Published ahead of print on August 9, 2007, doi:10.1165/rcmb.2007-0132OC
© 2008 American Thoracic Society DOI: 10.1165/rcmb.2007-0132OC Macrophage Turnover Kinetics in the Lungs of Mice Infected with Streptococcus pneumoniae1 Department of Pulmonary Medicine, Laboratory for Experimental Lung Research, and 5 Department of Radiotherapy, Hannover School of Medicine, Hannover, Germany; 2 Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama; 3 School of Molecular and Biomedical Science, University of Adelaide, Adelaide, Australia; and 4 Department of Pulmonary, Critical Care, and Sleep Medicine, University of Illinois at Chicago, Chicago, Illinois Correspondence and requests for reprints should be addressed to Ulrich A. Maus, Ph.D., Hannover School of Medicine, Laboratory for Experimental Lung Research, Feodor-Lynen-Strasse 21, Hannover 30625, Germany. E-mail: Maus.Ulrich{at}mh-hannover.de
Streptococcus pneumoniae is the most prevalent cause of community-acquired pneumonia and is known to induce apoptosis and necrosis in macrophages in vivo. We analyzed the kinetics of alveolar and lung parenchymal macrophage replacement by newly recruited exudate macrophages in vehicle-treated and S. pneumoniae–challenged bone marrow chimeric CD45.1 mice. After lethal irradiation, CD45.1 alloantigen-expressing recipient mice were transplanted with bone marrow cells from CD45.2 alloantigen-expressing donor mice. After only 24 hours of low-dose S. pneumoniae infection, approximately 60% of CD45.1pos recipient-type alveolar macrophages (AM) were replaced by CD45.2pos donor-type exudate AM in bronchoalveolar lavage fluid, and this increased to more than 80% on Day 7 of infection. In contrast, lung parenchymal macrophages of S. pneumoniae–infected chimeric CD45.1 mice were replaced by only about 10% by 24 hours, although this increased to over 80% by Days 3 to 7 of infection. This dramatic macrophage turnover was accompanied by early induction of apoptosis/necrosis in donor-type exudate AM peaking at 6 hours after infection, whereas peak apoptosis/necrosis induction in recipient-type AM was delayed until Day 7. Collectively, these data for the first time demonstrate that S. pneumoniae infection of the lung triggers a brisk turnover of both resident and recruited mononuclear phagocyte subsets, and suggest an important role of exudate but not resident macrophages in re-establishing alveolar and lung homeostasis.
Key Words: lung • infection • turnover • monocyte • macrophage
Streptococcus pneumoniae (the pneumococcus) is one of the most important bacterial pathogens in community-acquired pneumonia and is known to frequently progress to invasive pneumococcal disease associated with high morbidity and mortality worldwide (1, 2). S. pneumoniae is known to release pathogen-associated molecular patterns such as pneumolysin (PLY), which is a pore-forming toxin exerting strong cytotoxicities toward alveolar macrophages (AM) and alveolar epithelial cells (3). As such, PLY is considered to play an important role in pneumococcal disease progression (1). We recently showed that recombinant PLY delivered into the lungs of mice transiently depleted the pool of resident alveolar macrophages and caused severe lung edema (3). Other reports demonstrated that PLY may also act as a "classical" pathogen-associated molecular pattern (PAMP) signaling via Toll-like receptor 4 to elicit proinflammatory TNF-  release by macrophages challenged with S. pneumoniae (4), thereby triggering the recruitment of circulating neutrophils into the lung parenchymal and alveolar compartment as part of the innate immune response of the lung to challenge with S. pneumoniae. Moreover, liposomal clodronate–induced depletion of alveolar macrophages was found to strongly impair resolution/repair processes of the lung in pneumococcal pneumonia (5). Thus, alveolar macrophages may serve several important roles in bacterial lung infections by directly and indirectly interfering with invading pathogens, triggering proinflammatory cytokine responses, and contributing to the equally important lung resolution/repair phase to remove apoptotic/necrotic neutrophils to re-establish alveolar and lung homeostasis. This concept is supported by recent data from our group showing that deletion or pharmacological blockade of PI3K signaling pathways, which are critical to inflammatory leukocyte recruitment, strongly impaired the immigration of exudate macrophages into the alveolar compartment of S. pneumoniae–infected mice, with fatal consequences for the resolution/repair process and outcome (6). Recent reports from our group have shown that the constitutive alveolar macrophage turnover under noninflammatory conditions exhibited exceedingly slow kinetics that are strongly accelerated in the lungs of mice challenged with Escherichia coli endotoxin (7). However, despite the well-established importance of resident alveolar and lung macrophages as critical cellular components in lung protective immunity to inhaled bacterial pathogens, the fate of these professional phagocytes and whether they are replaced by newly immigrating exudate macrophages during pneumococcal pneumonia has not been determined so far. Elucidating the interplay between resident and recruited macrophage subsets in terms of facilitating resolution/repair processes within infected lungs could have potentially important implications in the treatment of both acute and chronic inflammatory lung diseases in humans (8). In the current study, we set out to determine the turnover of alveolar and lung parenchymal macrophages in a mouse model of lung infection with the prototype gram-positive bacterial pathogen, S. pneumoniae.
