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Review
. 2005 Oct;33(4):319-27.
doi: 10.1165/rcmb.F305.

Acute lung injury and the acute respiratory distress syndrome: four decades of inquiry into pathogenesis and rational management

Michael A Matthay  1 , Guy A Zimmerman
Affiliations
Review

Acute lung injury and the acute respiratory distress syndrome: four decades of inquiry into pathogenesis and rational management

Michael A Matthay et al. Am J Respir Cell Mol Biol. 2005 Oct.
No abstract available

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Figures

<b>Figure 1.</b>
Figure 1.
Increased permeability pulmonary edema is a hallmark of ALI/ARDS. Edema fluid to plasma protein concentrations expressed as a ratio to determine whether the edema fluid is a transudate as in hydrostatic pulmonary edema (< 0.65) or an exudate (> 0.65) as in increased permeability pulmonary edema (ALI/ARDS). The pulmonary edema fluid samples were obtained from patients within the 15 min of endotracheal intubation for acute respiratory failure. These are representative data from previously published and ongoing studies by Matthay and coworkers, some of which are discussed in Ref. 18.
<b>Figure 2.</b>
Figure 2.
Early events in ALI/ARDS. A variety of “direct” (lung infection, aspiration) and “indirect” (sepsis, multiple trauma with shock and large volume blood replacement) clinical insults lead to ALI. Initial clinical descriptions identified pulmonary edema as a major consequence. Subsequent investigations yielded evidence for inflammatory injury to the alveolar–capillary membrane as a central pathogenetic mechanism. The key effector cells, molecules, and mechanisms that lead to dysregulation of inflammatory and hemostatic pathways in ALI/ARDS remain incompletely defined. (Modified from Ref. 34.)
<b>Figure 3.</b>
Figure 3.
Histologic and ultrastructural analysis of the injured lung has been integral to current concepts of pathogenesis of ALI/ARDS. (A) A low-power light micrograph of a lung biopsy specimen collected 2 d after the onset of ALI/ARDS secondary to gram-negative sepsis demonstrates key features of diffuse alveolar damage, including hyaline membranes, inflammation, intraalveolar red cells and neutrophils, and thickening of the alveolar–capillary membrane. (B) A higher-power view of a different field illustrates a dense hyaline membrane and diffuse alveolar inflammation. Polymorphonuclear leukocytes are imbedded in the proteinaceous hyaline membrane structure (black arrows). The white arrow points to the edge of an adjacent alveolus, which contains myeloid leukocytes (thank you to K. Jones, M.D., UCSF Pathologist, for the histologic sections in A and B). (C) An electron micrograph from a classic analysis of ALI/ARDS showing injury to the capillary endothelium and the alveolar epithelium. LC refers to a leukocyte (a neutrophil) within the capillary lumen. EC designates enythrocytes. EN shows blebbing of the capillary endothelium. BM refers to exposed basement membrane where the epithelium has been denuded. C refers the capillary. A refers to the alveolar space. (Reprinted with permission from Ref. 24.)
<b>Figure 4.</b>
Figure 4.
Multiple cellular responses and mediators contribute to alveolar–capillary membrane injury (right-hand side) and the transition from normal alveolar structure and function (left-hand side) in the acute phase of ALI/ARDS. Original investigations of the pathogenesis of ALI/ARDS searched for single mediators that provided final common pathways to inflammation and alveolar edema in ALI/ARDS. Current concepts of pathogenesis involve multiple molecular factors of several classes, a variety of responding cells, and imbalance between injurious and reparative signals and pathways. See text and Refs. 5 and 12 for details. (Reprinted from Ref. 12 with permission.)
<b>Figure 5.</b>
Figure 5.
The natural history of ALI/ARDS includes resolution and repair versus persistence and progression. Clinical and epidemiologic studies demonstrate that ALI/ARDS resolves with return of alveolar function to normal or near normal in some patients, whereas in others there is persistence and/or progression of injury. The outcomes of persistence and progression include multiple organ failure, fibrosing alveolitis, pulmonary vascular obliteration with pulmonary hypertension, and death. The genetic, cellular, molecular and iatrogenic factors that contribute to each of these outcomes remain largely unknown. In addition, rational mechanism-based strategies that favorably influence repair of the alveolar–capillary membrane are undefined. (Modified from Ref. 34.)
<b>Figure 6.</b>
Figure 6.
Cellular and molecular pathways regulate the resolution of alveolar edema formation and resolution in ALI/ARDS. Histologic section from patients with a lung biopsy in the setting of lung injury from bacterial pneumonia and sepsis with protein rich alveolar edema. The insert refers to ENaC, the epithelial sodium channel, which is a major pathway for the uptake of sodium on the apical surface of alveolar epithelial type I and II cells as well as distal airway epithelia. NaKATPase refers to the sodium pump located in the basolateral surface of alveolar and airway epithelia that actively pumps sodium into the interstitial space, thus creating a mini–osmotic gradient for the absorption of edema fluid from the alveolar. Both ENaC and NaKATPase can be upregulated by several catecholamine dependent and independent mechanisms. See Refs. 18 and 19 for more details. (Reprinted with permission from Ref. 18.)
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References

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