title: Hypertensive rats are susceptible to TLR4-mediated signaling following exposure to combustion source particulate matter.
abstract: Toll-like receptor 4 (TLR4) has been shown to play a role in cell signaling that results in neutrophilic inflammation in response to lipopolysaccharide and respiratory syncytial virus infection. TLR4 also interacts with CD14, which upon complex formation triggers TLR4-associated signaling pathways to produce a proinflammatory response. This mechanism results in the activation of NF-kappa B and subsequent inflammatory gene induction. In order to determine the effect of combustion source particle matter (PM), rich in zinc and nickel but with negligible endotoxin, on a possible activation of TLR4-mediated cell signaling and inflammation, we intratracheally (IT) instilled 3.3 mg/kg of PM into 12-w-old healthy male Wistar Kyoto (WKY) and susceptible spontaneously hypertensive (SH) rats. Inflammation, inflammatory-mediator gene expression, bronchoalveolar lavage fluid (BALF) protein and LDH, TLR4 and CD14 protein, and NF-kappa B activation in the lung were determined after 24 h. Dose-response data (0.0, 0.83, 3.33, and 8.3 mg/kg PM) for BALF LDH were obtained as a marker of lung cell injury in SH rats. BALF neutrophils, but not macrophages, were significantly increased in the PM-exposed WKY and SH rats. SH rats showed a greater PMN increase than WKY rats. Similarly, BALF protein and LDH levels were also increased following PM exposure but to a significantly greater extent in SH rats. Plasma fibrinogen was increased only in SH rats exposed to PM. The increased inflammation seen in PM-exposed SH rats was accompanied by a significant increase in TLR4 protein in the lung tissue, which was primarily localized in alveolar macrophages and epithelial cells. CD14 was also increased by PM exposure in both SH and WKY rats but was significantly greater in the SH rats. These increases were associated with greater translocation of NF-kappa B in the lungs of SH rather than WKY rats. This was accompanied by increased macrophage inhibitory protein (MIP)-2 mRNA expression at 24 h of exposure. These data suggest that the increased inflammation in the lungs of PM-exposed SH rats compared to WKY rats is accompanied by an increase in TLR4-mediated cell signaling. Thus, one of the mechanisms for greater susceptibility of SH rats to PM exposure may involve an increased activation of the TLR4 signaling pathway.
authors.affiliation: Center for Environmental Medicine, Asthma and Lung Biology, School of Medicine, University of North Carolina at Chapel Hill, USA. gilmour.peter@epa.gov
authors.forename: Peter S
authors.initials: PS
authors.lastname: Gilmour
authors.forename: Mette C
authors.initials: MC
authors.lastname: Schladweiler
authors.forename: Judy H
authors.initials: JH
authors.lastname: Richards
authors.forename: Allen D
authors.initials: AD
authors.lastname: Ledbetter
authors.forename: Urmila P
authors.initials: UP
authors.lastname: Kodavanti
mesh_terms: D000393:Air Pollutants / Q000633:toxicity*; D000818:Animals; D001900:Boston; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D054426:Chemokine CXCL2; D006973:Hypertension / Q000097:blood / Q000235:genetics / Q000276:immunology*; D007150:Immunohistochemistry; D017745:Incineration; D007249:Inflammation / Q000209:etiology; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D018950:Lipopolysaccharide Receptors / Q000032:analysis / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000032:analysis; D008168:Lung / Q000187:drug effects* / Q000276:immunology* / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis / Q000096:biosynthesis / Q000276:immunology*; D008670:Metals / Q000633:toxicity; D015846:Monokines / Q000032:analysis; D016328:NF-kappa B / Q000032:analysis; D011210:Power Plants; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D011956:Receptors, Cell Surface / Q000032:analysis / Q000096:biosynthesis / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014132:Trachea; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
chemical_list: D000393:Air Pollutants; D054426:Chemokine CXCL2; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D008670:Metals; D015846:Monokines; D016328:NF-kappa B; D011956:Receptors, Cell Surface; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D007770:L-Lactate Dehydrogenase