Abstract
BackgroundCo-exposure to cigarette smoke and alcohol leads to the generation of high concentrations of acetaldehyde and malondialdehyde in the lung. These aldehydes being highly electrophilic in nature react with biologically relevant proteins such as surfactant protein D (SPD) through a Schiff base reaction to generate SPD adducted malondialdehyde-acetaldehyde adduct (SPD-MAA) in mouse lung. SPD-MAA results in an increase in lung pro-inflammatory chemokine, keratinocyte chemoattractant (KC), and the recruitment of lung lavage neutrophils. Previous in vitro studies in bronchial epithelial cells and macrophages show that scavenger receptor A (SR-A1/CD204) is a major receptor for SPD-MAA. No studies have yet examined the in vivo role of SR-A1 in MAA-mediated lung inflammation. Therefore, we hypothesize that in the absence of SR-A1, MAA-induced inflammation in the lung is reduced or diminished.MethodsTo test this hypothesis, C57BL/6 WT and SR-A1 KO mice were nasally instilled with 50 μg/mL of SPD-MAA for 3 weeks (wks). After 3 weeks, bronchoalveolar lavage (BAL) fluid was collected and assayed for a total cell count, a differential cell count and CXCL1 (KC) chemokine. Lung tissue sections were stained with hematoxylin and eosin (H&E) and antibodies to MAA adduct.ResultsResults showed that BAL cellularity and influx of neutrophils were decreased in SR-A1 KO mice as compared to WT following repetitive SPD-MAA exposure. MAA adduct staining in the lung epithelium was decreased in SR-A1 KO mice. In comparison to WT, no increase in CXCL1 was observed in BAL fluid from SR-A1 KO mice over time.ConclusionsOverall, the data demonstrate that SR-A1/CD204 plays an important role in SPD-MAA induced inflammation in lung.
Highlights
Co-exposure to cigarette smoke and alcohol leads to the generation of high concentrations of acetaldehyde and malondialdehyde in the lung
When Scavenger receptor A (SR-A1) KO mice were repeatedly instilled with surfactant protein D (SPD)-MAA (50 μg/mL) for 3 weeks, a significant decrease (p < 0.01) in total lung lavage cells was observed when compared to WT mice (Fig. 1)
SR-A1 KO mice showed decreased neutrophil influx following repetitive MAA instillation Repeated instillation for 3 weeks of 50 μg/mL SPD adducted malondialdehyde-acetaldehyde adduct (SPD-MAA) resulted in an increased influx of neutrophils in lung when compared to the saline-instilled group (Fig. 2d)
Summary
Co-exposure to cigarette smoke and alcohol leads to the generation of high concentrations of acetaldehyde and malondialdehyde in the lung. The CYP2E1 pathway is induced, leading to oxidative stress, lipid peroxidation and generation of malondialdehyde [10, 11]. Cigarette smoke induces oxidative stress, leading to lipid peroxidation resulting in high concentrations of MDA [14]. These aldehydes in lung, being highly reactive and electrophilic, bind to nucleophilic sites on proteins through a Schiff base reaction [15], leading to the formation of hybrid protein adducts. MAA adducted protein instilled into lungs of mice produce inflammatory injury [20]
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