Am. J. Respir. Crit. Care Med.,
Volume 160, Number 3, September 1999, 987-994
Antimyeloperoxidase-associated Lung Disease
An Experimental Model
PASCAL
FOUCHER,
PETER
HEERINGA,
ARJEN H.
PETERSEN,
MINKE G.
HUITEMA,
ELISABETH
BROUWER,
JAN W.
COHEN TERVAERT,
JOCHUM
PROP,
PHILIP
CAMUS,
JAN J.
WEENING,
and
CEES G. M.
KALLENBERG
Department of Clinical Immunology and Department of Cardiopulmonary Surgery, Research Division, University Hospital,
Groningen, The Netherlands; Service de Pneumologie et Réanimation Respiratoire, CHU Dijon, France; and Department
of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
The lung is a common target in systemic vasculitides associated with antineutrophil cytoplasmic antibodies (ANCA). In the present study, we tested the hypothesis that the presence of antibodies directed against myeloperoxidase (MPO) induces pulmonary (vasculitic) lesions when neutrophils release lysosomal enzymes. Brown Norway (BN) rats were immunized with human MPO in complete
Freund's adjuvant (CFA) or with CFA alone. Two weeks after immunization, rats had developed antibodies to human and rat MPO. Next, isolated single left lung perfusion was performed with human
neutrophil lysosomal extract containing MPO and proteolytic enzymes. Rats were killed at 15 min, 4 h,
and 10 d after perfusion. Tissue samples from the left and right lung were examined for vasculitic lesions and inflammatory cell infiltrates. At 15 min and 4 h, left lungs from control and MPO-immunized rats showed a mild influx of polymorphonuclear cells. At 10 d, patchy inflammatory cell infiltrates, consisting predominantly of polymorphonuclear leukocytes (PMNs) and monocytes, were
observed throughout the parenchyma of the left lung in MPO-immunized rats. Occasionally, granuloma-like lesions, giant cells, and foci of alveolar hemorrhage were observed as well. Far less severe lesions were seen in control immunized rats. Strikingly, at 10 d after perfusion, severe pulmonary tissue injury was observed also in right lungs from MPO-immunized rats whereas right lungs from control immunized rats appeared normal. The lesions were characterized by influx of PMNs and monocytes and, in some rats, foci of alveolar hemorrhage. These studies suggest that the presence of an
anti-MPO directed autoimmune response contributes to generalized pulmonary tissue injury after local release of products of activated neutrophils, which supports a pathogenic role of MPO-ANCA.
