Protein kinase C epsilon is important in modulating organic-dust-induced airway inflammation.
Organic dust samples from swine confinement facilities elicit pro-inflammatory cytokine/chemokine release from bronchial epithelial cells and monocytes, dependent, in part, upon dust-induced activation of the protein kinase C (PKC) isoform, PKCε. PKCε is also rapidly activated in murine tracheal epithelial cells following in vivo organic dust challenges, yet the functional role of PKCε in modulating dust-induced airway inflammatory outcomes is not defined. Utilizing an established intranasal inhalation animal model, experiments investigated the biologic and physiologic responses following organic dust extract (ODE) treatments in wild-type (WT) and PKCε knock-out (KO) mice. We found that neutrophil influx increased more than twofold in PKCε KO mice following both a one-time challenge and 3 weeks of daily challenges with ODE as compared with WT mice. Lung pathology revealed increased bronchiolar and alveolar inflammation, lymphoid aggregates, and T cell influx in ODE-treated PKCε KO mice. Airway hyperresponsiveness to methacholine increased in PKCε KO + ODE to a greater magnitude than WT + ODE animals. There were no significant differences in cytokine/chemokine release elicited by ODE treatment between groups. However, ODE-induced nitric oxide (NO) production differed in that ODE exposure increased nitrate levels in WT mice but not in PKCε KO mice. Moreover, ODE failed to upregulate NO from ex vivo stimulated PKCε KO lung macrophages. Collectively, these studies demonstrate that PKCε-deficient mice were hypersensitive to organic dust exposure and suggest that PKCε is important in the normative lung inflammatory response to ODE. Dampening of ODE-induced NO may contribute to these enhanced inflammatory findings.
Pulmonary, Critical Care, Sleep and Allergy Division, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska 68198-5300, USA. japoole@unmc.edu
Jill A
JA
Poole
Debra J
DJ
Romberger
Chris
C
Bauer
Angela M
AM
Gleason
Joseph H
JH
Sisson
Peter J
PJ
Oldenburg
William W
WW
West
Todd A
TA
Wyatt
D000818:Animals; D016535:Bronchial Hyperreactivity / Q000201:enzymology* / Q000235:genetics / Q000276:immunology; D001985:Bronchial Provocation Tests; D018925:Chemokines / Q000378:metabolism; D004195:Disease Models, Animal; D004391:Dust / Q000276:immunology*; D004781:Environmental Exposure / Q000009:adverse effects; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D005260:Female; D018836:Inflammation Mediators / Q000378:metabolism*; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D016210:Methacholine Chloride; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000187:drug effects; D051744:Protein Kinase C-epsilon / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D013601:T-Lymphocytes / Q000473:pathology
D018925:Chemokines; D004391:Dust; D018836:Inflammation Mediators; D016210:Methacholine Chloride; D051744:Protein Kinase C-epsilon