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The ₄₁ (Very Late Antigen (VLA)-4, CD49d/CD29) and ₅₁ (VLA-5, CD49e/CD29) Integrins Mediate ₂ (CD11/CD18) Integrin-Independent Neutrophil Recruitment to Endotoxin-Induced Lung Inflammation¹

J. Adam Burns^*, Thomas B. Issekutz^*, Hideo Yagita and Andrew C. Issekutz^2,*

^* Departments of Pediatrics, Microbiology/Immunology, and Pathology, Dalhousie University, Halifax, Nova Scotia, Canada; and Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan

The ₂ integrin cell adhesion molecules (CAM) mediate polymorphonuclear leukocyte (PMNL) emigration in most inflamed tissues, but, in the lung, other yet to be identified CAMs appear to be involved. In Lewis rats, the intratracheal injection of Escherichia coli-LPS induced acute (6-h) PMNL accumulation in the lung parenchyma (280 x 10⁶ by myeloperoxidase assay; PBS control = 35 x 10⁶) and bronchoalveolar lavage fluid (BALF = 27 x 10⁶; PBS = 0.1 x 10⁶). Parenchymal accumulation was not inhibited by a blocking Ab to ₂ integrins and only minimally inhibited (20.5%; p < 0.05) in BALF. We examined the role of ₄₁ and ₅₁ integrins and of selectins in this PMNL recruitment. Treatment with mAbs to ₄₁ or ₅₁, even in combination, had no effect on PMNL accumulation induced by intratracheal LPS. However, anti-₄ combined with anti-₂ mAbs inhibited PMNL recruitment to the parenchyma by 56% (p < 0.001) and to BALF by 58% (p < 0.01). The addition of anti-₅ mAb to ₂ plus ₄ blockade inhibited PMNL accumulation further (by 79%; p < 0.05). In contrast, blockade of L-, P-, and E-selectins in combination or together with ₂, ₄, and ₅ integrins had no effect. LPS-induced BALF protein accumulation was not inhibited by treatment with anti-₂ plus ₄ mAbs, but was prevented when ₅₁ was also blocked. Thus, while selectins appear to play no role, ₄₁ and ₅₁ function as major alternate CAMs to the ₂ integrins in mediating PMNL migration to lung and to pulmonary vascular and epithelial permeability.

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