Farmers and workers in concentrated animal feeding operations (CAFOs) experience work-related respiratory disease, particularly chronic bronchitis and chronic obstructive pulmonary disease (COPD). Although multiple substances in CAFOs may contribute to disease, dust from these facilities is well recognized as an important respiratory health hazard. Our previous work has been focused on defining mechanisms by which CAFO dust results in lung inflammation. Importantly, we have identified three critical elements of this CAFO dust-induced lung inflammation mechanism that we propose make excellent therapeutic targets for treatment of this important occupational lung disorder: 1) cytokine release, focusing on the TNF-alpha-dependent airway epithelial cell release of IL-6 and IL-8 with sequential activation of the airway epithelial protein kinase C isoforms (PKC), alpha followed by epsilon;2) the anti-inflammatory effects of the cyclic AMP dependent protein kinase (PKA);and 3) pro-inflammatory proteases as triggers present in CAFO dust. This proposal outlines how we will use a pre-clinical animal model to decipher the relative value of targeting these three mechanistic elements that may dampen and/or reverse CAFO dust-induced lung disease. Toward this end, we have demonstrated that inhaled dust extract causes respiratory inflammation in vivo in a mouse model that has all of the prominent features of the pulmonary disorders seen in persons working in swine confinement facilities. In this renewal we propose a strategy to utilize this mouse model in preclinical studies aimed at determining which of the therapeutic targets outlined above are feasible and efficacious. We hypothesize that: CAFO dust-induced lung inflammation is treatable by blocking PKC isoform-triggered airway cytokine release, activating PKA and inhibiting dust-derived proteases and their cellular targets. We will test this hypothesis via three specific aims:
Aim 1 : Establish how agents that specifically target TNF-alpha, IL-6, and IL-8 modulate dust extract-induced lung inflammation in vivo.
Aim 2 : Determine how agents that augment PKA, especially therapeutic beta-adrenergic agonists, dampen dust extract-induced PKC isoform activation and attenuate lung inflammation in vitro and in vivo.
Aim 3 : Determine the importance of proteases in dust extract-induced TNF-alpha/IL-6/IL-8 in vitro and in tissue inflammation in vivo and identify potential targets for attenuating the dust extract protease-induced inflammatory changes. Our proposal is designed to provide pre-clinical cell, lung slice, and animal data that will facilitate translational studies aimed at bringing potential interventions into the workplace. )
In our previous work, we determined that dust extract from swine confined animal feeding operations causes cells lining airways to release specific inflammatory mediators, namely TNF-1, IL-6, and IL-8 via the intracellular signal protein kinase C (PKC). We have also demonstrated that this dust extract causes inflammation in a mouse model that has features similar to that seen in workers. In this application, we will perform pre-clinical studies using our mouse model to determine if targeting specific mediators (TNF-1, IL-6, and IL-8) and pathways (PKC and cAMP dependent protein kinase) as well as substances in the dust (proteases) will decrease inflammation in the lungs, with a long-term goal of developing new treatment strategies to reduce airway inflammation before it causes disease in workers.
|Boissy, Robert J; Romberger, Debra J; Roughead, William A et al. (2014) Shotgun pyrosequencing metagenomic analyses of dusts from swine confinement and grain facilities. PLoS One 9:e95578|
|Wyatt, Todd A; Poole, Jill A; Nordgren, Tara M et al. (2014) cAMP-dependent protein kinase activation decreases cytokine release in bronchial epithelial cells. Am J Physiol Lung Cell Mol Physiol 307:L643-51|
|Tian, Chengju; Moore, Caronda J; Dodmane, Puttappa et al. (2013) Dust from hog confinement facilities impairs Ca2+ mobilization from sarco(endo)plasmic reticulum by inhibiting ryanodine receptors. J Appl Physiol (1985) 114:665-74|
|Poole, Jill A; Romberger, Debra J (2012) Immunological and inflammatory responses to organic dust in agriculture. Curr Opin Allergy Clin Immunol 12:126-32|
|Poole, Jill A; Wyatt, Todd A; Kielian, Tammy et al. (2011) Toll-like receptor 2 regulates organic dust-induced airway inflammation. Am J Respir Cell Mol Biol 45:711-9|
|Dodmane, Puttappa R; Schulte, Nancy A; Heires, Art J et al. (2011) Airway epithelial epidermal growth factor receptor mediates hogbarn dust-induced cytokine release but not Ca2+ response. Am J Respir Cell Mol Biol 45:882-8|
|Wyatt, Todd A; Slager, Rebecca E; Heires, Arthur J et al. (2010) Sequential activation of protein kinase C isoforms by organic dust is mediated by tumor necrosis factor. Am J Respir Cell Mol Biol 42:706-15|
|Tian, Chengju; Shao, Chun Hong; Fenster, Danielle S et al. (2010) Chloroform extract of hog barn dust modulates skeletal muscle ryanodine receptor calcium-release channel (RyR1). J Appl Physiol 109:830-9|
|Bailey, Kristina L; Sisson, Joseph H; Romberger, Debra J et al. (2010) Alcohol up-regulates TLR2 through a NO/cGMP dependent pathway. Alcohol Clin Exp Res 34:51-6|
|Bailey, Kristina L; Wyatt, Todd A; Romberger, Debra J et al. (2009) Alcohol functionally upregulates Toll-like receptor 2 in airway epithelial cells. Alcohol Clin Exp Res 33:499-504|
Showing the most recent 10 out of 14 publications