and biological function following nebulization are measured to ensure the feasibility of candidate formulations. Respiratory deposition is also characterized in experimental models of pulmonary dosing and of acute lung injury (ALI) in order to gather pharmacodynamic, pharmacokinetic, toxicological, and therapeutic response data. Collectively, this line of investigation enables the Stringer laboratory to test the feasibility of local pulmonary delivery of therapeutic proteins in humans.
- Pathogenesis of Inflammatory-Fibrin Lung Diseases
Pulmonary illnesses, such as acute lung injury (ALI), ARDS, IPF, and PB, are clinically challenging for a number of reasons, including poor understanding of complex physiology and patient heterogeneity. The absence of biomarkers that predict disease onset, progression, and severity has had a negative impact on our ability to identify and develop effective pharmacotherapy aimed at improving morbidity and mortality in patients with critical illness. The Stringer research group is utilizing a broad systems-biology approach that encompasses metabolomics, transcriptomics, and genomics together with the powerful tool of computational analysis. The work is aimed at identifying metabolic structures of ALI and PB.
- Mechanisms and Disposition of Therapeutic Proteins in Inflammatory Lung Disease
Inflammatory lung disease is a significant risk to human health. Presently, the Stringer lab is focusing on the use of pf-tPA for the treatment of PB: We are optimizing dosing strategies using ex vivo approaches that utilize casts from patients with PB. In addition, the lab is developing an animal model of PB that encompasses elements of derangement of the fibrinolytic and inflammatory systems so that a more accurate assessment of pf-tPA efficacy and safety in the treatment of PB can be made.
Selected publications from the Stringer lab
Min KA, Talattof A, Tsume Y, Stringer KA, Yu JY, Lim DH, Rosania GR. The extracellular microenvironment explains variations in passive drug transport across different airway epithelial cell types. Pharm Res. 2013 Aug;30(8):2118-32. doi: 10.1007/s11095-013-1069-5. Epub 2013 May 25.
Brooks K, Caruthers RL, Schumacher KR, Stringer KA. Pharmacotherapy challenges of Fontan-associated plastic bronchitis: a rare pediatric disease. Pharmacotherapy. 2013 Sep;33(9):922-34. doi: 10.1002/phar.1290. Epub 2013 May 17.
Racz J, Mane G, Ford M, Schmidt L, Myers J, Standiford TJ, Schumacher KR, Fifer C, Russell MW, Stringer KA. Immunophenotyping and protein profiling of Fontan-associated plastic bronchitis airway casts. Ann Am Thorac Soc. 2013 Apr;10(2):98-107. doi: 10.1513/AnnalsATS.201209-080OC.
Yuan ST, Ellingrod VL, Schipper M, Stringer KA, Cai X, Hayman JA, Yu J, Lawrence TS, Kong FM. Genetic variations in TGFβ1, tPA, and ACE and radiation-induced thoracic toxicities in patients with non-small-cell lung cancer. J Thorac Oncol. 2013 Feb;8(2):208-13. doi: 10.1097/JTO.0b013e318274592e.
Baik J, Stringer KA, Mane G, Rosania GR. Multiscale distribution and bioaccumulation analysis of clofazimine reveals a massive immune system-mediated xenobiotic sequestration response. Antimicrob Agents Chemother. 2013 Mar;57(3):1218-30. doi: 10.1128/AAC.01731-12. Epub 2012 Dec 21.
Caruthers RL, Kempa M, Loo A, Gulbransen E, Kelly E, Erickson SR, Hirsch JC, Schumacher KR, Stringer KA. Demographic characteristics and estimated prevalence of Fontan-associated plastic bronchitis. Pediatr Cardiol. 2013 Feb;34(2):256-61. doi: 10.1007/s00246-012-0430-5. Epub 2012 Jul 15.
Yu JY, Zheng N, Mane G, Min KA, Hinestroza JP, Zhu H, Stringer KA, Rosania GR. A cell-based computational modeling approach for developing site-directed molecular probes. PLoS Comput Biol. 2012;8(2):e1002378. doi: 10.1371/journal.pcbi.1002378. Epub 2012 Feb 23.
Suresh MV, Wagner MC, Rosania GR, Stringer KA, Min KA, Risler L, Shen DD, Georges GE, Reddy AT, Parkkinen J, Reddy RC. Pulmonary administration of a water-soluble curcumin complex reduces severity of acute lung injury. Am J Respir Cell Mol Biol. 2012 Sep;47(3):280-7. doi: 10.1165/rcmb.2011-0175OC. Epub 2012 Feb 3.
Karnovsky A, Weymouth T, Hull T, Tarcea VG, Scardoni G, Laudanna C, Sartor MA, Stringer KA, Jagadish HV, Burant C, Athey B, Omenn GS. Metscape 2 bioinformatics tool for the analysis and visualization of metabolomics and gene expression data. Bioinformatics. 2012 Feb 1;28(3):373-80. doi: 10.1093/bioinformatics/btr661. Epub 2011 Nov 30.
Heath L, Ling S, Racz J, Mane G, Schmidt L, Myers JL, Tsai WC, Caruthers RL, Hirsch JC, Stringer KA. Prospective, longitudinal study of plastic bronchitis cast pathology and responsiveness to tissue plasminogen activator. Pediatr Cardiol. 2011 Dec;32(8):1182-9. doi: 10.1007/s00246-011-0058-x. Epub 2011 Jul 24.
For a complete list of Prof. Stringer's publications, please see PubMed.