Chronic inhalation of organic dusts causes significant airway inflammatory diseases including asthma, bronchitis, and chronic obstructive pulmonary disease, particularly in agriculture-exposed persons. This population is also at increased risk of adverse systemic consequences including high rates of musculoskeletal disorders and fractures. To provide mechanistic insights and inform future therapeutic and/or prevention strategies, we developed and have utilized an animal inflammatory lung injury model following exposure to complex organic dusts from large animal farm confinements. During the previous funding period, we initiated a paradigm shift in this field by finding that gram-positive bacterial peptidoglycan (PGN), as opposed to gram- negative lipopolysaccharide (LPS), is a predominant driver of lung inflammatory consequences, with a strong role demonstrated for the Toll-like receptor 2 (TLR2) signaling pathway. We also defined roles for other pattern-recognition receptor pathways, but the strongest phenotype discovered was for the common TLR/IL-1R adaptor protein, MyD88, which forms the basis of this competitive renewal. Furthermore, our research evolved to understand the systemic consequences of these inhalant exposures on bone homeostasis. Importantly, using state-of-the-art micro-CT imaging we uncovered significant bone deterioration following treatment with organic dust exposures. This established, for the first time, an animal model connecting inhalant lung injury to bone disease. Importantly, our new preliminary studies support that inhalant organic dust exposures engage the lung-bone inflammatory axis through TLR/MyD88 signaling and downstream IL-6 effector pathways, which could be targeted to reduce disease burden. Using this innovative experimental model systems combined with our novel observations and preliminary data, we hypothesize that TLR/MyD88-dependent pathways are central in regulating the crosstalk between lung injury and systemic bone loss induced by organic dust inhalant exposures via downstream cytokine effectors. The goal of our research proposal is to investigate mechanisms, biomarkers, and therapeutic approaches in a relevant animal model that can be later translated to humans.
In Aim 1, we will expand upon our findings of a central role for MyD88 to establish how MyD88- dependent signaling pathways function in the lung to govern airway inflammatory responses to organic dust exposures. Understanding the mechanistic signals and lung cell biology regulating airway and lung parenchyma pathology may guide future therapeutic strategies.
In Aim 2, we will delineate the potential mechanisms governing the crosstalk between the lung-bone inflammatory-axis to explain how lung injury induced following inhalation of organic dusts and its microbial components mediate systemic bone loss through focused efforts on key TLR/MyD88 signaling pathway.
In Aim 3, we will target the downstream TLR/MyD88- mediated systemic IL-6 effector response as a pre-clinical, translatable approach to reduce bone deterioration induced by organic dust inhalant exposures.
This project will help identify mechanisms, biomarkers, and potential therapeutic targets regulating lung injury and lung injury-induced systemic bone loss that can be later translated to agriculture-exposed human cohorts to ultimately reduce disease burden.
|Dickinson, John D; Sweeter, Jenea M; Staab, Elizabeth B et al. (2018) MyD88 controls airway epithelial Muc5ac expression during TLR activation conditions from agricultural organic dust exposure. Am J Physiol Lung Cell Mol Physiol :|
|LeVan, Tricia D; Romberger, Debra J; Siahpush, Mohammad et al. (2018) Relationship of systemic IL-10 levels with proinflammatory cytokine responsiveness and lung function in agriculture workers. Respir Res 19:166|
|Chandra, Deepak; Poole, Jill A; Bailey, Kristina L et al. (2018) Dimethylarginine dimethylaminohydrolase (DDAH) overexpression enhances wound repair in airway epithelial cells exposed to agricultural organic dust. Inhal Toxicol 30:133-139|
|Nelson, Amy J; Roy, Shyamal K; Warren, Kristi et al. (2018) Sex differences impact the lung-bone inflammatory response to repetitive inhalant lipopolysaccharide exposures in mice. J Immunotoxicol 15:73-81|
|Carrington, Joseph M; Poole, Jill A (2018) The Effect of Inhalant Organic Dust on Bone Health. Curr Allergy Asthma Rep 18:16|
|Warren, Kristi J; Wyatt, Todd A; Romberger, Debra J et al. (2017) Post-injury and resolution response to repetitive inhalation exposure to agricultural organic dust in mice. Safety (Basel) 3:|
|Warren, Kristi J; Sweeter, Jenea M; Pavlik, Jacqueline A et al. (2017) Sex differences in activation of lung-related type 2 innate lymphoid cells in experimental asthma. Ann Allergy Asthma Immunol 118:233-234|
|Wells, Adam; Romberger, Debra J; Thiele, Geoffrey M et al. (2017) Systemic IL-6 Effector Response in Mediating Systemic Bone Loss Following Inhalation of Organic Dust. J Interferon Cytokine Res 37:9-19|
|Wyatt, Todd A; Canady, Kerry; Heires, Art J et al. (2017) Alcohol Inhibits Organic Dust-induced ICAM-1 Expression on Bronchial Epithelial Cells. Safety (Basel) 3:|
|Romberger, Debra J; Heires, Art J; Nordgren, Tara M et al. (2016) ?2-Adrenergic agonists attenuate organic dust-induced lung inflammation. Am J Physiol Lung Cell Mol Physiol 311:L101-10|
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