e2 42 Max M, Pison U, Floros J Frequency of SP B and SP A1 gene poly morphisms in the acute respiratory distress syndrome (ARDS) Appl Cardiopulm Physiol 1996;6 111 118 43 Quasney MW, Waterer GW, Dahme[.]
e2 42 Max M, Pison U, Floros J Frequency of SP-B and SP-A1 gene polymorphisms in the acute respiratory distress syndrome (ARDS) Appl Cardiopulm Physiol 1996;6:111-118 43 Quasney MW, Waterer GW, Dahmer MK, et al Association between surfactant protein B 11580 polymorphism and the risk of respiratory failure in adults with community-acquired pneumonia Crit Care Med 2004;32(5):1115-1119 44 Adamzik M, Frey U, Sixt S, et al ACE I/D but not AGT (-6)A/G polymorphism is a risk factor for mortality in ARDS Eur Respir J 2007;29(3):482-488 45 Jerng JS, Yu CJ, Wang HC, Chen KY, Cheng SL, Yang PC Polymorphism of the angiotensin-converting enzyme gene affects the outcome of acute respiratory distress syndrome Crit Care Med 2006;34(4):1001-1006 46 Marshall RP, Webb S, Bellingan GJ, et al Angiotensin converting enzyme insertion/deletion polymorphism is associated with susceptibility and outcome in acute respiratory distress syndrome Am J Respir Crit Care Med 2002;166(5):646-650 47 Marshall RP, Webb S, Hill MR, Humphries SE, Laurent GJ Genetic polymorphisms associated with susceptibility and outcome in ARDS Chest 2002;121(suppl 3):68S-69S 48 Flores C, Ma SF, Maresso K, Wade MS, Villar J, Garcia JG IL6 gene-wide haplotype is associated with susceptibility to acute lung injury Transl Res 2008;152(1):11-17 49 Nonas SA, Finigan JH, Gao L, Garcia JG Functional genomic insights into acute lung injury: role of ventilators and mechanical stress Proc Am Thorac Soc 2005;2(3):188-194 50 Sutherland AM, Walley KR, Manocha S, Russell JA The association of interleukin haplotype clades with mortality in critically ill adults Arch Intern Med 2005;165(1):75-82 51 Meyer NJ, Li M, Feng R, et al ANGPT2 genetic variant is associated with trauma-associated acute lung injury and altered plasma angiopoietin-2 isoform ratio Am J Respir Crit Care Med 2011; 183(10):1344-1353 52 Reilly JP, Wang F, Jones TK, et al Plasma angiopoietin-2 as a potential causal marker in sepsis-associated ARDS development: evidence from Mendelian randomization and mediation analysis Intensive Care Med 2018;44(11):1849-1858 53 Su L, Zhai R, Sheu CC, et al Genetic variants in the angiopoietin-2 gene are associated with increased risk of ARDS Intensive Care Med 2009;35(6):1024-1030 54 Dahmer MK, O’Cain P, Patwari PP, et al The influence of genetic variation in surfactant protein B on severe lung injury in black children Crit Care Med 2011;39:1138-1144 55 Patwari PP, O’Cain P, Goodman DM, et al Interleukin-1 receptor antagonist intron VNTR polymorphism and respiratory failure in children with community-acquired pneumonia Pediatr Crit Care Med 2008;9:553-559 56 Zhao X, He J, Xie G, et al Genetic variations in inflammation-related genes and their influence on the susceptibility of pediatric acute lung injury in a Chinese population Gene 2019;687:16-22 57 Baughn JM, Quasney MW, Simpson P, et al Association of cystic fibrosis transmembrane conductance regulator gene variants with acute lung injury in African American children with pneumonia Crit Care Med 2012;40(11):3042-3049 58 Bime C, Pouladi N, Sammani S, et al Genome-wide association study in African Americans with acute respiratory distress syndrome identifies the selectin P ligand gene as a risk factor Am J Respir Crit Care Med 2018;197(11):1421-1432 59 Shortt K, Chaudhary S, Grigoryev D, et al Identification of novel single nucleotide polymorphisms associated with acute respiratory distress syndrome by exome-seq PLoS One 2014;9(11):e111953 60 Shanley TP, Cvijanovich N, Lin R, et al Genome-level longitudinal expression of signaling pathways and gene networks in pediatric septic shock Mol Med 2007;13(9-10):495-508 61 