In this proposal, we describe a new pathway signaling neutrophil (PMN) influx and damage to the airways that may play a role as an initiator or cofactor for chronic inflammatory lung diseases such as cystic fibrosis (CF). We have previously demonstrated that proline-glycine-proline (PGP) peptides can cause a robust PMN influx into the airways of mice;this cellular specificity is due to structural relatedness to a receptor binding domain of CXC chemokines such as IL-8. The PI has shown that PGP is released from collagen by a stepwise process initially involving matrix metalloproteases (MMP)-8 and/or 9 with prolyl endopeptidase (PE) catalyzing the final reaction. Recently, the PI's lab has shown that PE is found in neutrophils and stimulated PMNs, when incubated on collagen, can cause notable PGP generation. Although work from the PI's group has demonstrated that PGP is found in CF airway secretions, the impact of PGP peptides in augmenting inflammatory responses in CF lung disease is not currently known. This grant application aims to address this by first investigating the impact of CXC ligands (including PGP and N-(-PGP) as a novel mechanism for the generation of PGP in ex vivo studies and further examining the specific intracellular pathways utilized for protease release from neutrophils. Then, these observations will be taken to a unique mouse model of CF lung disease, the (-ENaC overexpressor mouse (Specific Aim 2), to determine the impact of components of this inflammatory pathway on the phenotype and inflammatory response observed in this murine model. Determination of these fundamental pathways driving protease regulation/release have important implications to patients with chronic inflammatory disease, such as CF, where inflammatory stimuli such as CXC chemokines, are in increased abundance even during periods of disease stability. Our preliminary evidence suggests that at the beginning of an inpatient CF exacerbation, PGP levels are elevated but do decline by the end of hospitalization. However, even with this clinical improvement, PGP levels are still elevated compared to non-disease controls, suggesting that there continues to be ongoing inflammation in these airways. In the final aim of this proposal, we examine if clinically stable CF individuals have elevated levels of PGP and proteases in both sputum and serum. If so, it is possible that their elevation and persistence may predict the development of future disease exacerbations, serving as a unique biomarker for CF lung disease. The findings generated from these aims may have profound translational implications not only to CF lung disease but potentially to other neutrophilic inflammatory conditions.

Public Health Relevance

We have proposed a series of complementary experimental aims to examine the impact of PGP-containing peptides and their generating proteases in cystic fibrosis (CF). The implications of these findings may be broadly applicable to other conditions with prominent neutrophilic inflammation and extracellular matrix breakdown.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL102371-05
Application #
8670007
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Banks-Schlegel, Susan P
Project Start
2010-07-02
Project End
2015-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
5
Fiscal Year
2014
Total Cost
$357,786
Indirect Cost
$112,786
Name
University of Alabama Birmingham
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Deshane, Jessy S; Redden, David T; Zeng, Meiqin et al. (2015) Subsets of airway myeloid-derived regulatory cells distinguish mild asthma from chronic obstructive pulmonary disease. J Allergy Clin Immunol 135:413-424.e15
Abdul Roda, Mojtaba; Sadik, Mariam; Gaggar, Amit et al. (2014) Targeting prolyl endopeptidase with valproic acid as a potential modulator of neutrophilic inflammation. PLoS One 9:e97594
Sharifov, Oleg F; Xu, Xin; Gaggar, Amit et al. (2014) L-4F inhibits lipopolysaccharide-mediated activation of primary human neutrophils. Inflammation 37:1401-12
Thannickal, Victor J; Zhou, Yong; Gaggar, Amit et al. (2014) Fibrosis: ultimate and proximate causes. J Clin Invest 124:4673-7
Kong, Michele Y F; Clancy, John P; Peng, Ning et al. (2014) Pulmonary matrix metalloproteinase-9 activity in mechanically ventilated children with respiratory syncytial virus. Eur Respir J 43:1086-96
Bratcher, Preston E; Gaggar, Amit (2013) Characterization and prevention of the adsorption of surfactant protein D to polypropylene. PLoS One 8:e73467
Sharifov, Oleg F; Xu, Xin; Gaggar, Amit et al. (2013) Anti-inflammatory mechanisms of apolipoprotein A-I mimetic peptide in acute respiratory distress syndrome secondary to sepsis. PLoS One 8:e64486
Solomon, George M; Frederick, Carla; Zhang, Shaoyan et al. (2013) IP-10 is a potential biomarker of cystic fibrosis acute pulmonary exacerbations. PLoS One 8:e72398
Dransfield, Mark T; Wilhelm, Andrew M; Flanagan, Brian et al. (2013) Acquired cystic fibrosis transmembrane conductance regulator dysfunction in the lower airways in COPD. Chest 144:498-506
Gaggar, A; Hector, A; Bratcher, P E et al. (2011) The role of matrix metalloproteinases in cystic fibrosis lung disease. Eur Respir J 38:721-7

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