Animals Recipient B6.SJL-Ptprca mice (C57BL/6) expressing the CD45.1 alloantigen (Ly5.1 PTP) (9) on the cell surface of resident alveolar and lung parenchymal macrophages were purchased from Jackson Laboratories (Bar Harbor, ME). Donor C57BL/6J mice expressing the CD45.2 alloantigen (Ly5.2 protein tyrosine phosphatase, PTP) (9) on the cell surface of circulating leukocytes were obtained from Charles River (Sulzfeld, Germany). Animals were housed under conventional conditions and were used for the described experiments at the age of 8 to 10 weeks (body weight, 18–21 g). This animal study was approved by our local government authorities.
Reagents
Isolation of CD45.2-Positive Bone Marrow Cells and Generation of Chimeric CD45.1 Alloantigen-Expressing Recipient Mice
Culture and Quantification of S. pneumoniae and Infection of Chimeric CD45.1 Mice Low-dose infection of chimeric CD45.1 mice with S. pneumoniae was initiated at 3 weeks after bone marrow transplantation (BMT) using freshly prepared dilutions of thawed aliquots adjusted to 1 x 106 CFU/mouse in THB without additional supplements (6). This infection dose was chosen because application of higher bacterial loads (5 x 106 CFU S. pneumoniae) resulted in strongly accelerated macrophage turnover kinetics as early as 24 hours after infection, thereby limiting a sophisticated fluorescence-activated cell sorter (FACS) analysis of infection-induced macrophage turnover in mice (data not shown). Briefly, tracheas were exposed by surgical resection, and intratracheal instillation of the pneumococci was performed under stereomicroscopic control (MS 5; Leica, Wetzlar, Germany) using a 26-gauge catheter (Abbocath; Abbott, Wiesbaden, Germany) inserted into the trachea. After instillation, the neck wound was closed with sterile sutures. Control chimeric CD45.1 recipient mice received intratracheal instillations of sterile vehicle (50 µl THB).
Isolation of Peripheral Blood Leukocytes, Alveolar and Lung Parenchymal Macrophages, and Determination of Bacterial Loads
To determine the macrophage turnover in lung parenchymal tissue of chimeric CD45.1 recipient mice challenged with S. pneumoniae, mice were killed with isoflurane and the lungs were subjected to BAL as described above. Subsequently, the lungs were perfused in situ via the right ventricle with Hank's balanced salt solution (HBSS) until the lungs were visually free of blood, then removed and cut into small pieces followed by digestion of the dissected tissue in RPMI 1640 supplemented with collagenase A (5 mg/ml) and DNAse I (1 mg/ml) for 90 minutes at 37°C. Subsequently, the digested tissue was repeatedly passed through a 1-ml pipette and filtered through 100 µM and 40 µM cell strainers (BD Biosciences). Finally, enzymatic activity was stopped by adding 10 ml of RPMI 1640 medium containing 10% FCS. Macrophages contained in lung parenchymal tissue digests were further purified by magnetic cell separation using magnetic bead–conjugated antibodies with specificity for CD11c, as outlined recently (7, 11). Briefly, cell suspensions were re-suspended in MACS buffer (PBS/2 mM EDTA/0.5% BSA) in the presence of magnetic bead–conjugated anti-CD11c antibodies (10 µl/107 cells) for 15 minutes at 4°C, according to the manufacturer's instructions (Miltenyi, Bergisch-Gladbach, Germany). After incubation and washing, anti-CD11c antibody-labeled cell suspensions were passed through MS columns and CD11cpos cells were eluted with MACS buffer, resulting in highly enriched (
FACS Analysis of CD45.1 versus CD45.2 Cell Surface Antigen Expression and Analysis of Apoptosis/Necrosis Analysis of apoptosis induction in FITC-conjugated anti-CD45.1 antibody-stained recipient-type alveolar macrophages or FITC-conjugated anti-CD45.2 antibody-stained donor-type exudate macrophages contained in BAL fluids of vehicle-treated or S. pneumoniae–infected chimeric CD45.1 mice was done by gating the macrophages according to their FSC/SSC and FSC/F4/80 cell surface expression followed by incubation of respective macrophage aliquots with PE-labeled annexin V for the determination of apoptosis in the presence of 7-AAD for the determination of necrosis for 15 minutes at room temperature, according to the manufacturer's instructions (BD Biosciences). Subsequently, the percentage of apoptotic or necrotic macrophage subsets was analyzed in the fluorescence 2 channel (Annexin-PE) or fluorescence 3 channel (7-AAD) of the flow cytometer after careful post-acquisition compensation settings (7).