Wong HR, Cvijanovich N, Allen GL, et al Genomic expression profiling across the pediatric systemic inflammatory response syndrome, sepsis, and septic shock spectrum Crit Care Med 2009;37(5): 1558-1556 62 Wong HR, Shanley TP, Sakthivel B, et al Genome-level expression profiles in pediatric septic shock indicate a role for altered zinc homeostasis in poor outcome Physiol Genomics 2007;30(2):146-155 63 Wong HR, Cvijanovich N, Lin R, et al Identification of pediatric septic shock subclasses based on genome-wide expression profiling BMC Med 2009;7:34 64 Wong HR, Cvijanovich NZ, Allen GL, et al Validation of a gene expression-based subclassification strategy for pediatric septic shock Crit Care Med 2011;39(11):2511-2517 65 Wong HR, Wheeler DS, Tegtmeyer K, et al Toward a clinically feasible gene expression-based subclassification strategy for septic shock: proof of concept Crit Care Med 2010;38(10):1955-1961 66 Wong HR, Cvijanovich NZ, Anas N, et al Developing a clinically feasible personalized medicine approach to pediatric septic shock Am J Respir Crit Care Med 2015;191(3):309-315 67 Wong HR, Sweeney TE, Hart KW, Khatri P, Lindsell CJ Pediatric sepsis endotypes among adults with sepsis Crit Care Med 2017;45(12):e1289-e1291 68 Burnham KL, Davenport EE, Radhakrishnan J, et al Shared and distinct aspects of the sepsis transcriptomic response to fecal peritonitis and pneumonia Am J Respir Crit Care Med 2017;196(3):328-339 69 Davenport EE, Burnham KL, Radhakrishnan J, et al Genomic landscape of the individual host response and outcomes in sepsis: a prospective cohort study Lancet Respir Med 2016;4(4):259-271 70 Yehya N, Thomas NJ, Wong HR Evidence of endotypes in pediatric acute hypoxemic respiratory failure caused by sepsis Pediatr Crit Care Med 2019;20(2):110-112 71 Wong HR, Salisbury S, Xiao Q, et al The pediatric sepsis biomarker risk model Crit Care 2012;16(5):R174 72 Wong HR, Weiss SL, Giuliano Jr JS, et al Testing the prognostic accuracy of the updated pediatric sepsis biomarker risk model PLoS One 2014;9(1):e86242 73 Wong HR, Lindsell CJ, Pettila V, et al A multibiomarker-based outcome risk stratification model for adult septic shock Crit Care Med 2014;42(4):781-789 74 Wong HR, Cvijanovich NZ, Anas N, et al Prospective testing and redesign of a temporal biomarker based risk model for patients with septic shock: implications for septic shock biology EBioMedicine 2015;2(12):2087-2093 75 Wong HR, Cvijanovich NZ, Anas N, et al Pediatric Sepsis Biomarker Risk Model-II: redefining the pediatric sepsis biomarker risk model with septic shock phenotype Crit Care Med 2016; 44(11):2010-2017 76 Wong HR, Cvijanovich NZ, Anas N, et al Improved risk stratification in pediatric septic shock using both protein and mRNA biomarkers PERSEVERE-XP Am J Respir Crit Care Med 2017;196(4): 494-501 77 Calfee CS, Delucchi K, Parsons PE, et al Subphenotypes in acute respiratory distress syndrome: latent class analysis of data from two randomised controlled trials Lancet Respir Med 2014;2(8):611-620 78 Calfee CS, Delucchi KL, Sinha P, et al Acute respiratory distress syndrome subphenotypes and differential response to simvastatin: secondary analysis of a randomised controlled trial Lancet Respir Med 2018;6(9):691-698 79 Famous KR, Delucchi K, Ware LB, et al Acute respiratory distress syndrome subphenotypes respond differently to randomized fluid management strategy Am J Respir Crit Care Med 2017;195(3): 331-338 80 Sinha P, Delucchi KL, Thompson BT, et al Latent class analysis of ARDS subphenotypes: a secondary analysis of the statins for acutely injured lungs from sepsis (SAILS) study Intensive Care Med 2018;44(11):1859-1869 81 Delucchi K, Famous KR, Ware LB, Parsons PE, Thompson BT, Calfee CS Stability of ARDS subphenotypes over time in two randomized control trials Thorax 2018;73:439-445 e3 82 Bos LD, Schouten LR, van Vught