Reduction of neutrophilic inflammation in idiopathic pulmonary fibrosis via metabolism of n-alpha-pgp by leukotriene A4 hydrolase

Idiopathic Pulmonary Fibrosis (IPF) is a progressive and lethal disease characterized by injury and accumulation of fibroblasts, and abnormal remodeling of the lung parenchyma. IPF is a rare disease with no effective treatment. Due to etiology of IPF, several pathogenic mechanisms have been implicated in its development including: aberrant repair of injured epithelium, consistent fibroblast activation and epithelial-to-mesenchymal transition (EMT). The main focus of this research is on the regulation of a bifunctional enzyme called Leukotriene A4 Hydrolase (LTA4H), with pro and anti-inflammatory functions. While LTA4H catalyzes the conversion of leukotriene A4 to the proinflammatory mediator leukotriene B4 (LTB4), it has an aminopeptidase activity that has shown to degrade N-alpha-Proline-Glycine-Proline (N-α-PGP) and non-acetylated PGP, leading to resolution of acute neutrophils driven inflammation in collagen break down during repair process. Chronic neutrophilic inflammation is observed in lung diseases such as cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD), mediating extensive tissue damage and contributing to organ dysfunction. These studies demonstrated that tissues and fibroblasts cultured from lungs tissues of IPF patients to contain more PGP content and lack extracellular LTA4H and matrix metalloproteinases 8 and 9 (MMP 8/9). In addition, LTA4H expression was much lower in fibrotic lungs when compared to normal patients. Immunohistochemistry (IHC) analysis of the tissue microarray of the IPF and normal patients indicated a reduction in LTA4H in basal, central and lingual part of the lung. In addition to LTA4H studies, it has been also demonstrated that phosphorylation of the c-Jun N-terminal kinases 1/2(JNK), a mitogen-activated protein kinase family which are responsive to stress stimuli, might be linked to remodelling and progression of the IPF. While the expression of JNK was not different across the IPF and normal patients, activated JNK was elevated in the IPF fibroblasts. In addition, the same fibroblast cells were shown to produce more pro-collagen I A; while utilizing the phospho-JNK (P-JNK) inhibitor 1/2, reduced the collagen formation in the IPF fibroblast cells.Further studies are needed to understand the role of LTA4H and PGP breakdown as well as P-JNK pathway in IPF patients, with a hope to control this devastating disease.Medicine, Faculty ofExperimental Medicine, Division ofMedicine, Department ofGraduat