title: Low pH environmental stress inhibits LPS and LTA-stimulated proinflammatory cytokine production in rat alveolar macrophages.
abstract: Gastric aspiration increases the risks for developing secondary bacterial pneumonia. Cytokine elaboration through pathogen recognition receptors (PRRs) is an important mechanism in initiating innate immune host response. Effects of low pH stress, a critical component of aspiration pathogenesis, on the PRR pathways were examined, specifically toll-like receptor-2 (TLR2) and TLR4, using isolated rat alveolar macrophages (aMØs). We assessed the ability of aMØs after brief exposure to acidified saline to elaborate proinflammatory cytokines in response to lipopolysaccharide (LPS) and lipoteichoic acid (LTA) stimulation, known ligands of TLR4 and TLR2, respectively. Low pH stress reduced LPS- and LTA-mediated cytokine release (CINC-1, MIP-2, TNF-α, MCP-1, and IFN-β). LPS and LTA increased intracellular Ca²⁺ concentrations while Ca²⁺ chelation by BAPTA decreased LPS- and LTA-mediated cytokine responses. BAPTA blocked the effects of low pH stress on most of LPS-stimulated cytokines but not of LTA-stimulated responses. In vivo mouse model demonstrates suppressed E. coli and S. pneumoniae clearance following acid aspiration. In conclusion, low pH stress inhibits antibacterial cytokine response of aMØs due to impaired TLR2 (MyD88 pathway) and TLR4 signaling (MyD88 and TRIF pathways). The role of Ca²⁺ in low pH stress-induced signaling is complex but appears to be distinct between LPS- and LTA-mediated responses.
authors.affiliation: Department of Medicine, Division of Cardiovascular Medicine, University at Buffalo, Suite 7030, 875 Ellicott Street, Buffalo, NY 14203, USA.
authors.forename: Stanley F
authors.initials: SF
authors.lastname: Fernandez
authors.forename: Christopher
authors.initials: C
authors.lastname: Fung
authors.forename: Jadwiga D
authors.initials: JD
authors.lastname: Helinski
authors.forename: Ravi
authors.initials: R
authors.lastname: Alluri
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Davidson
authors.forename: Paul R
authors.initials: PR
authors.lastname: Knight
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis*; D004781:Environmental Exposure / Q000009:adverse effects*; D006863:Hydrogen-Ion Concentration; D008070:Lipopolysaccharides / Q000633:toxicity*; D016676:Macrophages, Alveolar / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D051381:Rats; D020318:Rats, Long-Evans; D013312:Stress, Physiological / Q000187:drug effects*; D013682:Teichoic Acids / Q000633:toxicity*; D051195:Toll-Like Receptor 2 / Q000096:biosynthesis; D051197:Toll-Like Receptor 4 / Q000096:biosynthesis
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D013682:Teichoic Acids; C495343:Tlr2 protein, rat; C495347:Tlr4 protein, rat; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; C009900:lipoteichoic acid; D002118:Calcium