Patrick Phelan, MD, Heather E

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Differential toll-like receptor activation in lung ischemia reperfusion injury Patrick Phelan, MD, Heather E. Merry, MD, Billanna Hwang, MPH, Michael S. Mulligan, MD The Journal of Thoracic and Cardiovascular Surgery Volume 149, Issue 6, Pages 1653-1661 (June 2015) DOI: 10.1016/j.jtcvs.2015.02.045 Copyright © 2015 Terms and Conditions

Figure 1 Overview of TLR activation in lung ischemia reperfusion injury; oxidative stress is initially transduced through TLR-4 activation in AM, triggering an inflammatory signaling cascade, leading to the development of lung injury. Products of AM activation augment and amplify the inflammatory responses, via TLR-2 pathways from both PAEC and T2P. TLR, Toll-like receptor; AM, alveolar macrophages; PAEC, pulmonary artery endothelial cells; ERK, extracellular signal-regulated kinase; T2P, type 2 pneumocytes; MAPK, mitogen-activated protein kinase; NFкβ, nuclear factor kappa beta. The Journal of Thoracic and Cardiovascular Surgery 2015 149, 1653-1661DOI: (10.1016/j.jtcvs.2015.02.045) Copyright © 2015 Terms and Conditions

Figure 2 Sequence-specific TLR-2 knockdown in vitro; primary cultures of alveolar macrophages pretreated with TLR-2 siRNA sequence-1, sequence-2, and sequence-3 demonstrated a reduction in TLR-2 expression by 87% (P < .001), 78% (P < .01), and 84% (P < .001), respectively, compared with alveolar macrophages pretreated with noncoding siRNA, as assessed by relative optical densitometry of Western blot analysis (n = 12 wells per group). siRNA, Short interference ribonucleic acid; TLR, toll-like receptor. The Journal of Thoracic and Cardiovascular Surgery 2015 149, 1653-1661DOI: (10.1016/j.jtcvs.2015.02.045) Copyright © 2015 Terms and Conditions

Figure 3 Mitogen-activated protein kinase phosphorylation after TLR-2 knockdown in alveolar macrophages; phosphorylation of p38 and JNK (pJNK) persisted (P > .02 and P > .02, respectively) in alveolar macrophages pretreated with TLR-2 siRNA, compared with noncoding siRNA–pretreated control alveolar macrophages after undergoing HR15, as assessed by relative optical densitometry of Western blot analysis (n = 12 wells per group). TLR, Toll-like receptor; siRNA, short interference ribonucleic acid; HR, hypoxia and reoxygenation; pp38, phosphorylation of p38; JNK, c-Jun N-terminal protein kinases; pJNK, phosphorylation of JNK. The Journal of Thoracic and Cardiovascular Surgery 2015 149, 1653-1661DOI: (10.1016/j.jtcvs.2015.02.045) Copyright © 2015 Terms and Conditions

Figure 4 Extracellular signal-regulated kinase phosphorylation after TLR-2 knockdown in vitro; pulmonary artery endothelial cells (PAEC) and T2P pretreated with TLR-2 siRNA demonstrated significant reduction in ERK phosphorylation (P < .01 and P < .01, respectively), compared with noncoding siRNA–pretreated control cells after undergoing HR15, as assessed by relative optical densitometry of Western blot analysis (n = 12 wells per group). TLR, Toll-like receptor; siRNA, short interference ribonucleic acid; HR, hypoxia and reoxygenation; PAEC, pulmonary artery endothelial cells; T2P, type 2 pneumocytes. The Journal of Thoracic and Cardiovascular Surgery 2015 149, 1653-1661DOI: (10.1016/j.jtcvs.2015.02.045) Copyright © 2015 Terms and Conditions

Figure 5 Extracellular signal-regulated kinase phosphorylation after TLR-2 knockdown of PAEC; no alteration occurred (P > .02) in extracellular signal-regulated kinase phosphorylation in PAEC pretreated with TLR-4 siRNA, compared with noncoding siRNA–pretreated control PAEC after undergoing HR15, as assessed by relative optical densitometry of Western blot analysis (n = 12 wells per group). siRNA, Short interference ribonucleic acid; HR, hypoxia and reoxygenation; TLR, toll-like receptor; PAEC, pulmonary artery endothelial cells. The Journal of Thoracic and Cardiovascular Surgery 2015 149, 1653-1661DOI: (10.1016/j.jtcvs.2015.02.045) Copyright © 2015 Terms and Conditions

Figure 6 Cytokine production after TLR-2 and TLR-4 knockdown in vitro; CINC production is not affected (P > .02 and P > .02, respectively) by TLR-4 knockdown in pulmonary artery endothelial cells or type 2 pneumocytes, but is reduced by 76% (P < .001) and 78% (P < .001), respectively, with TLR-2 knockdown in these cell types, compared with noncoding siRNA–pretreated control cells after undergoing HR4. Conversely, CINC production is not affected (P > .02) by TLR-2 knockdown in alveolar macrophages, but is reduced by 97% (P < .001) with TLR-4 knockdown in alveolar macrophages, compared with noncoding siRNA–pretreated control cells after undergoing HR4. CINC, Cytokine-induced neutrophil chemoattractant; siRNA, Short interference ribonucleic acid; HR, hypoxia and reoxygenation; TLR, toll-like receptor. The Journal of Thoracic and Cardiovascular Surgery 2015 149, 1653-1661DOI: (10.1016/j.jtcvs.2015.02.045) Copyright © 2015 Terms and Conditions

Figure 7 Permeability index after TLR-2 and TLR-4 knockdown in vivo; with TLR-4 siRNA pretreatment, the vascular permeability was reduced by 85% (P < .001), compared with noncoding siRNA–pretreated control animals after undergoing ischemia and reperfusion. No statistical difference was found (P > .02) in the vascular permeability in animals pretreated with TLR-4 siRNA before undergoing ischemia and reperfusion versus negative control animals that did not receive pretreatment or undergo ischemia reperfusion. In contrast, pretreatment with TLR-2 siRNA did not confer protection (P > .02) from subsequent ischemia reperfusion injury, compared with noncoding siRNA–pretreated animals after undergoing ischemia and reperfusion (n = 4 animals per group). siRNA, Short interference ribonucleic acid; HR, hypoxia and reoxygenation; TLR, toll-like receptor. The Journal of Thoracic and Cardiovascular Surgery 2015 149, 1653-1661DOI: (10.1016/j.jtcvs.2015.02.045) Copyright © 2015 Terms and Conditions

Overview of toll-like receptor activation in lung ischemia reperfusion injury. The Journal of Thoracic and Cardiovascular Surgery 2015 149, 1653-1661DOI: (10.1016/j.jtcvs.2015.02.045) Copyright © 2015 Terms and Conditions