Identification and functional role of a novel integrin, alpha-D (ad), in an in vivo model of pulmonary inflammation

Thomas P. Shanky, Roscoe L. Warner, Lvry Crouch, Gregory N. Dtetsch', W. Michael Gallatin, Peter A. Ward

Research output: Contribution to journalArticlepeer-review


Introduction: In models of acute lung injury, the recruitment of neutrophils from the intravascular space to the alveolar compartment has been the focus of ongoing studies. Previous data demonstrated a role for B2-integhns in mediating this process via engagement to their counter-receptor, ICAM-1. The cloning and functional expression of a novel integral, alpha-d (ad), in the rat has allowed us to explore die role of this integral in acute lung inflammation. Methods: Rat ad was subcloned from activated splcnocytes and expressed as a fusion protein with human IgG. Antiserum to mis protein demonstrated no crossreactivity to other known B-integrins. An in vivo model of hing inflammation initiated by intraalveolar deposition of IgG immune complexes was employed to determine the expression (Normern and Western blot analyses) of od in lungs of injured Long-Evans rats. Lung permeability was measured by 125I-aibumin leak. BAL fluids were recovered for determination of the following: neutrophil counts, TNF-a (measured by a cytotoxic bioassay), and NONO, levels (measured by the Greiss reaction). Resalts: While upregulation of od at both the mRNA and protein level was observed from whole lungs and peaked between 1 and 3 hrs, immunostaining was restricted to alveolar macrophages indicating this cell as a principal source. Blocking of ad with polycloaal antibody (300 ug/rat) resulted in significant decreases in lung permeability (55%), BAL fluid neutrophils (44%), and TNF-a (86%). Similar results were obtained using a monoclonal anti-rat cut antibody. In whole lungs, the most intense staining for od on alveolar macrophages was seen at their apposition to epithelial cells. In vitro, disruption of mis apposition results in decreased iNOS expression as reflected by NOj/NO, levels. Similarly, in vivo, antibody blockade of ad resulted in a significant decrease in BAL fluid NOj/NO, levels. CcmclosioBs: The novel integral, ad, is upregulated in hing macrophages in die setting of acute lung inflammation and is required for full activation of macrophages as determined by expression of TNF-a and iNOS, as well as recruitment of neutrophils. and full development of injury.

Original languageEnglish (US)
Pages (from-to)A75
JournalCritical care medicine
Issue number1 SUPPL.
StatePublished - 1998
Externally publishedYes

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine


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