Statistics
Bone Marrow Engraftment Efficiency in Chimeric CD45.1 Mice In initial experiments, we analyzed the bone marrow engraftment efficiency in chimeric CD45.1 recipient-type mice lethally irradiated and subsequently transplanted with bone marrow cells from donor-type CD45.2 mice. Analysis of peripheral blood leukocytes isolated from chimeric CD45.1 mice showed an engraftment efficiency of approximately 90% by 3 weeks after BMT, consistent with recent reports (Ref. 7, and data not shown in detail). Accordingly, CD115pos/F4/80pos peripheral blood monocytes of CD45.1 mice lacking CD45.2 cell surface antigen expression (Figures 1A and 1B) were replaced by CD115pos/F4/80pos, CD45.2-positive monocytes in chimeric CD45.1 mice at 3 weeks after BMT (Figures 1A and 1B), thus illustrating the efficient engraftment process by which CD45.2neg recipient-type peripheral blood monocytes were replaced by CD45.2pos donor-type peripheral blood monocytes in chimeric CD45.1 mice. On the other hand, FACS analysis of CD45.1 versus CD45.2 antigen expression by resident alveolar macrophages collected by bronchoalveolar lavage from vehicle-treated chimeric CD45.1 mice at 3 weeks after BMT showed that more than 90% of BAL fluid AM were CD45.1pos recipient-type AM, while staining of AM with anti-CD45.2 Abs revealed a population of approximately 8% of the total pool of BAL fluid AM to represent donor-type AM (Figure 1C), thus illustrating that at 3 weeks after BMT, less than 10% of the total pool of AM in the lungs of vehicle-treated chimeric CD45.1 mice were replaced by CD45.2pos donor-type AM.
Low-Dose Infection of Chimeric CD45.1 Mice with S. pneumoniae Triggers a Brisk Replacement of Recipient-Type Macrophages Both in the Alveolar and Lung Parenchymal Compartment Low-dose intratracheal infection of chimeric CD45.1 mice with approximately 106 CFU S. pneumoniae induced a moderate pneumonia without invasive disease progression, characterized by a mild neutrophilic alveolitis peaking by 24 hours after infection and rapidly declining toward baseline levels by Day 7 after infection, which was lacking in vehicle-treated chimeric CD45.1 mice (Figure 2A). Quantification of bacterial loads in BAL fluids of CD45.1 mice and chimeric CD45.1 mice infected with approximately 106 CFU S. pneumoniae showed similar CFU at 6 hours and 24 hours after infection. At 72 hours after infection, no CFU were detected in BAL fluids of CD45.1 mice, whereas in chimeric CD45.1 mice bacteria were recovered, nevertheless reaching an approximately 97% clearance of initially applied bacteria at this time point with no significant differences noted between groups. By Day 7 after infection, no CFU counts were detectable in BAL fluids of infected mice of either treatment group (Figure 2B).