LA, et al Identification and validation of distinct biological phenotypes in patients with acute respiratory distress syndrome by cluster analysis Thorax 2017;72(10):876-883 83 Bos LDJ, Scicluna BP, Ong DSY, Cremer O, van der Poll T, Schultz MJ Understanding heterogeneity in biologic phenotypes of acute respiratory distress syndrome by leukocyte expression profiles Am J Respir Crit Care Med 2019;200(1):42-50 84 Flori H, Sapru A, Quasney MW, et al A prospective investigation of interleukin-8 levels in pediatric acute respiratory failure and acute respiratory distress syndrome Crit Care 2019;23(1):128 85 Sapru A, Flori H, Quasney MW, Dahmer MK for the Pediatric Acute Lung Injury Consensus Conference Pathobiology of acute respiratory distress syndrome Pediatr Crit Care Med 2015;16: S41-S50 e4 Abstract: Significant heterogeneity exists in patients with sepsis and acute respiratory distress syndrome (ARDS) Failure of many treatments tested in these cohorts has been attributed in part to heterogeneity Multiple approaches have been used to begin to address heterogeneity in patients with sepsis and ARDS, including genomics, transcriptomics, and novel analyses of plasma biomarkers These approaches are designed to identify subgroups of individuals with increased risk for poor outcome (prognostic enrichment) or with common pathophysiology (predictive enrichment) Results suggest that patients with septic shock and ARDS can be separated into at least two subgroups distinguished by characteristics of their immune response Key words: sepsis, septic shock, pediatric acute respiratory distress syndrome, genome-wide association, transcriptomics, children, precision medicine, predictive enrichment, prognostic enrichment 83 Molecular Foundations of Cellular Injury JOCELYN R GRUNWELL AND CRAIG M COOPERSMITH • Cell death can occur via either regulated or unregulated pathways.1 Exposure of cells to extreme physical or chemical environmental conditions—such as high temperatures and pressures, shear stress, dangerous pH variations, and steep osmotic gradients—results in accidental or unregulated cell death In contrast, the host has evolutionarily conserved machinery dedicated to removing unneeded or dangerous cells via multiple complementary mechanisms Together, these are termed regulated cell death (RCD) On a chronic basis, the need to balance cellular proliferation with cellular elimination is straightforward, since continued production of new cells without any method to eliminate older or unnecessary cells would end up with an untenable state of an everincreasing number of cells in the body (especially for rapidly proliferating cell types) In addition, the body needs a method to rapidly respond to an acute insult, such as would be seen in a critically ill patient For example, tissue injury and inflammation associated with infectious organisms result in the release of pathogen-associated molecular patterns (PAMPs) and dying host cells release danger-associated molecular patterns (DAMPs) to alert surrounding host cells of a threat Both PAMPs and DAMPs alert the body to the presence of microbes and endogenous danger, respectively In turn, each can activate signaling pathways that may culminate in RCD RCD is directly relevant to critical care since cell death occurs in multiple processes in the intensive care unit, including (but not limited to) sepsis, trauma, ischemia-reperfusion injury, oncology, autoimmune, autoinflammatory diseases, and multiple-organ dysfunction syndrome (MODS) Notably, RCD is neither “good” nor “bad” but needs to be understood within the context of the underlying physiologic state RCD is clearly adaptive over the course of a host’s life when appropriately regulated, although it 996 • • Cell death is an important physiologic homeostatic mechanism critical for host survival Regulated cell death pathways