Page 635 - Hall et al (2015) Principles of Critical Care-McGraw-Hill

454 PART 4: Pulmonary Disorders

alveolar barrier integrity are central mechanisms in the pathogenesis of apoptosis may be an important mechanism in ARDS, and elevated
112
ARDS. 34,38,39,74-76 In addition to ongoing inflammation and oxidation, fac- levels of granulocyte-macrophage colony-stimulating factor (GM-CSF)
tors specific to apoptosis, edema fluid resolution, fibrosis, and repair are may play a role in this mechanism. 113-115
likely to be important in the resolving and late phases of ARDS. 34,38,39,74,76 Neutrophils act on pathogens through intracellular and extracellular
■ DYSREGULATED INFLAMMATION mechanisms, including phagocytosis, degranulation of toxic proteins
contained in neutrophils granules, and the formation of neutrophil
116
ARDS develops after both systemic inflammatory insults and directly as extracellular traps (NETs). NETs are composed of a core DNA element
a result of pulmonary infections and injury. Inflammatory mechanisms, that affixes histones and contents of neutrophils granules. Neutrophil
when properly regulated, are important to containment and healing degranulation and NET formation are intended to immobilize and
from insults such as pneumonia, aspiration, and systemic infection and destroy pathogens; however, these mechanisms can lead to substantial
injury. However, for reasons that are incompletely understood, in ARDS tissue damage in ARDS. Recently, NETs have been shown to be key
these same mechanisms become dysregulated, leading to pulmonary mediators of transfusion associated ALI. 117
accumulation of immune cells and platelets, unopposed oxidant injury ■
to lung tissues, enhanced coagulation and impaired fibrinolysis, and OXIDANT INJURY
disruption of the normal function of the alveolar-capillary membrane. Neutrophils in the alveolar and interstitial spaces may result in lung
This early response to tissue damage or pathogens leads to early injury due to neutrophil-mediated release of reactive oxygen spe-
release of inflammatory cytokines and chemokines by resident lung cies (ROS) and resulting oxidant stress. Oxidant stress refers to an
cells, including dendritic cells. Two of the major early proinflammatory imbalance between endogenously produced oxidants and endogenous
cytokines are tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1), antioxidants. Products of oxidant stress include superoxide, hydroxyl
118
both of whose production can be increased by hypoxia. 77-79 These cytokines radicals, and peroxynitrite. Although some levels of ROS may be
have similar effects in initiating and propagating inflammation. 77,80-83 Their important in normal homeostasis, ROS are highly unstable and react
actions include (1) recruitment, differentiation, amplification, and local- quickly with surrounding proteins, DNA, and lipids, resulting in
ization of macrophages to the lung parenchyma; (2) stimulation of other molecular damage. 118
inflammatory cytokines such as interleukins-6 and -8 (IL-6 and IL-8); A widely held hypothesis is that excessive oxidant stress contributes
and (3) adherence of neutrophils to endothelium (see Fig. 52-4). 77,84-86 to the pathogenesis of ALI. 119-126 ROS can be generated by neutro-
Both BAL and plasma fluids consistently have been reported to contain phils (polymorphonuclear [PMN] cells), 119,121,127 or by the pulmonary
elevated levels of TNF-α and IL-1 in ARDS patients. 87-91 Macrophages endothelium. 128,129 Both PMN-mediated and endothelial generation of
that have been stimulated by TNF-α and IL-1, in turn produce IL-6, ROS may be important to initiation and development of lung injury.
which has diverse functions. Like TNF-α and IL-1, persistently elevated Evidence from clinical studies supporting excess ROS in ALI and ARDS
IL-6 levels have been associated with an increased risk of death in ARDS include findings of increased hydrogen peroxide in exhaled breath of
patients. In addition, in the ARDSNet ARMA trial the lung-protective ARDS patients 130,131 ; decreased levels of glutathione in lung lavage fluids
92
treatment arm that had decreased mortality showed a greater attenu- of ARDS patients 132,133 ; increased nitrotyrosine and chlorotyrosine in
134
ation in inflammatory cytokines (IL-6) and chemokines (IL-8) com- lavage fluids of ARDS patients ; increased lipid peroxidation products
137
pared to the higher-tidal-volume arm. 3,93 in plasma 135,136 ; increased protein carbonyl levels ; increased plasma
138
Recently, it has been increasingly recognized that innate immune mech- hypoxanthine ; increased levels of nitrated fibrinogen in the plasma
139
anisms in response to pathogens or tissue damage are key to this early of ALI/ARDS patients ; and increased serum ferritin levels in ARDS
inflammatory response. Innate immune pattern recognition receptors that patients compared with at-risk patients. 140,141 Although some of these
74
are either localized in the cell membrane (eg, Toll-like receptors, TLRs) findings may be nonspecific for ARDS, taken together, they make a
or in the cytoplasm (eg, Nod-like receptors, NLRs) can become activated strong case for the role of oxidant stress in the pathogenesis of ARDS.