FACS analysis of the AM turnover in vehicle-treated chimeric CD45.1 mice analyzed at 3 weeks after BMT showed that more than 90% of the total pool of BAL fluid macrophages were found to express the CD45.1 recipient-type alloantigen (Figure 3A). By 24 hours after infection, approximately 40% of BAL fluid macrophages expressed the CD45.1 recipient-type alloantigen, whereas approximately 60% of BAL fluid macrophages were found to be CD45.2pos, thus representing newly recruited exudate donor-type macrophages (Figure 3B). This infection-induced macrophage turnover was accompanied by a significant expansion of the pool of BAL fluid macrophages by 24 hours after infection (Figure 3D). By Day 7 after infection, the pool of BAL fluid macrophages was further expanded in S. pneumoniae–infected but not vehicle-treated mice, and the percentage of donor-type macrophages in BAL fluids was further increased to over 80% of total numbers of BAL fluid macrophages, with numbers of residual recipient-type AM further decreasing during the course of infection (Figures 3C–3F). At the same time, vehicle-treated mice demonstrated an overall constitutive AM turnover of approximately 10% during the observation period of 7 days.
We next analyzed the kinetics of lung parenchymal macrophage turnover in chimeric CD45.1 mice infected with S. pneumoniae. Identification of macrophages collected from lung parenchymal tissue of untreated CD45.1 mice was done according to their CD11cpos, CD11bneg cell surface expression in conjunction with their green autofluorescence characteristics (Figure 4A). Of note, the β2 integrin CD11b is lacking on the cell surface of unstimulated alveolar and lung parenchymal macrophages, as opposed to circulating blood monocytes (13). However, exudate macrophages may upregulate CD11b in vivo (12), as do macrophages upon inflammatory activation (14). As shown in Figure 4A, lung macrophages of untreated CD45.1 control mice lacked CD45.2 expression while expressing CD45.1 alloantigen on their cell surface, thus confirming the alloantigen specificity of the employed antibodies (Figure 4A). Moreover, lung macrophages isolated from chimeric CD45.1 mice at 3 weeks after BMT also lacked CD11b expression (P1, Figure 4B) and were found to comprise approximately 94% CD45.2neg recipient-type lung macrophages, with CD45.2pos donor-type macrophages amounting to only approximately 6% of the total pool of lung macrophages (Figure 4B). Interestingly, we observed that by 24 hours after pneumococcal lung infection, CD11cpos lung macrophages demonstrated a shift toward increased CD11b cell surface expression (see P1, Figure 4C as compared to P1, Figure 4B), with few lung macrophages showing a strong CD11b expression (P2, Figure 4C), thus reflecting their inflammatory activation. A subset-specific analysis of their CD45.2 expression profile to identify the portion of donor-type macrophages showed that CD11blow lung macrophages (P1 in Figure 4C) were CD45.2neg, thus representing activated, CD11blow recipient-type lung macrophages. Moreover, CD11bhigh lung macrophages (P2 in Figure 4C) were found to largely consist of CD45.2neg recipient-type macrophages, with CD45.2pos donor-type macrophages only amounting to approximately 10% of total lung macrophage numbers (Figure 4C). At the same time, we found that by 24 hours after infection, no significant expansion of the total pool of lung macrophages was observed in chimeric CD45.1 mice, in striking contrast to the strongly expanded pool of alveolar macrophages observed at 24 hours after treatment (Figures 3D and 3E). However, FACS analysis of lung macrophages collected from lung parenchymal tissue of chimeric CD45.1 mice infected with S. pneumoniae for 7 days revealed that over 90% of lung macrophages demonstrated a strong CD11b expression (P2, Figure 4D), and these CD11cpos and CD11bpos green autofluorescent cells were found to homogeneously express the CD45.2 alloantigen, thus representing newly recruited donor-type lung macrophages. In contrast, residual CD11blow lung macrophages (P1, Figure 4D) were largely found to be CD45.2neg, thus representing recipient-type lung macrophages. Based on this lung macrophage subset-specific immunophenotypic analysis, we found that infection of chimeric CD45.1 mice with S. pneumoniae triggered a rapid turnover of resident CD11cpos, CD11bneg, CD45.2neg recipient-type lung macrophages starting by 72 hours after infection toward newly recruited CD11cpos and CD11bpos, CD45.2pos donor-type lung macrophages with a peak turnover observed by Day 7 after infection (Figures 4E and 4F).
Resident AM Are Replaced by Newly Recruited Macrophages via Apoptosis/Necrosis Induction in Response to S. pneumoniae We next examined the mechanism by which recipient-type alveolar macrophages are turned over in response to infection of the lung with S. pneumoniae. As shown in Figure 5, CD45.1pos recipient-type macrophages collected from the lungs of chimeric CD45.1 mice infected with S. pneumoniae demonstrated both apoptosis and necrosis induction, which was observed to increase over time. At the same time, apoptosis/necrosis induction in alveolar macrophages of vehicle-treated chimeric CD45.1 mice was less than 10% during the observation period (Figures 5A and 5B). In striking contrast, CD45.2pos donor-type BAL fluid macrophages of S. pneumoniae–infected chimeric CD45.1 mice responded with peak apoptosis/necrosis induction as early as 6 hours and 24 hours after infection and rapidly declining thereafter toward baseline levels (Figures 5C–5E).