are evolutionarily conserved processes and include caspase-dependent (apoptosis, pyroptosis) and caspase-independent (necroptosis, mitochondrial permeability transition mediated-regulated necrosis, ferroptosis, and parthanatos) mechanisms Mechanisms of cell death are important in many critical illnesses, including sepsis, solid organ transplant, ischemia- • • • PEARLS reperfusion injury, acute kidney injury, acute respiratory distress syndrome, trauma and traumatic brain injury, and multiple-organ dysfunction syndrome Apoptosis is the least immunogenic regulated cell death pathway Autophagy is a recycling mechanism for a cell to reuse damaged proteins and organelles Understanding mechanisms of regulated cell death is important, as these signaling pathways are targets for developing treatments for human critical illness can be maladaptive when machinery is either over- or underactive While RCD can also be beneficial in the acute setting, excessive induction of RCD can be maladaptive, such as when excessive death of lymphocytes in sepsis leads to an immunosuppressed host As such, in selected clinical scenarios, RCD represents a therapeutic target that could be potentially harnessed to disrupt pathologic inflammation–cell death circuits resulting in shock, organ failure, and, ultimately, patient death The understanding of RCD has expanded recently, and guidelines have been formulated to define RCD by molecular mechanisms and machinery involved in each process.2 RCD pathways are categorized as to whether they are immunogenic and caspasedependent (Fig 83.1) Immunogenic cell death is a form of RCD that is sufficient to activate an adaptive immune response in an immunocompetent host Caspases are a family of cysteine-aspartic proteases that have an essential role in some forms of RCD, specifically apoptosis and pyroptosis The objective of this chapter is to introduce a framework to understand the multiple forms of RCD, highlight key rodent studies demonstrating either a direct causative linkage between RCD and mortality or important mechanistic insights, and to review data relevant to human critical illness Caspase-Dependent Forms of Regulated Cell Death Apoptosis and pyroptosis are caspase-dependent forms of RCD Apoptosis, the most widely studied method of RCD, is considered less immunogenic than pyroptosis because there is no disruption of the plasma membrane and therefore no release of CHAPTER 83 Molecular Foundations of Cellular Injury Caspase independent Caspase dependent Apoptosis Extrinsic Intrinsic Caspase Transient MOMP Necroptosis Pyroptosis Inflammasomes TLR3 or TLR4 Death receptor IFNs MPT-RN Parthanatos Ferroptosis NETosis Ca2+ PARP1 hyperactivation Cystine deprivation Neutrophil activation PAR polymers Glutathione depletion Persistent MOMP Persistent MOMP GPX4 inhibition AIF release? AIF release? Lipid peroxidation STAT3 PKR Caspase • Caspase • Caspase • Caspase • IL-1β • IL-18 Blebbing 997 Caspase 11 TRIF DAI RIPK3 RIPK1 pMLKL Persistent plasma membrane integrity Plasma membrane rupture Non-immunogenic clearance of dead cells Inflammation • Fig 83.1 Overview of regulated cell death (RCD) signaling pathways RCD pathways may be classified as caspase dependent or independent Apoptosis and pyroptosis are caspase dependent; however, apoptosis is the least immunogenic of RCD pathways due to the presence of an intact plasma membrane Apoptosis can be instigated by extrinsic signals initiated by cell surface death receptors or by intrinsic mitochondrial stress signals Pyroptosis is an immunogenic form of RCD that requires two stress signals sensed by a multiprotein inflammasome complex, of which there are several types, resulting in activation of proinflammatory cytokines, IL-1b and IL-18 Necroptosis, mitochondrial permeability transition-medicated regulated necrosis (MPT-RN), ferroptosis, and NETosis