BACKGROUND:
Cigarette smoking is the major cause of
chronic obstructive pulmonary disease (
COPD) and
lung cancer.
Respiratory bacterial infections have been shown to be involved in the development of
COPD along with
impaired airway innate immunity. METHODOLOGY/PRINCIPAL FINDINGS: To address the in vivo impact of
cigarette smoke (CS) exclusively on host innate
defense mechanisms, we took advantage of
Caenorhabditis elegans (
C. elegans), which has an
innate immune system but lacks adaptive
immune function.
Pseudomonas aeruginosa (PA) clearance from
intestines of
C. elegans was dampened by CS.
Microarray analysis identified 6
candidate genes with a 2-fold or greater reduction after CS exposure, that have a human
orthologue, and that may participate in
innate immunity. To confirm a role of CS-down-regulated genes in the
innate immune response to PA,
RNA interference (
RNAi) by feeding was carried out in
C. elegans to inhibit the gene of interest, followed by PA
infection to determine if the gene affected
innate immunity. Inhibition of lbp-7, which encodes a
lipid binding protein, resulted in increased levels of
intestinal PA. Primary human
bronchial epithelial cells were shown to express
mRNA of human
Fatty Acid Binding Protein 5 (FABP-5), the human
orthologue of lpb-7. Interestingly, FABP-5
mRNA levels from human smokers with
COPD were significantly lower (p = 0.036) than those from smokers without
COPD. Furthermore, FABP-5
mRNA levels were up-regulated (7-fold) after
bacterial (i.e.,
Mycoplasma pneumoniae)
infection in primary human
bronchial epithelial cell culture (air-liquid interface culture). CONCLUSIONS: Our results suggest that the
C. elegans model offers a novel in vivo approach to specifically study innate
immune deficiencies resulting from exposure to
cigarette smoke, and that results from the
nematode may provide insight into human
airway epithelial cell biology and
cigarette smoke exposure.
