Be activated by multiple stimuli. Regarding the potential for HCA to delay pulmonary epithelial wound

Be activated by multiple stimuli. Regarding the potential for HCA to delay pulmonary epithelial wound repair following mechanical injury, these studies raise concerns regarding epithelial repair in patients with ALI/ARDS undergoing `permissive’ hypercapnia.Pulmonary artery endothelial cellsAlveolar macrophages play a prominent role in the pathogenesis of ventilator-induced lung injury (VILI), possibly through the generation of cytokines, chemokines, nitric oxide (NO) and free radicals [47-49]. Upon stimulation, alveolar macrophages release proinflammatory cytokines and chemokines, resulting in the activation of polymorphonuclear leucocytes (reviewed in [50]). Activated polymorphonuclear leucocytes increase endothelial and epithelial permeability, resulting in tissue edema and accumulation of high-molecular-weight proteins in the airspaces (reviewed in [50]). HCA decreases cytokine release by alveolar macrophages and this effect appears to be primarily pH-mediated [51,52]. For instance, Lang and colleagues [53] demonstrated that CO2 decreased lipopolysaccharide (LPS)-induced TNF- secretion in rat alveolar macrophages in a dose-dependent fashion. Four hours after exposure to 20 CO2 (pH 5.8), TNF- secretion was only 50 compared to cells exposed to 2.5 CO2 (pH 7.2). However, buffering the culture medium pH to 7.2 completely abolished the effect of hypercapnia. A decrease in cell metabolic activity appeared to be responsible for the pH-induced decline in cytokine release in these cells as incubation with 20 CO2 resulted in an approximately 40 reduction in metabolic activity and an equal reduction in LPSstimulated TNF- secretion [54].Alveolar type II epithelial cellsHCA has been demonstrated to inhibit NF-B in pulmonary artery endothelial cells [60]. In isolated human pulmonary artery endothelial cells, Takeshita and colleagues [60] demonstrated that HCA suppressed IB degradation, resulting in reduced NF-B activity. This resulted in decreased expression of ICAM-1 and IL-8 with PX-478 site subsequent inhibition of neutrophil adherence (Figure 1). As inflammation plays an important role in the pathogenesis of VILI, this modulating effect of HCA on the inflammatory response may further reduce lung injury during mechanical ventilation associated with hypercapnia.Experiments in ex vivo lung preparationsHypercapnia has detrimental effects on alveolar type II epithelial cells. For example, in buffered fetal rat type II alveolar epithelial cells, injury is caused by a hypercapniamediated increase in NO, NO synthase and 3-nitrotyrosine leading to protein tyrosine nitration [55]. Additionally, in a scratch injury model where primary type II rat alveolar epithelial cells were injured with a surgical blade, HCA caused more permanent plasma membrane defects and an impaired rate of plasma membrane repair [56]. Recently, O’Toole and colleagues [57] reported impaired pulmonary epithelial wound healing by HCA-induced diminished cellular migration through inhibition of NF-B. NF-B is a transcription factor responsible for the transcription of intercellular adhesion molecule (ICAM)-1 and pro-inflammatory cytokines such as TNF-, IL-1, IL-6 and IL-8 (reviewed in [58,59]). NF-B is present in the cytoplasm in anIn isolated perfused rabbit lungs it has been demonstrated that HCA (pH 6.84, PCO2 15.96 kPa) prevents the development of microvascular permeability by PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/26740125 warm ischemia-reperfusion and free-radical-mediated lung injury, possibly via inhibition of endogenous xanthine ox.