Under certain circumstances, polymorphonuclear leukocyte (PMN) recruitment to sites of airway inflammation can lead to tissue damage via the production of proteases, reactive oxygen species, proinflammatory cytokines and chemokines. PMN are thought to play a role in acute lung diseases as well as chronic obstructive pulmonary diseases and contribute to inflammation and lung damage in cystic fibrosis. We herein describe a novel pathway of PMN influx and damage to the airways that may represent a new therapeutic target for certain pulmonary diseases. In particular, when collagen is chemically or enzymatically degraded a tripeptide, PGP, is generated that is chemotactic for PMN in vitro. In vivo, airway exposure to PGP elicits a marked influx of PMN, but not monocytes. More chronic airway exposure to PGP causes alveolar enlargement and right ventricular hypertrophy. Using electrospray ionization-liquid chromatography- mass spectrometry (ESI-LC-MS/MS), PGP is detected in the airways of animals exposed to endotoxin (LPS). In addition, the peptide substantially contributes to PMN influx into inflamed airways. The chemotactic activity of PGP apparently results from an extraordinary structural relatedness to a receptor binding motif of CXC chemokines, like IL-8 that contain this sequence or a close analog. We have designed a novel peptide with the sequence arginine-threonine-arginine (RTR) that binds PGP and potently blocks the peptide's in vitro chemotactic activity and in vivo pathophysiologic effects. RTR also inhibits CXC chemokine activity apparently as a result of the shared structure between PGP and the chemokines. Thus, RTR represents a potential therapeutic agent that can block both the chemokine and PGP pathways of inflammation. These results have led to the following goals for this application. 1. Determine whether PGP binds CXC chemokine receptors (R) and activates CXCR coupled effector pathways. 2. Evaluate the spectrum of PGP-containing peptides that are produced during airway inflammation and whether PGP recruits PMN to the airways during acute inflammation. 3. Determine whether PMN are necessary for PGP-mediated alveolar enlargement and right ventricular hypertrophy. 4. Evaluate the relative pathophysiologic roles of PGP as compared to CXC chemokines in a model of persistent LPS-mediated pulmonary disease. 5. Test RTR as an antagonist of the PGP and CXC chemokine pathways in the LPS-mediated pulmonary disease model. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL077783-02
Application #
7201584
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Croxton, Thomas
Project Start
2006-04-01
Project End
2010-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
2
Fiscal Year
2007
Total Cost
$353,201
Indirect Cost
Name
University of Alabama Birmingham
Department
Physiology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Larson-Casey, Jennifer L; Gu, Linlin; Jackson, Patricia L et al. (2018) Macrophage Rac2 Is Required to Reduce the Severity of Cigarette Smoke-induced Pneumonia. Am J Respir Crit Care Med 198:1288-1301
Payne, Gregory A; Li, Jindong; Xu, Xin et al. (2017) The Matrikine Acetylated Proline-Glycine-Proline Couples Vascular Inflammation and Acute Cardiac Rejection. Sci Rep 7:7563
O'Reilly, Philip J; Ding, Qiang; Akthar, Samia et al. (2017) Angiotensin-converting enzyme defines matrikine-regulated inflammation and fibrosis. JCI Insight 2:
Low, Caroline M; Akthar, Samia; Patel, Dhiren F et al. (2017) The development of novel LTA4H modulators to selectively target LTB4 generation. Sci Rep 7:44449
Zhao, Xue-Ke; Che, Pulin; Cheng, Ming-Liang et al. (2016) Tristetraprolin Down-Regulation Contributes to Persistent TNF-Alpha Expression Induced by Cigarette Smoke Extract through a Post-Transcriptional Mechanism. PLoS One 11:e0167451
Russell, Derek W; Wells, J Michael; Blalock, J Edwin (2016) Disease phenotyping in chronic obstructive pulmonary disease: the neutrophilic endotype. Curr Opin Pulm Med 22:91-9
Noerager, Brett D; Xu, Xin; Davis, Virginia A et al. (2015) A Potential Role for Acrolein in Neutrophil-Mediated Chronic Inflammation. Inflammation 38:2279-87
Hahn, Cornelia S; Scott, David W; Xu, Xin et al. (2015) The matrikine N-?-PGP couples extracellular matrix fragmentation to endothelial permeability. Sci Adv 1:
Wells, J Michael; Gaggar, Amit; Blalock, J Edwin (2015) MMP generated matrikines. Matrix Biol 44-46:122-9
Russell, Derek W; Blalock, J Edwin (2015) The soot of all evil. Elife 4:e11709

Showing the most recent 10 out of 34 publications