Dimethylarginine Dimethylaminohydose(DDAH) Overexpression Attenuates Agricultural Organic Dust Extract-Induced Inflammation

Abstract

Modern, industrialized farming practices have lead to working conditions that include high levels of airborne dust. Agricultural workers inhale these complex organic dusts on a daily basis, leading to airway inflammation and higher risk for developing chronic obstructive pulmonary disease. The mechanisms regulating the organic dust-induced airway inflammatory response are not well-defined. We investigated whether overexpression of dimethylarginine dimethylaminohydrolase (DDAH) would lead to diminished pulmonary inflammation in an animal model of organic dust extract exposure. We instilled wild-type (WT) and DDAH overexpressing mice with an aqueous organic dust extract (ODE) collected from a swine confinement building. We found that inflammatory indices such as neutrophil influx and inflammatory cytokine production was lower in the DDAH overexpressing mice compared to WT after organic dust extract (ODE) instillation. We went on to determine how DDAH was mediating the decrease in inflammation induced by ODE. PKCα and PKCε play an essential role in the ODE inflammatory response. In a model of lung slices from WT and DDAH overexpressing mice, we demonstrated an increase in PKCα and PKCε in the WT mice exposed to ODE. This increase was diminished in the DDAH overexpressing mice exposed to ODE. We also tested an important component of the ODE, peptidoglycan (PGN). We noted a similar decrease in neutrophils and inflammatory cytokines in the DDAH overexpressing animals instilled with PGN compared to WT. In conclusion, our studies found a role for DDAH in regulating the ODE-triggered activation of epithelial PKCα and PKCε, a previously unrecognized mechanism of action. This ultimately results in diminished pulmonary inflammation.

Neutrophilic oxidative stress mediates organic dust-induced pulmonary inflammation and airway hyperresponsiveness

“…In humans, OD exposure is associated with increases in oxidative stress markers (28, 44). Bailey et al (3) demonstrated that overexpression of dimethylarginine dimethylaminohydrolase, which inactivates the nitric oxide inhibitor asymmetric dimethylarginine by hydrolyzing it into citrulline and dimethylamine inhibitor, was effective in attenuating neutrophilia induced by OD exposure in mice. Taken together, our data and human study data suggest that exposure to OD exposure induces upregulation of antioxidant pathways, specifically NRF-2, and these changes are associated with neutrophil presence.…”

“…Because severe pulmonary neutrophilia is a hallmark of OD exposure in both human and animal models, mostly as assessed by BAL fluid analyses (3,10,20), we sought to address the importance of neutrophils using a granulocyte depletion antibody, anti-Ly6G. Despite not reaching 100% reduction in neutrophils, the anti-Ly6G effect on cell depletion was selective for neutrophils.…”

Dynamic change of glomerular filtration rate in the early stage is associated with kidney allograft status: a preliminary report

“…Aggravated capillary damage, inflammation, and oxidative stress following successful reperfusion are possible explanations for the case. Putative mechanisms for these phenomena are interaction of reperfusion-induced hyperfiltration, high intraglomerular capillary pressure, oxidative stress, increased polymorphonuclear cell infiltration, and inflammation [ 13 , 14 ]. In the early stage post renal transplantation, the glomerular filtration membrane is constantly exposed to high pressure for several days, which may lead to proteinuria and potential tissue injury.…”

Dimethylarginine dimethylaminohydrolase (DDAH) overexpression enhances wound repair in airway epithelial cells exposed to agricultural organic dust

“…Organic dust that had settled onto horizontal surfaces in a moderately-sized (approximately 500–700 head) swine confinement facility was collected as previously described (K. Bailey et al 2014).…”

“…This inhibition of the NO pathway can be reversed with dimethylarginine dimethylaminohydrolase (DDAH), an inhibitor of ADMA (Tran, Leiper, Vallance 2003). Thus, transgenic mice that overexpress DDAH demonstrate a decreased in vivo inflammatory response to hog barn dust (K. Bailey et al 2014).…”