Abstract
BackgroundCigarette smoke exposure can affect pulmonary lipid homeostasis and cause a progressive increase in pulmonary antibodies against oxidized low-density lipoproteins (OxLDL). Similarly, increased anti-OxLDL antibodies are observed in atherosclerosis, a pathology also tightly associated with smoking and lipid homeostasis disruption. Several immunization strategies against oxidized lipid species to help with their clearance have been shown to reduce the formation of atherosclerotic lesions. Since oxidized lipids are generated during cigarette smoke exposure, we investigated the impact of a prophylactic immunization protocol against OxLDL on the pulmonary effects of cigarette smoke exposure in mice.MethodsMice were immunized systemically with a mixture of human OxLDL (antigen source) and AddaVax (adjuvant) or PBS alone prior to the initiation of acute (2 week) or sub-chronic (8 weeks) cigarette smoke exposure protocols. Anti-OxLDL antibodies were measured in the bronchoalveolar lavage (BAL) fluid and serum by direct ELISA. Pulmonary impacts of cigarette smoke exposure and OxLDL immunization were assessed by measuring BAL inflammatory cells, lung functions, and changes in lung structure and gene levels of matrix/matrix-related genes.ResultsImmunization to OxLDL led to a marked increase in circulating and pulmonary antibodies against OxLDL that persisted during cigarette smoke exposure. OxLDL immunization did not exacerbate or reduce the inflammatory response following acute or sub-chronic exposure to cigarette smoke. OxLDL immunization alone had effects similar to cigarette smoke exposure on lung functions but OxLDL immunization and cigarette smoke exposure had no additive effects on these parameters. No obvious changes in lung histology, airspace or levels of matrix and matrix-related genes were caused by OxLDL immunization compared to vehicle treatment.ConclusionsOverall, this study shows for the first time that a prophylactic immunization protocol against OxLDL can potentially have detrimental effects lung functions, without having additive effects over cigarette smoke exposure. This work sheds light on a complex dynamic between anti-OxLDL antibodies and the pulmonary response to cigarette smoke exposure.
Highlights
Tobacco smoking is well known to trigger a rapid and robust inflammatory response in the lungs along with progressive structural alterations
bronchoalveolar lavage (BAL) Monocyte chemoattractant protein-1 (MCP-1) and cxcl5 lung mRNA levels were assessed as they are both rapidly induced by cigarette smoke exposure and linked to monocyte/ macrophage and neutrophil recruitment [5, 11]
Immunization to oxidized low-density lipoproteins (OxLDL) had no significant effect on smoking-induced neutrophilia (Fig. 2a and d) or MCP-1 levels (Fig. 2b and e)
Summary
Tobacco smoking is well known to trigger a rapid and robust inflammatory response in the lungs along with progressive structural alterations. Several groups showed a beneficial impact of this type of approach to limit atherosclerotic processes in animals [7,8,9,10] Since both the cigarette smoke-exposed lung and atherosclerotic lesions display local lipid homeostasis disruption, activated lipid-laden macrophages, progressive and chronic inflammation, gradual tissue alterations, spontaneous increase in anti-OxLDL antibodies, we hypothesized that increasing antibodies against OxLDL trough a vaccine-like process would affect the pulmonary response to cigarette smoke, at both immunological and functional levels. This would provide information on their biological relevance and possible a new therapeutic paradigm. Since oxidized lipids are generated during cigarette smoke exposure, we investigated the impact of a prophylactic immunization protocol against OxLDL on the pulmonary effects of cigarette smoke exposure in mice
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