are also immunogenic caspase-independent forms of RCD ADP, Adenosine diphosphate; AIF, apoptosis-inducing factor; DAI, DNA-dependent activator of IFN-regulatory factors; GPX4, glutathione peroxidase 4; IFN, interferon; IL, interleukin; MOMP, mitochondrial outer membrane permeabilization; NET, neutrophil extracellular trap; PAR, poly(ADP-ribose); PARP1, PAR polymerase 1; PKR, protein kinase R; pMLKL, phosphorylated mixed-lineage kinase domain-like protein; RIPK, receptor-interacting serine/threonine-protein kinase; STAT3, signal transducer and activator of transcription 3; TLR, Toll-like receptor; TRIF, TIR domain-containing adaptor protein inducing IFN-b (Modified from Linkermann A, Stockwell BR, Krautwald S, et al Regulated cell death and inflammation: an auto-amplification loop causes organ failure Nat Rev Immunol 2014;14[11]:759–767.) cytosolic contents into the interstitial space to act as DAMPS, thereby instigating an inflammatory response Rather, apoptotic cells and their organelles shrink in size; their nuclei condense (pyknosis) and fragment (karyorrhexis); the cell membrane phospholipid, phosphatidylserine, is exposed to the outside environment and acts as an “eat-me” signal; and cell cytoplasm forms blebs without disruption of the plasma membrane, with eventual formation of apoptotic bodies that are engulfed by phagocytes.3–7 By contrast, activation of pyroptosis results in proinflammatory cytokine maturation and necrotic cell death characterized by cellular swelling, plasma membrane disruption, and release of cytosolic contents into the interstitial space.8,9 Thus, pyroptosis is a highly immunogenic RCD pathway Apoptosis Apoptosis can be triggered by either an extrinsic pathway involving cell surface receptor-ligand interactions or by an intrinsic pathway involving transient mitochondrial outer membrane permeabilization disruption.2 The extrinsic pathway is most commonly activated by the interaction of Fas ligand (FasL) with Fas or tumor necrosis factor-a (TNF-a) interaction with TNF receptor-1 (TNFR-1; Fig 83.2) Adaptor proteins interact with death domains on the intracellular portion of FasL, resulting in the recruitment of a multiprotein death-inducing signaling complex (DISC) that recruits and activates the initiator caspase, pro-caspase-8 Activation of caspase-8 leads to activation of the executioner caspase complex containing caspase-3, caspase-6, and caspase-7 The intrinsic pathway is initiated by multiple inciting factors that stimulate the release of mitochondrial cytochrome c into the cytosol due to transient mitochondrial outer membrane permeabilization (MOMP) from cellular stress Cytochrome c interacts with an adaptor protein, apoptotic protease-activating factor–1 (APAF-1), which recruits the initiator caspase-9 and leads to the formation of a caspase-activating multiprotein complex called the apoptosome (see Fig 83.2) Once formed, the apoptosome activates the executioner caspases Within the intrinsic apoptosis pathway, the balance between a complex family of pro- and antiapoptotic proteins regulates cytochrome c release from the mitochondria Proapoptotic family members such as Bax and Bak promote cytochrome c release whereas antiapoptotic proteins, such as Bcl-2 and Bcl-xL, suppress mitochondrial ... dysfunction syndrome (MODS) Notably, RCD is neither “good” nor “bad” but needs to be understood within the context of the underlying physiologic state RCD is clearly adaptive over the course of... an essential role in some forms of RCD, specifically apoptosis and pyroptosis The objective of this chapter is to introduce a framework to understand the multiple forms of RCD, highlight key... NETosis Ca2+ PARP1 hyperactivation Cystine deprivation Neutrophil activation PAR polymers Glutathione depletion Persistent MOMP Persistent MOMP GPX4 inhibition AIF release? AIF release? Lipid