CD36 Mediates Endothelial Dysfunction Downstream of Circulating Factors Induced by O3 Exposure

Abstract

Inhaled pollutants induce the release of vasoactive factors into the systemic circulation, but little information is available regarding the nature of these factors or their receptors. The pattern recognition receptor CD36 interacts with many damage-related circulating molecules, leading to activation of endothelial cells and promoting vascular inflammation; therefore, we hypothesized that CD36 plays a pivotal role in mediating cross talk between inhaled ozone (O3)-induced circulating factors and systemic vascular dysfunction. O3 exposure (1 ppm × 4h) induced lung inflammation in wild-type (WT) mice, which was absent in the CD36 deficient (CD36(-/-)) mice. Acetylcholine (ACh)-evoked vasorelaxation was impaired in isolated aortas from O3-exposed WT mice but not in vessels from CD36(-/-) mice. To delineate whether vascular impairments were caused by lung inflammation or CD36-mediated generation of circulating factors, naïve aortas were treated with diluted serum from control or O3-exposed WT mice, which recapitulated the impairments of vasorelaxation observed after inhalation exposures. Aortas from CD36(-/-) mice were insensitive to the effects of O3-induced circulating factors, with robust vasorelaxation responses in the presence of serum from O3-exposed WT mice. Lung inflammation was not a requirement for production of circulating vasoactive factors, as serum from O3-exposed CD36(-/-) mice could inhibit vasorelaxation in naïve WT aortas. These results suggest that O3 inhalation induces the release of circulating bioactive factors capable of impairing vasorelaxation to ACh via a CD36-dependent signaling mechanism. Although lung inflammatory and systemic vascular effects were both dependent on CD36, the presence of circulating factors appears to be independent of CD36 and inflammatory responses.

Ozone Exposure Triggers Insulin Resistance Through Muscle c-Jun N-Terminal Kinase Activation

“…Taken together, these results strongly suggest that inflammation is not directly responsible for the defects observed in muscle. This is consistent with a recent study (14) showing that lung inflammation was not a requirement for the production of circulating vasoactive factors after O 3 exposure. Lung inflammation is, however, an important source of radical species (47) and may contribute to the oxidative chain reactions induced by O 3 .…”

“…Children and the elderly are particularly sensitive to the pulmonary health effects of O 3 , inducing or worsening asthma, chronic obstructive pulmonary diseases, and lung inflammation (8,9). In addition, many extrapulmonary effects of O 3 have been described: activation of stress-responsive regions, catecholamine biosynthesis, cell degeneration, neurochemical alterations in the central nervous system (10,11), increased production of nitric oxide, enhanced protein synthesis and inflammation in the liver (12), compensatory changes, edema, and increased oxidative stress in heart tissue (13,14). Taken together, these studies demonstrate that O 3 can exert many deleterious effects in distant tissues.…”

Serum-borne bioactivity caused by pulmonary multiwalled carbon nanotubes induces neuroinflammation via blood–brain barrier impairment

“…In the present study, serum TSP-1 level was elevated by MWCNT aspiration, and the absence of CD36 prevented both the increased BBB permeability and neuroinflammation induced by MWCNT exposure. Importantly, previous studies with related pollutants have noted the involvement of related scavenger receptors (including CD36, Toll-like receptor 4, and lectin-like receptor for oxidized low-density lipoprotein 1) and ligands (including oxidized lipids and lipoproteins) (17,50). Thus, TSP-1 is likely an important facet of a more complex response to inhaled agents, and further studies are needed to identify the origin of TSP-1 and the timing of the response, to mechanistically confirm the interaction with CD36 and/or CD47 on endothelial cells, and to ascertain whether TSP-1 specifically crosses into the brain.…”

“…protein cluster of differentiation 36 (CD36) as a mediator of vasodilatory impairment following pulmonary exposure to ozone (17). CD36 is a class II scavenger receptor involved in a wide range of processes, including fatty acid metabolism (29), heart disease, and atherosclerosis (30).…”

“…Despite their very limited ability to translocate beyond the lung (12), MWCNTs have been shown to induce extrapulmonary toxicity through as-yet unknown pathways (13)(14)(15). Pulmonary interactions with inhaled pollutants, including MWCNTs, can generate secondary bioactive factors that spill over into the systemic circulation and are distributed throughout the body (15)(16)(17). One consequence of these circulating factors is activation of the endothelium, characterized by the expression of adhesion molecules and recruitment/activation of circulating inflammatory cells (18).…”