Chronic respiratory disease (CRD) is the third leading cause of death affecting approximately 7.4% of the world population causing an estimated 4 million premature deaths annually. Air pollution, smoking and other occupational and environmental exposures are major risk factors for CRD and to this end, have a detrimental impact on the health of billions of people. Obstructive lung diseases (ObLD) are some of the most common conditions, including chronic obstructive pulmonary disease (COPD) and asthma. ObLD are extremely heterogeneous conditions, driven by diverse cell and molecular mechanisms, which are influenced by exposure history and genetics.
Our research focuses on the cell and molecular mechanisms of ObLD, with a special focus on alarmin/DAMP signaling in asthma. Much of our recent work has focused on investigating the role of the receptor for advanced glycation endproducts (RAGE) in human cell and mouse models of asthma/allergic airway disease. Asthma is extremely heterogeneous in terms of inflammatory phenotype and disease severity, in which several sub-phenotypes are resistant to conventional therapies without any effective biologic treatments available. We leverage a diverse range of mouse models of asthma, which exhibit the heterotypic features of inflammation, mucus metaplasia, airway remodeling and airway hyperresponsiveness seen in human asthma. We seek to define molecular mechanisms which drive the pathologic features of asthma and other ObLD, in effort to develop novel preventative and therapeutic intervention strategies.
Currently, our research also has several collaborative projects both within the University of Pittsburgh community and externally. This includes investigating the mechanisms driving inflammation in respiratory syncytial virus infection, and asthma exacerbation with Dr. Kerry Empey (University of Pittsburgh, School of Pharmacy). We are also collaborating with Dr. Richard Johnston (National Institutes of Occupational Safety and Health), to examine molecular mechanisms of Ozone-mediated lung injury and ObLD exacerbation and Arrowhead Pharmaceuticals investigating RAGE-mediated asthma pathology.
Full list of publications (Pubmed): https://www.ncbi.nlm.nih.gov/myncbi/14ODq3JBfpAkz/bibliography/public/
Representative Research Articles:
Kosanovich JL, Eichinger KM, Lipp MA, Gidwani SV, Brahmbhatt D, Yondola M, Chi DH, Perkins TN, Empey KM. Lung ILC2s are activated in BALB/c mice born to immunized mothers despite complete protection against respiratory syncytial virus. Front Immunol. 2024 May DOI 10.3389/fimmu.2024.1374818.
Killian KN, Kosanovich JL, Lipp MA, Empey KM, Oury TD, Perkins TN. RAGE contributes to allergen driven severe neutrophilic airway inflammation in mice. Front Immunol. 2023 Jan 26;14:1039997.
Perkins TN, Oczypok EA, Dutz RE, Donnell ML, Myerburg MM, Oury TD. The receptor for advanced glycation endproducts is a critical mediator of type 2 cytokine signaling in the lungs. J Allergy and Clin Immunol. 2019 Sep;144(3):796-808.e12 (*Featured in an editorial in the same issue)
Perkins TN, Oczypok EA, Milutinovic PS, Dutz RE, Oury TD. RAGE-dependent VCAM-1 expression in the lung endothelium mediates IL-33 induced allergic airway inflammation. Allergy. 2019 Jan;74(1):89-99
Perkins TN, Peeters PM, Albrecht C, Schins RP, Stassen FR, Dentener MA, Wouters EFM, Reynaert NL. Crystalline silica alters Sulfatase-1 expression in rat lungs which influences hyper-proliferative and fibrogenic effects in lung epithelial cells. Toxicol Appl Pharmacol. 2018 Jun 1;348:43-53
Perkins TN, Peeters PM, Shukla A, Arijs A, Dragon J, Wouters EF, Reynaert NL, Mossman BT. Indications for distinct pathogenic mechanisms of asbestos and silica through gene expression profiling of the response of human lung epithelial cells. Hum Mol Genet. 2015 Mar 1;24(5):1374-89
Perkins TN, Shukla A, Peeters PM, Steinbacher JL, Landry CC, Lathrop SA, Steele C, Reynaert NL, Wouters EFM, Mossman BT. Differences in Gene Expression and Cytokine Production by Crystalline vs. Amorphous Silica in Human Lung Epithelial Cells. Part Fibre Toxicol. 2012 Feb 2;9:1
Recent Reviews of Current Interests:
Reynaert NL, Vanfleteren LEGW, Perkins TN. The AGE-RAGE axis and the pathophysiology of multimorbidity in COPD. J Clin Med. 2023 May 9;12(10):3366.
Perkins TN, Oury TD. The perplexing role of RAGE in pulmonary fibrosis: Causality or casualty.Ther Adv Respir Dis. 2021 Jan-Dec;15.
Perkins TN, Donnell, ML, Oury TD. The Axis of the Receptor for Advanced Glycation Endproducts in Asthma and Allergic Airway Disease. Allergy 2021 May;76(5):1350-1366.