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J Investig Med. 1994 Dec;42(4):640-51.

Acute lung injury: the role of cytokines in the elicitation of neutrophils.

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Department of Internal Medicine, University of Michigan Medical School, Ann Arbor 48109-0360, USA.

Erratum in

  • J Investig Med 1995 Apr;43(2):204.


Cytokine networks between immune and nonimmune cells of the alveolar-capillary membrane are necessary for cellular communication during pulmonary inflammation. The subsequent events of these cellular/humoral interactions are pivotal to the initiation and propagation of the inflammatory response leading to pulmonary injury. The studies cited in this paper underscore the interrelationship of early response cytokines, adhesion molecules, and the chemokine IL-8 that orchestrate the recruitment of neutrophils into the lung. The paradigm for neutrophil extravasation is likely operative in the microvasculature of the lung, and consists of four or more steps (Figure 3). First, acute lung injury results in the activation of microvascular endothelium in response to the local generation of TNF or IL-1, leading to expression of endothelial cell-derived E- and P-selectins and ICAM-1. The constitutive presence of neutrophil-derived L-selectin allows for the initial adhesive interaction of neutrophils with endothelial cell selectins leading to the "rolling" effect. Second, generation of IL-8 leads to the activation of neutrophils in the vascular compartment and expression of beta 2 integrins, while L-selectin is concomitantly shed. Third, the interaction of the neutrophil beta 2 integrin with its receptor/ligand, ICAM-1, results in the rapid arrest of neutrophils on the endothelium. Fourth, the subsequent events leading to neutrophil extravasation beyond the vascular compartment are dependent upon a combination of haplotaxis (migration in response to an insoluble gradient), the continued expression of beta 2 integrins on neutrophils and ICAM-1 on nonimmune cells, and the maintenance of a neutrophil specific (IL-8) chemotactic gradient. The participation of IL-8 and potentially other C-X-C chemokines in the inflammatory response appears to be critical for the orchestration of the directed migration of inflammatory leukocytes into the lung. After arriving in the lung, these activated leukocytes can respond to noxious stimuli or induce pulmonary injury through the release of reactive oxygen metabolites, proteolytic enzymes, and additional cytokines. Our current knowledge and future investigations regarding the mechanisms involved in neutrophil elicitation may allow us to employ clinical interventional strategies that will attenuate neutrophil-dependent acute lung injury, such as ARDS.

[Indexed for MEDLINE]

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