We have recently shown that IgA immune complexes can cause acute injury in rat lung. Whether a similar mechanism pertains in human interstitial lung diseases is not known, although IgA immune complex injury represents a significant problem in human renal glomerular and vascular diseases. Lung injury produced by IgA immune complexes has been found to be dependent on complement but independent of neutrophils, whereas IgG immune complex injury requires both mediator systems. We will measusre in vitro the production of oxygen radicals in both rat neutrophils and alveolar macrophages using a variety of agonists, including IgG and IgA immune complexes. Additional parameters of cell activation to be employed will include enzyme secretion and generation of arachidonate products. We will also explore the ability of complement activation products to """"""""potentiate"""""""" phagocytic cells for O2-. production stimulated by IgG and IgA immune complexes. These studies will be aided by the use of highly sensitive flow cytometric techniques. A series of in vivo studies will be carried out in order to determine if oxygen radicals participate in IgA-immune complex induced acute lung injury and, if so, what types of oxygen products are involved. We will take advantage of recent studies in which we have developed a series of interventions designed to define the role of oxygen radicals and to characterize, to the extent possible, the nature of the radical involved. In vivo studies will also be done to determine if products of arachidonic acid are involved in the tissue injury. Finally, phagocytic cells retrieved from IgG and IgA immune complex injured lungs will be examined in vitro for spontaneous as well as stimulated production of oxygen radicals. These studies should provide additional information on the role of oxygen radicals in IgA immune complex induced injury and should lead to a better understanding of the way in which IgA immune complexes bring about tissue injury.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL034635-04
Application #
3347736
Study Section
Pathology A Study Section (PTHA)
Project Start
1985-09-15
Project End
1990-09-14
Budget Start
1988-09-15
Budget End
1989-09-14
Support Year
4
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Gannon, D E; He, X M; Ward, P A et al. (1990) Time-dependent inhibition of oxygen radical induced lung injury. Inflammation 14:509-22
Ward, P A; Walker, B A; Hagenlocker, B E (1990) Functional consequences of interactions between human neutrophils and ATP, ATP gamma S, and adenosine. Ann N Y Acad Sci 603:108-18;discussion 118-9
Warren, J S; Johnson, K J; Ward, P A (1990) PAF and immune complex-induced injury. J Lipid Mediat 2 Suppl:S229-37
Warren, J S; Yabroff, K R; Mandel, D M et al. (1990) Role of O2- in neutrophil recruitment into sites of dermal and pulmonary vasculitis. Free Radic Biol Med 8:163-72
Ward, P A; Warren, J S; Till, G O et al. (1989) Modification of disease by preventing free radical formation: a new concept in pharmacological intervention. Baillieres Clin Haematol 2:391-402
Ward, P A; Cunningham, T W; Johnson, K J (1989) Signal transduction events in stimulated rat neutrophils: effects of adenine nucleotides. Clin Immunol Immunopathol 50:30-41
Walker, B A; Cunningham, T W; Freyer, D R et al. (1989) Regulation of superoxide responses of human neutrophils by adenine compounds. Independence of requirement for cytoplasmic granules. Lab Invest 61:515-21
Warren, J S; Mandel, D M; Johnson, K J et al. (1989) Evidence for the role of platelet-activating factor in immune complex vasculitis in the rat. J Clin Invest 83:669-78
Ward, P A; Cunningham, T W; Walker, B A et al. (1988) Differing calcium requirements for regulatory effects of ATP, ATP gamma S and adenosine on O2.- responses of human neutrophils. Biochem Biophys Res Commun 154:746-51
Warren, J S; Ward, P A; Johnson, K J (1988) Tumor necrosis factor: a plurifunctional mediator of acute inflammation. Mod Pathol 1:242-7

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