Acrolein Inhalation Suppresses Lipopolysaccharide-Induced Inflammatory Cytokine Production but Does Not Affect Acute Airways Neutrophilia

Abstract

Acrolein is a reactive unsaturated aldehyde that is produced during endogenous oxidative processes and is a major bioactive component of environmental pollutants such as cigarette smoke. Because in vitro studies demonstrate that acrolein can inhibit neutrophil apoptosis, we evaluated the effects of in vivo acrolein exposure on acute lung inflammation induced by LPS. Male C57BL/6J mice received 300 μg/kg intratracheal LPS and were exposed to acrolein (5 parts per million, 6 h/day), either before or after LPS challenge. Exposure to acrolein either before or after LPS challenge did not significantly affect the overall extent of LPS-induced lung inflammation, or the duration of the inflammatory response, as observed from recovered lung lavage leukocytes and histology. However, exposure to acrolein after LPS instillation markedly diminished the LPS-induced production of several inflammatory cytokines, specifically TNF-α, IL-12, and the Th1 cytokine IFN-γ, which was associated with reduction in NF-κB activation. Our data demonstrate that acrolein exposure suppresses LPS-induced Th1 cytokine responses without affecting acute neutrophilia. Disruption of cytokine signaling by acrolein may represent a mechanism by which smoking contributes to chronic disease in chronic obstructive pulmonary disease and asthma.

The Tobacco Smoke Component, Acrolein, Suppresses Innate Macrophage Responses by Direct Alkylation of c-Jun N-Terminal Kinase

“…Acrolein is known to be capable of suppressing macrophage activation (21), and our previous studies indicate that in vivo exposure of mice to acrolein leads to reduced innate immune responses to LPS (29), similar to previously reported effects of CS. Although the biochemical mechanisms involved in these immunosuppressive effects are incompletely understood, they were associated with impaired NF-kB signaling (29).…”

“…Acrolein is known to be capable of suppressing macrophage activation (21), and our previous studies indicate that in vivo exposure of mice to acrolein leads to reduced innate immune responses to LPS (29), similar to previously reported effects of CS. Although the biochemical mechanisms involved in these immunosuppressive effects are incompletely understood, they were associated with impaired NF-kB signaling (29). Based on its chemical reactivity, the cellular effects of acrolein are mediated by depletion of cellular GSH and indirect dysregulation of redox signaling pathways, or by interference with cellular processes by direct alkylation of nucleophilic targets within critical proteins.…”

“…Such alterations in macrophage or DC responses have been associated with immunoregulatory actions of nicotine (49,50), but also are noted to involve redox-dependent mechanisms, demonstrated by findings that CS-mediated alterations in AM phenotype and function are linked to changes in GSH, and can be prevented by approaches to restore GSH status (14)(15)(16). Our results point to a prominent role for the reactive electrophile, acrolein, as exposure to acrolein readily suppresses innate AM responses, primarily M1-polarized responses characterized by production of NOS2, IL-12, and TNF-a (29). Moreover, similar to reported effects of smoking (3,4), acrolein exposure was found to primarily attenuate macrophage M1 responses, with relatively little effect or even stimulatory actions on anti-inflammatory M2 responses.…”

“…X02AI99C15A57H5; Specialty Glass, Houston, TX) and exposed to vaporized acrolein (Fluka BioChemika, Buchs, Switzerland) for 4 hours at a concentration of 5 ppm (11.5 mg/m 3 ) (29). After exposure, AMs were obtained by bronchoalveolar lavage, involving four washes of 0.5 ml sterile PBS, collected by centrifugation (1,500 rpm; 5 min) and used for in vitro experiments and analysis.…”

Modulation of NF-κB and Hypoxia-Inducible Factor−1 byS-Nitrosoglutathione Does Not Alter Allergic Airway Inflammation in Mice

“…Transcripts were amplified using the primers listed in Table E1 in the online supplement, with GAPDH (FAM channel) assay on demand (Applied Biosystems) as a housekeeping gene. The amplification reaction was run for 35 cycles, and relative quantity was calculated using DDCt analysis, as described previously (20).…”