in the early stages in ARDS. Both danger- and pathogen-associated In addition, evidence of higher levels of oxidant stress in nonsurvivors
142
molecular pattern (DAMPs and PAMPs) recognition play an important of ARDS is illustrated by lower levels of plasma thiol groups, and
role. 94,95 Stimuli for activation of these pathways include bacterial and viral higher levels of hydrogen peroxide in urine of ARDS patients who are
pathogens, lysosomal disruption, neutrophil- or mitochondria-derived nonsurvivors. 143
97
96
these pathways can lead to formation of inflammasomes, which are proin- ■ COAGULATION AND IMPAIRED FIBRINOLYSIS
and cell apoptosis.
reactive oxygen species (ROS),
Activation of
99,100
98,99
flammatory macromolecular complexes that activate caspase-1, resulting The histopathology of the early exudative phase of ARDS is notable for
in IL-1β and IL-18 release. Inflammasome activation has been demon- diffuse alveolar fibrin deposition in the form of hyaline membranes
101
strated in clinical studies, solidifying the key role in ARDS pathogenesis. (see Fig. 52-3). 71,72,109,144,145 In addition, a shift in the procoagulant and
Furthermore, recent studies suggest that an imbalance between IL-1β anticoagulant balance to favor coagulation has been demonstrated in
and the IL-1 receptor antagonist (IL1-RA) is important in ARDS risk and the BAL fluid of patients with ARDS. 146-150 Furthermore, there are likely
outcome. Genetic regulation of this pathway is likewise implicated in important links between the coagulation system activation and activa-
102
ARDS pathophysiology. 53 tion of the inflammatory system. For example, TNF-α and IL-1 can act
Stimulated dendritic cells and tissue macrophages in the lung also pro- synergistically to produce a procoagulant state through effects on tissue
duce IL-23, which in turn induces production of interleukin-17 (IL-17) factor, thrombomodulin, and plasminogen activator inhibitor 151-153 and
by T-helper cells. IL-17A is the original member of what is now the there exists an independent relationship between markers of inflam-
IL-17 family of cytokines. IL-17 is the major product of TH17 cells, mation, neutrophil migration, and coagulation and fibrinolysis and
103
which are a helper T-cell subtype characterized by enhanced inflamma- mortality in ALI patients. Although prior studies found plasma
154
tory response, particularly in mucosal immunity and lung injury. 104-106 protein C levels are decreased in ALI and decreased levels are asso-
155
IL-17A is thought to have pleiotropic effects; however, promotion of ciated with worse outcomes, a small randomized trial of activated
156
neutrophil chemotaxis is dominant. Neutrophil migration into the protein C for use in patients with ALI did not appear to improve
107
airspaces is evident in the early histopathology of ARDS and is further outcomes. Furthermore, in 2011, activated protein C was withdrawn
157
mediated by IL-8 and intercellular adhesion molecules (eg, intercellular from the market for patients with severe sepsis after a large trial failed
adhesion molecule-1 [ICAM]). 108,109 BAL fluid of subjects with ARDS to demonstrate efficacy. Despite strong scientific rationale, interven-
158
reveals a predominance of neutrophils. Conversely, recovery is associ- tions aimed at correcting abnormalities in coagulation and fibrinolysis
110
ated with resolution of neutrophilia. Normally, neutrophils become in critically ill patients have not improved outcomes to date, although
111
apoptotic and are then removed by macrophages. Impaired neutrophil further research is warranted.
section04.indd 454 1/23/2015 2:19:39 PM