Stroke‐induced activation of the α7 nicotinic receptor increasesPseudomonas aeruginosalung injury

Abstract

Infectious complications, predominantly pneumonia, are the most common cause of death in the postacute phase of stroke, although the mechanisms underlying the corresponding immunosuppression are not fully understood. We tested the hypothesis that activation of the α7 nicotinic acetylcholine receptor (α7nAChR) pathway is important in the stroke-induced increase in lung injury caused by Pseudomonas aeruginosa pneumonia in mice. Prior stroke increased lung vascular permeability caused by P. aeruginosa pneumonia and was associated with decreased lung neutrophil recruitment and bacterial clearance in mice. Pharmacologic inhibition (methyllycaconitine IC(50): 0.2-0.6 nM) or genetic deletion of the α7nAChR significantly (P<0.05) attenuates the effect of prior stroke on lung injury and mortality caused by P. aeruginosa pneumonia in mice. Finally, pretreatment with PNU-282987, a pharmacologic activator of the α7nAChR (EC(50): 0.2 μM), significantly (P<0.05) increased lung injury caused by P. aeruginosa pneumonia, significantly (P<0.05) decreased the release of KC, a major neutrophil chemokine, and significantly (P<0.05) decreased intracellular bacterial killing by a mouse alveolar macrophage cell line and primary mouse neutrophils. In summary, the α7 nicotinic cholinergic pathway plays an important role in mediating the systemic immunosuppression observed after stroke and directly contributes to more severe lung damage induced by P. aeruginosa.

The Use of microRNAs to Modulate Redox and Immune Response to Stroke

“…The absence of T cells has been shown by several groups to reduce ischemic injury, although the extent of reperfusion may be important to this effect (193). Paradoxically, poststroke immune suppression is known to render stroke patients vulnerable to infections, including pneumonia and sepsis, acting, in part, by activation of the a7 nicotinic acetylcholine receptor to inhibit neutrophil and macrophage accumulation and function (91). Increased sympathetic activation and impairment of the hypothalamic/pituitary/adrenal axis lead to a reduction in T and B lymphocytes, thereby increasing the risk of diminished neurological outcome and death (78).…”

Acetylcholine Protects against Candida albicans Infection by Inhibiting Biofilm Formation and Promoting Hemocyte Function in a Galleria mellonella Infection Model

“…Furthermore, ␣7nAChR Ϫ/Ϫ mice infected with Escherichia coli developed more severe lung injury and had higher mortality rates than ␣7nAChR ϩ/ϩ mice (10), and ␣7nAChR activation attenuated systemic inflammation in a polymicrobial abdominal sepsis model (11). In contrast, activation of the "cholinergic anti-inflammatory pathway" had a detrimental effect on disease outcome in mouse models of E. coli-induced peritonitis (12) and pneumonia (13), as well as stroke-induced Pseudomonas aeruginosa lung infection (14). Therefore, the role ACh plays in the pathogenesis of bacterial disease depends on the site of infection and etiological agent.…”

Heat-shock Response Increases Lung Injury Caused by Pseudomonas aeruginosa via an Interleukin-10-dependent Mechanism in Mice

“…The assay was performed, as we have previously published 26 . MH-S cells, a murine alveolar macrophage cell line (1× 10 6 cells), were heat shocked at 43°C for 30 min, then recovered at 37°C for 1 h before adding 10 7 CFU (colony forming units)/ml of P. aeruginosa PAK for 45 min at 37°C.…”

“…The mouse pneumonia model was performed, as we have previously reported 26 . Briefly, mice were anesthetized with tribromoethanol (250 mg/kg, intraperitoneally).…”

“…Lung endothelial permeability to protein (%) and excess lung water (µl) was measured, as previously described 26 . Briefly, 0.5 µCi of 125 I-albumin was injected intraperitoneally 2 h before sacrificing the animals to ensure adequate tracer distribution.…”