Oxidized phospholipids impair pulmonary antibacterial defenses: Evidence in mice exposed to cigarette smoke

Abstract

Patients with COPD are associated with poor pulmonary anti-bacterial innate defenses, which increase the risk for frequent acute exacerbations caused by bacterial infection. Despite elevated numbers of phagocytes (macrophages and neutrophils), airways of patients with COPD show stable bacterial colonization. A defect in the phagocytic ability of alveolar macrophages (AMs) is one of the primary reasons for failure to clear the invading bacteria in airways of smokers and COPD patients and also in mice exposed to cigarette smoke (CS). Oxidative stress, as a result of CS exposure is implicated; however, the factors or mediators that inhibit phagocytic activity of AMs in lungs of smokers remain unclear. In the current study, we provide evidence that accumulation of oxidized phospholipids (Ox-PLs) mediate inhibition of phagocytic function of AMs in CS-exposed mice. Mice exposed to 6 months of CS showed impaired bacterial phagocytosis and clearance by AMs and elevated levels of Ox-PLs in bronchoalveolar lavage fluid (BALF), compared to mice exposed to room air. Intratracheal instillation of oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (OX-PAPC) inhibited phagocytic activity of AMs and impaired pulmonary bacterial clearance in mice. In vitro studies demonstrated that exposure of J774 macrophages to OX-PAPC inhibited bacterial phagocytosis and clearance. However, pre-treatment of OX-PAPC with the monoclonal antibody EO6, which specifically binds to oxidized phospholipid but not native phospholipid, abolished OX-PAPC induced inhibition of bacterial phagocytosis and clearance. Incubation of BALF retrieved from CS-exposed mice impaired bacterial phagocytosis by J774 macrophages, which was abolished by pre-treatment of BALF with the EO6 antibody. In conclusion, our study shows that Ox-PLs generated following chronic CS exposure could play a crucial role in inhibiting phagocytic function of AMs and thus impair pulmonary anti-bacterial innate defenses in CS-exposed mice. Therapeutic approaches that augment pulmonary antioxidant defenses could be beneficial in reducing oxidative stress-driven impairment of phagocytosis by AMs in smokers and COPD patients.

Impacts of peroxisome proliferator-activated receptor-γ activation on cigarette smoke-induced exacerbated response to bacteria

“…PPARγ is known to activate lipid metabolism [10]. It has recently been shown that cigarette smoke exposure leads to the generation of modified phospholipids that inhibit phagocytosis of bacteria [22]. Therefore, PPARγ activation may help in processing inhibitory phospholipids from the extracellular lung environment to allow binding of the bacteria by alveolar macrophages and neutrophils.…”

“…PPARγ activation does not restore phagocytic activity of alveolar macrophages Cigarette smoke exposure has been shown to compromise phagocytic activity of alveolar macrophages [21,22]. We next investigated if rosiglitazone treatment restored the phagocytic activity of alveolar macrophages ex vivo.…”

B Cells and Humoral Immunity in Atherosclerosis

“…78 Indeed, T15/E06 IgM has been found to prevent OxPAPC (oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine)–induced IL-6 secretion by macrophages 79 and to block the ability of OxPL to decrease macrophage phagocytosis. 80 Many more natural IgMs with specificity for other OSEs exist, which represent a prominent fraction (20%–30%) of all natural IgMs in mice and humans. 66 For example, IgM with specificity for malondialdehyde epitopes, such as the natural IgM NA17, also bind apoptotic cells and enhance the in vivo clearance of injected apoptotic cells by peritoneal macrophages.…”

Neutrophils and emerging targets for treatment in chronic obstructive pulmonary disease

“…Furthermore, NF-kB is upregulated leading to an increased expression of proinflammatory cytokines and an increased activation of recruited immune cells. Furthermore, high levels of ROS can induce the formation of oxygenated phospholipids, which potently inhibit phagocytic activity of alveolar macrophages [62,106]. The dysfunction of these cells is thought to be the reason COPD patients show stable bacterial colonization, despite the increased infiltration of phagocytic cells in the lungs.…”