ROLE OF MATRIX METALLOPROTEINASE-3 IN DEPLOYMENT-RELATED PULMONARY FIBROSIS

Project: Research project

Project Details

Description

Overarching Goal: The goal of this application is to determine the mechanisms by which inhalational exposure to silicate-containing respirable particulate matter (PM) during military deployment to Southwest Asia leads to chronic pulmonary inflammation and fibrosis and to investigate strategies to diagnose and repair this damage.Research Idea and Military Relevance: Since the onset of military operations in Afghanistan in 2001, more than 2.8 million military personnel, contractors, and US government and non-government employees have been deployed to Southwest Asia. These personnel have been exposed to high levels of dust generated by wind erosion of desert sand, movement of vehicles and troops, and combustion and construction activities with short- and long-term health consequences. Levels of PM in Southwest Asia may exceed 1500 mu-g/m3, far higher than the World Health Organization air quality guideline of 20 mu-g/m3. In deployed military personnel, high levels of PM have been causally implicated in an increase in respiratory symptoms, asthma, bronchiolitis, and eosinophilic and interstitial lung disease. Acutely affected military personnel may be less able to carry out their duties. Over the long term, these exposures may lead to disability, chronic illness with attendant morbidity, absences from work, and increased healthcare expenditures. The mechanisms responsible for these adverse respiratory outcomes are not well understood. Our experimental construct is that inhalational exposure to silicate-containing PM leads to chronic inflammation centered on terminal bronchioles and alveolar ducts that progresses to more diffuse interstitial pulmonary fibrosis. Our published and preliminary data demonstrate elevated levels of matrix metalloproteinase (MMP)-3 in the lungs of mice with experimental pulmonary fibrosis and in humans with idiopathic pulmonary fibrosis (IPF). Notably, Mmp3-/- mice are protected from experimental pulmonary fibrosis, underscoring the importance of MMP-3 in the pathogenesis of pulmonary fibrosis.Hypothesis: Exposure of deployed military personnel to respirable PM from Southwest Asia ('desert dust') leads to chronic inflammation and dysregulated secretion of MMP-3 in the lung that liberates fibrogenic cytokines and glycoproteins bound to the extracellular matrix (ECM) that drive chronic inflammation leading to parenchymal fibrosis.Specific Aim 1: Determine the role of MMP-3 in preclinical models of PM-induced pulmonary fibrosis. We will compare the extent of pulmonary fibrosis induced by intratracheal instillation of PM from Camp Victory (Baghdad, Iraq) or purified silica in wild-type (WT) C57BL/6 and Mmp3-/- mice. The well-characterized model of intratracheal bleomycin will be used as comparison. We will compare these observations using inhalational exposure over 6 weeks to aerosolized sand from Camp Victory or silica in WT and Mmp3-/- mice using the Naval Medical Research Unit (NAMRU) inhalational toxicology facility. We will identify MMP-3-induced molecular alterations in the ECM including proteolytic cleavage of matrix-bound osteopontin and release of profibrotic peptides and define how this promotes pulmonary fibrosis.Specific Aim 2: Develop an MMP-3-selective Tissue Inhibitor of Metalloproteinase (TIMP) as therapeutic target for progressive pulmonary fibrosis. We will use in silico and in vitro approaches to develop an MMP-3-selective (M3S)-TIMP and then evaluate the effectiveness of this M3S-TIMP in attenuating pulmonary fibrosis induced by exposure to Iraqi PM and silica in the murine models described in Aim 1.Specific Aim 3: Determine if MMP-3 levels are elevated in the lungs and blood of patients with pulmonary fibrosis and in military personnel previously deployed to Southwest Asia and can be used as a biomarker for disease progression. Preliminary studies using Laser Ablation Inductively Coupled Plasma Mass Spectrometry (LA-ICP-MS) have revealed increased silica content in the lungs of symptomatic deployers compared to controls. Using this technique, we will measure levels of silicate PM and associated metal contaminants in bronchoalveolar lavage fluid and lung tissue from deployers from Southwest Asia. Samples from pulmonary fibrosis patients will be used as controls. We will also determine if elevated levels of MMP-3 and peptides derived from proteolysis of osteopontin are associated with disease progression.Impact: These studies will provide key information on the exposures of deployed military personnel to respirable PM from Southwest Asia and determine the mechanisms by which these exposures may lead to chronic inflammation and pulmonary fibrosis. These studies will have major clinical implications for development of therapeutic strategies to prevent and/or mitigate acute and long-lasting lung damage from deployment-related lung injury.

StatusFinished
Effective start/end date8/15/168/14/19

Funding

  • Congressionally Directed Medical Research Programs: $733,813.00

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