Mechanisms involved in direct pulmonary insults

Direct pulmonary lesions lead to damage to the lung epithelium (alveolar cells and surfactant) and activation of alveolar macrophages. Both these elements are capable of reciprocal interactions and amplification. Three phases can be distinguished: an exudative phase, with formation of edema, hemorrhage, and inflammation, a proliferative phase, with organization of the intraluminal exudate and the start of reparative processes, and a fibrotic phase, which is only present when regeneration is pathological. The final phase only concerns a limited number of patients.

The exudative phase (corresponding roughly to the first week) is characterized by alveolar and interstitial edema, swelling of capillaries, and intra-alveolar hemorrhage. This phase appears to be initiated by activation of macrophages (by micro-organisms and/or toxins) and direct injury of surfactant-producing and epithelial cells caused by these agents or by the initial trauma itself. The activated macrophages produce activated oxygen species, which in turn cause oxidative stress in neighboring cells, and liberate enzymes and peptide, protein, and lipid mediators. These mediators have multiple properties, including modification of the alveolocapillary membrane and chemoattraction for blood-borne leukocytes.

The inflammatory reaction rapidly reaches nearby endothelial cells, which react by producing new inflammatory mediators (cytokines, procoagulant factors, lipid mediators, vasoactive substances, etc.) and expressing adhesion receptors. These allow (or amplify) the binding of polymorphonuclear neutrophils which are marginated in the pulmonary vasculature, having been attracted by chemotactant agents released locally. This stimulation of adhesion, combined with the presence of chemoattractants and mediators capable of stimulating polymorphonuclear neutrophils, leads to diapedesis of neutrophils into the alveoli. This is followed by further expression of adhesion molecules and production of inflammatory mediators.

Concomitant with the passage of the polymorphonuclear neutrophils into the alveoli, there is an influx of protein- and mediator-rich fluid, as well as other cellular elements including lymphocytes, platelets, and erythrocytes. Bronchoalveolar lavage fluid collected early in the development of ARDS is the best evidence of processes occurring during this initial phase. This fluid is rich in polymorphonuclear neutrophils (up to 90 per cent of cells present), albumin, and inflammatory mediators such as cytokines, prostanoids (e.g. prostaglandin E2), and leukotrienes. Products of complement activation, coagulation by-products, peptides, proteolytic and granulocyte enzymes (myeloperoxidase, elastase, collagenase, lactoferrin), and even active oxygen species (such as hydrogen peroxide) can also be detected in bronchoalveolar lavage fluid. These products are markers of the intra-alveolar activation of macrophages and neutrophils, which propagates the inflammatory reaction and leads to loss of surfactant and pneumocytes. This in turn leads to denudation of the basement membrane, so that the pulmonary interstitium comes into contact with the alveolar space. Cellular debris and hyaline membranes, which form during this initial phase, become adherent to the inside of the alveolus. Previously aerated lung becomes congested, edematous, and compacted, and obviously can no longer participate in gas exchange. Platelet and fibrin microthrombi together with leukocyte aggregates, both of which predispose to cellular hypoxia, form within the capillaries.

During the subsequent phases of proliferation and fibrosis, the inflammatory exudate begins to organize within the alveoli and interstial spaces, while the type II pneumocytes multiply, fill in denuded areas of the basal membrane, and differentiate. Under the influence of humoral factors liberated by various groups of cells (endothelial cells, platelets, macrophages, etc.), fibroblasts and myofibroblasts proliferate in the interstitium and the alveolar septae, and contribute to the reconstitution of functional alveoli. This reparative response is directed by several molecular species, including growth factors (tumor growth factor-a, epidermal growth factor, platelet-derived growth factor, etc.), as well as fibronectin, collagen fragments, elastin, and fibrin resulting from excessive enzymatic proteolysis.

In ARDS, these regulatory processes are often modified, with incomplete repair and/or excessive cellular proliferation. Thus fibroblasts can attach to the epithelial basement membrane and secrete matrix components which progressively fill the alveolar space and reduce pulmonary compliance. A fibrocellular proliferation can also be seen in the intima of the pulmonary vessels; this, in combination with the cellular aggregates and thrombi mentioned previously, increases the areas of hypoxia. Mesenchymal cells also proliferate abnormally, and intra-alveolar angiogenesis can also be seen. These processes contribute to alveolar fibrosis and loss of pulmonary function, and can lead to the late deaths described in ARDS. However, if the reparative processes are normally controlled, the patient recovers almost normal pulmonary function after several months.

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