Pulmonary fibrosis (PF) is a devastating disease characterized by dyspnea, cough, fatigue and poor survival. Veterans who served in desert regions overseas have an increased risk of developing respiratory diseases including PF as a result of exposures in theater. The incidence of respiratory disease in Veterans is ~4-16-fold greater than those exposed to inhaled occupational hazards alone (based on Work-Related Lung Disease Surveillance Report 2007, NIOS and Health Analysis of VA Health Care Utilization among OEF/OIF/OND Veterans Report, VHA), suggesting an additional factor contributes to Veterans? risk. Chronic psychological stress-associated mental health diseases disproportionately affect Veterans, are associated with increased inflammation, and may be one contributing factor to respiratory disease among Veterans. Current therapeutics provide limited effectiveness and do not address the multifactorial nature of PF, indicating the critical need to understand risk factors for PF and develop improved therapeutics for our nation?s Veterans. Our preliminary data demonstrated that chronic stress exacerbated PF. Our laboratory has identified a novel myeloid circulating fibroblast precursor (CFP) population that is elevated in a silica-induced model of PF and in chronic stress. CFPs exhibited an activated phenotype defined by increased co-stimulatory molecule expression, and promoted a pro-inflammatory pulmonary microenvironment in PF. Therefore, we hypothesize that chronic stress exacerbates silica exposure-induced PF through myeloid lineage dependent mechanisms. Toward this, a chronic unpredictable stress (CUS) model in conjunction with a highly relevant silica exposure-induced model of PF will be employed in three specific aims:
Aim 1 will determine the impact of CUS on exacerbation of PF through clinically relevant parameters in vivo and examine the temporal participation and activated phenotype of myeloid cells in disease.
Aim 2 will determine the role of glucocorticoid (GC) signaling in myeloid proinflammatory cytokine production and in disease promotion.
Aim 3 will examine the role of DDR2/collagen I signaling in the immune functions of CFPs in PF exacerbated by CUS. Adoptive transfer gain-of-function studies and transplantation-based loss-of-function studies will be employed to directly test the causal role of CFPs in PF. These studies will provide critical insight into immune response to combat exposures and an understanding of the pathological impact of chronic stress. These studies are innovative in the use of highly relevant models of CUS and exposure-induced PF with direct applicability to Veterans? health. Short-term, these studies will provide increased understanding of the myeloid-dependent, CFP-driven mechanisms, and molecular (glucocorticoid signaling) mechanisms leading to CUS exacerbation of PF. These studies will also identify unexplored mechanisms of immune function through activation of the novel CFP and will determine the causal role of the CFP in CUS exacerbation of PF. Long-term, examination of therapeutic agents targeting specific cellular populations and pathways identified in these studies may lead to new translatable therapeutic targets for PF. These studies utilize state-of-the-art small animal imaging, behavioral, flow cytometric, and shRNA core facilities. The multi-disciplinary mentoring team has expertise in immunology, fibrosis, signaling, and statistics and will ensure the success of the proposed studies. The Applicant is genuinely committed to the missions of the VA and has a strong record of publication, collaboration, and contributions to the VA research community. The immediate goal of this CDA is to allow the Applicant to develop new areas of expertise, technical skills, and career tools necessary to pursue a career as an independent VA investigator. This will be accomplished through coursework, hands-on training, networking, and mentoring opportunities provided by the CDA mechanism. Long-term this will allow the Applicant to develop an independent, innovative, and collaborative research program focused on exposure-induced PF and co-morbidities that disproportionately affect Veterans.
Combat exposures such as inhaled sand and dust may lead to increased risk and severity of respiratory diseases including pulmonary fibrosis (PF) among Veterans. In addition, chronic psychological stress related to deployment is associated with chronic inflammation and may contribute to disease severity. Using a model of PF that mimics sand inhalation, combined with a model of chronic unpredictable stress (CUS), a novel circulating fibroblast precursor (CFP) cell was identified that is increased, activated, and promotes inflammation in PF. This study will determine how CUS exacerbates PF and identify CUS-driven mechanisms by which CFPs become activated to promote disease progression toward development of new therapies for PF. These studies are directly applicable to Veterans as they address the impact of chronic stress/mental health on a devastating disease disproportionately affecting our Nation?s Veterans.
