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Alveolar Macrophages

Wielding the Double-Edged Sword of Inflammation

Department of Medicine Pulmonary Division Minneapolis Veteran's Administration Medical Center University of Minnesota Minneapolis, Minnesota

The alveolar macrophage stands as the guardian of the alveolar–blood interface, serving as the front line of cellular defense against respiratory pathogens (1). Alveolar macrophages are the primary phagocytes of the innate immune system, clearing the air spaces of infectious, toxic, or allergic particles that have evaded the mechanical defenses of the respiratory tract, such as the nasal passages, the glottis, and the mucociliary transport system. By secretion of oxygen metabolites, lysozyme, antimicrobial peptides and proteases, and through processes of phagocytosis and intracellular killing, alveolar macrophages can eliminate the small inocula of typical microbes which are aspirated daily in the normal host (1). Alveolar macrophages also function as regulators of innate alveolar defenses against respiratory infection. When faced with larger numbers of infectious particles or more virulent microbes, alveolar macrophages synthesize and secrete a wide array of cytokines (including interleukins-1, -6, and tumor necrosis factor-), chemokines (including interleukin-8), and arachidonic metabolites (2). Using these cell to cell signals, alveolar macrophages initiate inflammatory responses and recruit activated neutrophils into the alveolar spaces.

Recent evidence suggests that the alveolar macrophage has an equally important role in resolving inflammation within the airspace (2). As inflammatory responses to an infectious challenge resolve, neutrophils undergo programmed cell death, or apoptosis. During apoptosis, neutrophil surface membranes remain intact, containing their potentially injurious cytoplasmic contents. If apoptotic neutrophils are not efficiently cleared, devitalized neutrophils further degrade and leak their intracellular proteases into the alveolus, producing further tissue injury and perpetuating inflammation. Changes in membrane surface markers, including exposure of phosphatidylserine, loss of sialic acid residues on surface immunoglobulins, and decreased expression of surface CD16 moieties (3), targets the apoptotic neutrophil for phagocytosis and clearance by alveolar macrophages. Efficient clearance of apoptotic neutrophils by alveolar macrophages also requires the coordinated expression of soluble factors such as ß 2-glycoprotein, complement proteins, thrombospondin, and particularly surfactant proteins A and D (3). Phagocytosis of neutrophils reduces macrophage secretion of proinflammatory cytokines and also stimulates production of antiinflammatory cytokines, such as transforming growth factor-ß and interleukin-10 (2)

Pneumococcal pneumonia is the prototypical respiratory infection in which these two functions of the alveolar macrophage, initiating and resolving pulmonary inflammation, are particularly important in the preservation of normal lung function. Lobar pneumococcal pneumonia is typically associated with a massive inflammatory response, with activated neutrophils and inflammatory exudate filling airspaces, and notably with complete resolution of this inflammation without residual alveolar injury. In this issue of AJRCCM (pp. 171–179), Knapp and colleagues (4) demonstrate for the first time the consequences of inadequate alveolar macrophage function in the resolution of experimental pneumococcal pneumonia. After pretreating mice with intranasal instillation of liposomal dichloromethylene-bisphosphonate to selectively deplete alveolar macrophages, the authors demonstrated that macrophage-depleted mice had a higher mortality from experimental pneumococcal pneumonia than did control mice pretreated with either intranasal saline or liposomes. Interestingly, bacterial clearance and degrees of bacteremia did not differ between alveolar macrophage–depleted mice and control mice, suggesting that the higher mortality was not due to lack of initiation of local or systemic inflammatory responses. In fact, macrophage-depleted mice had higher levels of intrapulmonary cytokines tumor necrosis factor-, interleukin-1ß, and KC, and greater numbers of activated neutrophils, than did control mice. Further investigation revealed that macrophage-depleted mice had greater numbers of apoptotic and dead neutrophils in whole lung lavage fluid than did control mice, even though caspase-3 activity, a marker of apoptotic activity, was only slightly elevated in the treated animals. Therefore, depletion of alveolar macrophages produced decreased clearance of apoptotic neutrophils, some of which proceeded to necrosis. In addition, levels of the antiinflammatory cytokine interleukin-10 were lower in lungs of macrophage-depleted mice compared with control mice. Finally, lungs of macrophage–depleted mice showed focal areas of parenchymal destruction, which presumably was absent in control mice.

Thus, the data presented suggest that, at least in this model of experimental pneumococcal pneumonia, depletion of alveolar macrophages leads primarily to failure to clear apoptotic neutrophils, with the consequence of persistent production of proinflammatory cytokines, influx of activated neutrophils, and alveolar capillary injury. Presumably, these events were the cause of the higher mortality from pneumococcal pneumonia in the macrophage-depleted mice, although data were not presented to distinguish whether animals died from respiratory failure as opposed to sepsis and shock. Interestingly, macrophage depletion did not significantly affect the initiation of inflammatory responses against pneumococcal challenge nor the numbers of bacteria in lungs and blood within the first 48 hours after infection, in contrast to studies in experimental gram-negative pneumonia (5, 6).

The limitations of the study design do not allow us to know whether the persistent inflammation in the macrophage-depleted mice caused their death, as bacterial, cytokine, and histological studies were performed at 20 and 44 hours after infection, whereas significant differences in survival were seen at 72 hours after infection. In addition, the authors' conclusions that alveolar macrophages are less important in the initial defense against pneumococcal pneumonia may be unfounded. This study used a macrophage-depletion method that only reduced alveolar macrophage numbers in treated mice by 74% compared with control mice. Conceivably, the reduced numbers of alveolar macrophages in the treated mice may have been sufficient to initiate inflammatory responses and recruit activated neutrophils, whereas greater numbers of alveolar macrophages are necessary to appropriately resolve inflammation. Also, the authors studied infection with one particular pneumococcal isolate, serotype 3, which is thought to alter pulmonary inflammatory responses, possibly by shedding of its abundant capsular polysaccharides (7). Further investigation using other methods to deplete alveolar macrophages, and studying the pathogenesis of infection with other pneumococcal serotypes at later times after infection is needed to confirm and extend these findings. Nevertheless, this study contributes importantly to ongoing research on the dual roles of the alveolar macrophage as guardian of the alveolar-blood borders.

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