Page 636 - Hall et al (2015) Principles of Critical Care-McGraw-Hill

CHAPTER 52: Acute Lung Injury and the Acute Respiratory Distress Syndrome 455

■ ALVEOLAR-CAPILLARY MEMBRANE INJURY AND DISRUPTION for the development of ALI and an explanation for the observed associa-

Dysregulated inflammation and direct injury can lead to disruption tion between diabetes and decreased risk for ALI resistance. 179
Other important modulators of the remodeling of fibrosis include
of the alveolar-capillary membrane. Several key mediators of endo- 180-182
thelial permeability, inflammation, and angiogenesis have been sug- matrix and cell surface proteoglycans and glycosaminoglycans ;
; matrix metallopro-
matricellular proteins that affect cell adhesion
183,184
gested in ARDS pathogenesis. For example, angiopoietin-2 (Ang-2) 185
and vascular endothelial growth factor (VEGF) are mediators of teases ; and the balance of coagulation and fibrinolysis (particularly
through the actions of plasminogen activator inhibitor-1 [PAI-1]).
137
endothelial permeability and angiogenesis. Ang-2 expression inhibits
angiopoietin-1, an endothelial stabilizing factor. Increased levels of The interplay of these mediators with the potential for targeted therapies
is the focus of current investigations.
Ang-2 have been associated with the development of ALI and adverse
In addition to remodeling of fibrosis, resolution of lung injury in
outcomes in those who develop ALI and variation in the ANGPT2 the ARDS patient requires several overlapping reparative mechanisms,
159
alters risk of development of ALI. As a marker of endothelial injury,
160
von Willebrand factor antigen (vWF) predicted the development of including deactivation and clearance of inflammatory cells from the
alveolar space, repair of the epithelial barrier, and resorption of edema
ALI in several at-risk populations, 161,162 although these findings have
not been replicated consistently. Likewise, a recent study suggests that fluid. For the most part, these mechanisms are occurring during over-
lapping time intervals as the injured lung attempts to repair and restore
lower levels of endocan, a proteoglycan expressed by endothelial cells,
may be associated with development of trauma-associated ALI as its physiological state.
Resolution of inflammation requires local production of counterregu-
the protective effect of endocan to inhibit leukocyte recruitment via
ICAM-1 may be reduced. 163 latory inhibitory molecules of the inflammatory response (including
TLR, NOD, cytokine inhibitors). Molecules important in the resolution
Furthermore, recent research into alveolar barrier integrity suggests
several additional mechanisms with potential therapeutic targets. phase are produced locally and include lipoxins, resolvins, and D-series
prostaglandins, among others. An important part of this process
186
Recent evidence supports a role of the balance between angiotensin-
converting enzymes 1 and 2, in modulating inflammatory lung injury in involves clearance of apoptotic neutrophils and other inflammatory
debris from the alveolar space my alveolar macrophages. Regulatory
187
pulmonary and systemic infections. 164,165 Vascular endothelial cadherin
(VE-cadherin) is a junction protein that is involved in maintenance T cells play a key role in this process, forming an “immune synapse” with
alveolar macrophages to help orchestrate the process.
188
of barrier integrity in lung microvessels. Instability in complexes of
166
Recovery of the alveolar epithelium requires repopulation of the
VE-cadherin and catenin may affect capillary leak and inflammatory alveolus with type I epithelial cells. At baseline, the human lung has
cell extravasation. 167,168 The recently recognized Robo4/Slit signaling
system is expressed on endothelial cells and serves to stabilize the little cell turn over compared to some organ systems; however, the lung
can rapidly regenerate new cells after injury. Epithelial cells may arise
189
endothelial barrier in the lung. A member of this system, Slit2N reduces
permeability in microvascular endothelial cells caused by inflammatory from differentiation of Type II pneumocytes, or from recently described
Recovery of epithelial cells may require
human lung stem cells.
189,190
cytokines, influenza, and sepsis. Sphingosine-1-phosphate (S1P) is a
169
lipid present in high concentrations in plasma that binds to receptors on epithelial-mesenchymal interaction with triggering of developmental
