Elsevier

Clinics in Chest Medicine

Volume 21, Issue 3, 1 September 2000, Pages 435-466
Clinics in Chest Medicine

PULMONARY PATHOLOGY OF ACUTE RESPIRATORY DISTRESS SYNDROME

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Acute respiratory distress syndrome (ARDS) encompasses a relatively uniform constellation of clinical, radiographic, and physiologic features in patients with rapidly evolving respiratory failure.3, 5 The syndrome is a wide avenue entered via many different sidestreets that represent the various initiating causes of severe lung injury. Just as the clinical syndrome is a generalized response, the pathologic features of the lung are stereotypic. Histologic examination of lung tissue rarely affords the pathologist a definitive diagnosis of the original insult, and communication between clinician and pathologist is paramount in attempting to discern the probable cause of this often fatal condition. Interpretation of lung biopsies or tissue at autopsy is further hampered by the fact that many of the clinical events common during the course of ARDS, such as shock, disseminated intravascular coagulation, septicemia, or the inhalation of high concentrations of oxygen, produce pulmonary lesions resembling those of the initial insult.

The pathologic features of the lung in ARDS derive from severe injury to the alveolocapillary unit. Extravasation of intravascular fluid dominates the onset of the disease and the term ARDS is often simplistically equated with permeability pulmonary edema. As the process unfolds, however, edema is overshadowed by cellular necrosis, epithelial hyperplasia, inflammation, and fibrosis. The morphologic picture of the lung in ARDS has been labeled diffuse alveolar damage (DAD).36 The histologic appearance of this damage is temporal and can be conveniently divided into three interrelated and overlapping phases that correlate with the clinical evolution of the disease: (1) the exudative phase of edema and hemorrhage; (2) the proliferative phase of organization and repair; and (3) the fibrotic phase of end-stage fibrosis.36, 52, 60 The pathologic features of DAD correlate more with the time frame than with the initiating cause (Table 1). In the following discussion, each of these phases is described separately and morphologic features are correlated with clinical events and proposed mechanisms of injury.

Table 1. TEMPORAL FEATURES OF DIFFUSE ALVEOLAR DAMAGE

Exudative Phase (Day 17)*Proliferative Phase (Day 721)Fibrotic Phase (> Day 21)
Interstitial and intra-alveolar edemaInterstitial myofibroblast reactionCollagenous fibrosis
HemorrhageLumenal organizing fibrosisMicrocystic honeycombing
LeukoagglutinationChronic inflammationTraction bronchiectasis
NecrosisParenchymal necrosisArterial tortuosity
   Type 1 pneumocyteType II pneumocyte hyperplasiaMural fibrosis
   Endothelial cellsMedial hypertrophy
Hyaline membranesObliterative endarteritis
Platelet-fibrin thrombiMacrothrombi
*

Dates are approximations

Section snippets

EXUDATIVE PHASE

The exudative phase occupies approximately the first week after the onset of respiratory failure.36 The lungs of patients who die within this period are rigid, dusky red–blue, and exceedingly heavy, with a combined weight that usually exceeds 2000 g. The parenchymal surface is hemorrhagic, with a firm, airless consistency, and, unlike the picture in cardiogenic pulmonary edema, does not exude frothy fluid.43, 52, 75 On close inspection, air spaces less than 1 mm in diameter, representing

PROLIFERATIVE PHASE

The proliferative phase of DAD is the stage of organization of the intra-alveolar and interstitial exudate acquired in the acute phase.19, 36, 52, 55, 59 Type 2 cells begin to proliferate along alveolar septa as early as 3 days following the onset of clinical ARDS, and fibrosis is apparent by the 10th day.36, 59 This rapid conversion of the lung to a noncompliant, end-stage organ is an important limiting factor for survival in ARDS.28, 41

Between the first and third weeks following injury, the

FIBROTIC PHASE

In ventilator-dependent patients who survive beyond 3 or 4 weeks from the onset of ARDS, the lung is completely remodeled by sparsely cellular collagenous tissue. Macroscopically, the pleural surface demonstrates a coarse, cobblestoned appearance. The parenchymal cut surface is pale, spongy, and replaced by alternating areas of microcystic air spaces, 1 to 2 mm in diameter, and irregular zones of diffuse scarring (Fig. 18). The transformation of lung parenchyma into contiguous large cysts,

Normal Pulmonary Arterial Anatomy

Pulmonary vascular injury is an important feature of ARDS and pulmonary hypertension secondary to increased pulmonary vascular resistance is usually present.32, 83 To place the vascular lesions of ARDS in proper perspective, a brief review of normal pulmonary vascular anatomy is necessary. The path of the pulmonary artery from hilum to periphery is called the axial pathway. Along this pathway, arterial branches accompany the airways and an artery can be landmarked histologically by the adjacent

LOCALIZATION OF LESIONS: REGIONAL ALVEOLAR DAMAGE

As originally defined, ARDS is considered to be a generalized lung process characterized roentgenographically by diffuse bilateral alveolar infiltrates.3, 5 Similarly, generalized lung involvement is also implied in the histopathologic term diffuse alveolar damage.28, 36, 41, 43, 55, 75 The concept that ARDS–DAD is always a diffuse bilateral process is not consistent with clinical or morphologic data. Murray et al,50 reviewing published studies of patients at risk for developing acute lung

IMMUNOHISTOCHEMICAL PROFILE AND MORPHOGENESIS OF DIFFUSE ALVEOLAR DAMAGE

In the 10 years since the pathology of ARDS previously was reviewed in Clinics in Chest Medicine, the expanded application of immunohistochemical markers to human lung tissue, coupled with enhanced understanding of biochemical mediators and principles of basic molecular biology, have resulted in new information and concepts of the pathogenesis of DAD.76

Matrix metalloproteinases and their inhibitors have been identified and implicated in tissue destruction in ARDS.26 Matrix metalloproteinase-2

CLINICOPATHOLOGIC CORRELATIONS

The structural alterations of ARDS serve as a basis for understanding its major clinical and functional manifestations. Hypoxemia results from shunting caused by a maldistribution of ventilation and perfusion. Intraalveolar exudate, fibrous tissue, and microatelectasis all contribute to shunting.5 Lamy et al41 observed that patients with a fixed shunt at all fractions of inspired oxygen demonstrate consolidative edema, exudation, and hemorrhage on open lung biopsy, whereas lesser degrees of

SUMMARY

Lung morphology in ARDS reflects the rapid evolution from interstitial and alveolar edema to end-stage fibrosis consequent to injury of the alveolocapillary unit. This morphologic progression, termed diffuse alveolar damage, has been subdivided into sequentially occurring exudative, proliferative, and fibrotic phases. Pulmonary lesions correlate with the phase of alveolar damage rather than its specific cause. The pathologic features are consistent with the effects of a host of injurious

ACKNOWLEDGMENTS

The author would like to thank Jack Williamson, David Dunsmore, Vince Messina, and Spencer Jones for the illustrations. The secretarial assistance of Debra Moscalink is also deeply appreciated.

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