Enhanced superoxide release and tumoricidal activity by a postlavage, in situ pulmonary macrophage population in response to activation by Mycobacterium bovis BCG exposure

Abstract

The monocytic phagocyte population of rat lungs is heterogeneous. In addition to the freely lavagable alveolar macrophages, there is a fixed in situ tissue-associated subpopulation of pulmonary macrophages. The response of this subpopulation to classical macrophage activation by Mycobacterium bovis BCG exposure was monitored. Results indicate that this population can be activated both metabolically and functionally, as evidenced by enhanced release of superoxide anions and demonstrable tumoricidal activity against syngeneic and xenogeneic target cells. The pattern of metabolic activation of in situ tissue-associated macrophages differed somewhat from that of alveolar macrophages and was observed only after subsequent exposure of the cells to either zymosan particles or phorbol myristate acetate. Upon such exposure, the activated zymosantreated tissue macrophages released approximately twice as much superoxide as the nonactivated cells and amounts comparable to the amounts released by activated alveolar macrophages. The tissue macrophages also displayed greater levels of cytotoxicity toward xenogenic targets than the alveolar cells and may have an important role in preventing microbial or tumor cell colonization of respiratory systems.Recent information suggests that the monocytic phagocyte population of lungs is heterogeneous and may be characterized as comprised of either cells at different maturational stages or distinct subpopulations of phagocytes which may have arisen from separate stem cell progenitors (1,10,14,16). These cells may occupy the same lung compartment (i.e., the alveoli), be freely lavagable, and yet have distinct immunological, metabolic, and functional properties when they are isolated on Percoll gradients, or they may reside at separate geographic sites (i.e., the bronchi or lung parenchyma) and be separable only by mechanical or enzymatic tissue disruption (1, 7, 10). One such population of lung tissue-associated pulmonary macrophages which are capable of releasing greater quantities of superoxide upon stimulation, responding to endogenous factors with enhanced phagocytic avidity, and containing readily measurable quantities of peroxidase compared with freely lavagable alveolar macrophages has been described recently (1).Since biochemical methods usually examine a population of cells, the problem arises as to whether subsets of, for example, pulmonary macrophages that constitute resident, elicited, or activated populations account for the overall biochemical properties observed. If an activated macrophage population produces greatly enhanced amounts of superoxide upon stimulation and is more cytotoxic than resident macrophages, then it becomes important to determine whether both of these properties are the result of a subset of cells present in greater proportion in the activated population than in the resident population. The key question addressed in this paper is whether macrophage activation involves only the free lavagable alveolar cells or whether fixed or tissue-associated macrophage...

Significant Involvement of CCL2 (MCP‐1) in Inflammatory Disorders of the Lung

“…This immunoneutralization of CCL2 was not associated with altered expression of other chemoattractants, such as eotaxin or RANTES. In contrast to CCL2 inhibition, neutralizing antibodies to eotaxin were effective in attenuating BAL and interstitial eosinophilia irrespective of whether administered during the entire sensitization/challenge period (days [8][9][10][11][12][13][14][15][16][17][18][19][20][21] or only on day 21 before the last allergen challenge. However, for attenuation of AHR, it was necessary for anti-eotaxin antibodies to be administered on the final day of challenge (day 21)-omission of the final anti-eotaxin antibody treatment on day 21 re- sulted in loss of the inhibitory effect on AHR in the OVA-challenged mice.…”

“…Moreover, monocytes localizing to the alveoli in response to intratracheal CCL2 are activated, with increased potential to generate proinflammatory cytokines such as TNF-␣ once they encounter lipopolysaccharide (LPS). Thus, once recruited to the lung, mononuclear phagocytes are highly capable of contributing to lung injury in ARDS, with release of multiple cytotoxic proinflammatory cytokines such as IL-1␤ and TNF-␣ (16,82), platelet-activating factor (34), toxic oxygen radicals including superoxide (18), and a myriad of peptides and complement which both attract and activate other effector leukocytes (60). Lastly, Rosseau and colleagues (71) divided their patients with ARDS into two groups: one in which mononuclear phagocytes transformed to alveolar macrophages and BAL CCL2 levels decreased; and the other, in which the mononuclear cells retained the characteristics of monocytes, and BAL CCL2 levels did not decrease.…”