pathways, such as Wnt signaling pathways.
189
endothelial cells to enhance pulmonary endothelial barrier integrity in
Additionally, epithelial protection and recovery have recently been
a variety of pathogenic conditions. 170,171 Future research into the regula- shown to rely on interactions with innate lymphoid cell (ILC) popula-
tion of different S1P receptors during the time course of lung injury
is necessary. 172 tions, which are similar to CD4+ T-helper cells and play critical roles
in antipathogen immunity, regulation of inflammation, and promotion
of wound healing and tissue repair at barrier surfaces. 190-199 Recently,
FIBROSIS, RESOLUTION, AND REPAIR MECHANISMS ILC2 cells have been shown to have a major role in maintaining alveolar
200
Although there is considerable temporal overlap of the exudative and homeostasis during injury response in the lung. In the presence of
inflammatory phases (see Fig. 52-3), the later phases of ARDS are pathogens, IL-33 and IL-25 induce lineage negative ILC2 cells to pro-
characterized by accumulation of matrix and cells in the interstitial duce amphiregulin, which binds to the EGFR receptor to protect epithe-
and alveolar spaces, contributing to disruption of the alveolar architec- lium from damage by maintaining barrier function, enhancing epithelial
ture. 71,72 Recovery from ARDS requires resolution of this phase of the growth and repair, and maintaining oxygenation. 200
Clinical studies of ARDS patients indicate that the alveolus is repaired ■ ALVEOLAR EDEMA CLEARANCE
tissue injury–repair spectrum to restore the normal lung architecture.
under concurrent and ongoing inflammation. Soluble collagen precur- Considerable evidence supports the role of active transport of sodium
78
sor, type III procollagen peptide, in the edema fluid of early ARDS can and water by the pulmonary epithelium as a means to remove pul-
differentiate between subjects who will have longer or shorter courses monary edema from alveoli. This process appears to be regulated
201
of ARDS and fibroblast mitogenic activity in BAL fluid is lower in sur- by epithelial sodium channels predominantly on alveolar type I cells,
vivors of ARDS than nonsurvivors, suggesting that fibroproliferation potentially stimulated by catecholamines. 202,203 Furthermore, the direc-
173
begins early in the course of lung injury. 174,175 tional flow of fluid across the alveolus may be altered in conditions of
An orchestrated balance of different growth factors, cytokines, and hypoxia, 204,205 as well as by reactive nitrogen and oxygen species. 206
chemokines occurs in the fibroproliferative and reparative phases of There is considerable evidence of epithelial injury and dysfunction
ALI. 74,176 A variety of animal, basic, and clinical studies have dem- in clinical ARDS. Biomarkers of epithelial injury have demonstrated
onstrated the importance of transforming growth factor-β (TGF-β) association with clinical ARDS risk and/or outcome including surfac-
to fibroproliferation in the lung. 177,178 A key step in fibroproliferation tant proteins, 207,208 Clara cell protein secreted by the epithelial Clara
involves the activation of TGF-β from its latent form. This can be cell, and the receptor for advanced glycation end products (RAGE).
210
209
accomplished through interaction with a variety of mediators, includ- Clinical studies in ventilated patients have illustrated impaired fluid
ing matrix metalloproteinases (MMPs), thrombospondin, plasmin, transport in ARDS when compared with hydrostatic pulmonary
acid environments, α -macroglobulin, and ROS. In addition, TGF-β edema. 38,211,212 In addition, subjects who upregulate alveolar fluid
177
2
has extensive interactions with inflammatory cytokines, chemokines, clearance have a lower hospital mortality. 212,213 However, a recent trial
and interferon-γ in regulating fibrosis. Leptin, a protein secreted by designed to augment the rate of alveolar edema clearance through the
adipose tissue that decreases hunger through a signal to the brain, is use of β-adrenergic receptor agonists was terminated early due to futility,
also an inflammatory mediator that has been implicated in fibrogenesis. indicating that restoration of the epithelial cell barrier is essential to
Recently, leptin resistance was identified as a potential protective factor fluid resorption. 214
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