In the current study, we examined the kinetics of alveolar and lung parenchymal macrophage turnover in chimeric CD45.1 mice infected with S. pneumoniae. Employing a genetically stable and activation-independent CD45 alloantigen expression system to discriminate resident alveolar and lung parenchymal macrophages from macrophage subsets that are recruited into the lungs of mice in response to pneumococcal challenge, we show that S. pneumoniae infection of the lung triggers a rapid replacement of recipient-type alveolar and lung parenchymal macrophages by newly recruited donor-type CD45.2pos exudate macrophages. This process of inflammatory macrophage turnover is mediated by increased apoptosis and necrosis induction in recipient-type macrophages but also, even more pronounced, in donor-type macrophages in response to bacterial infection. Thus, the presented data show that the pool of both resident alveolar and lung parenchymal macrophages is virtually completely replaced by newly immigrating exudate macrophages in response to bacterial infections, thus highlighting an important role of exudate macrophages in the resolution/repair phase of bacterial infections of the lung.
We recently showed that alveolar and lung macrophages are rapidly replaced by newly immigrating exudate macrophages in response to bacterial PAMPs such as E. coli LPS with peak macrophage turnover rates of more than 80% observed at 8 weeks after endotoxin treatment (7). However, bolus instillation of purified bacterial PAMPs into the lungs of mice may result in inflammatory macrophage turnover kinetics that may be different from those elicited by "real-life" bacterial infections of the lung. Therefore, in the current study, we evaluated for the first time the inflammatory macrophage turnover in the lungs of mice infected with S. pneumoniae, one of the most important prototype gram-positive bacterial pathogens prevailing in community-acquired pneumonia worldwide. S. pneumoniae is known to exert strong cytotoxicity not only toward resident AM but also toward sessile cells of the alveolar compartment, including alveolar epithelial cells, which is partially mediated by the release of cytotoxic virulence factors such as pneumolysin (1, 3, 15). In fact, we recently observed that intratracheal application of purified, recombinant pneumolysin into the lungs of mice provoked a drastic drop in numbers of BAL fluid alveolar macrophages followed by the de novo mobilization of exudate macrophages into the alveolar airspace to regain alveolar macrophage homeostasis. In addition, we recently found that infection of mice with S. pneumoniae transiently depleted the pool of alveolar and lung macrophages, thereby triggering a CCR2- and PI3K
Apoptosis induction in host sentinel cells such as alveolar macrophages is a well-described feature of pneumococcal lung infection. Induction of apoptosis during pneumococcal lung infection may have at least two important implications. According to current concepts, alveolar macrophages undergoing apoptosis in response to S. pneumoniae infection may benefit the host by enhancing bacterial killing, and in addition do not further contribute to the proinflammatory response to inhaled bacteria, thereby limiting the lung (and systemic) inflammatory response to S. pneumoniae infection (18–21). Recently, Dockrell and colleagues found that caspase inhibition in a mouse model of pneumococcal pneumonia decreased AM apoptosis, thereby resulting in increased bacteremic mice (18, 20). On the other hand, apoptosis-induced removal of AM from the alveolar compartment, though initially aiding in the early pathogen elimination process, may be harmful to the infected host when considering the later developing resolution/repair phase, which in addition to the bacterial pathogen elimination process is equally important to regain alveolar and lung homeostasis (12). In the current study, we observed that infection of chimeric CD45.1 mice triggered an apoptosis- and necrosis-induced replacement of recipient-type CD45.1 macrophages against CD45.2 donor-type macrophages, both in the alveolar and lung parenchymal compartment. This rapid turnover of recipient-type against donor-type macrophages was followed by a strong expansion of donor-type lung macrophages peaking by Day 7 after infection, where both the bacterial pathogen elimination process and the alveolar neutrophil recruitment ("classical" characteristics of bacterial lung infections) had already returned to baseline. This transiently "overshooting" donor-type macrophage mobilization observed in the late phase of pneumococcal pneumonia may reflect the necessity of a previously infected lung to mount an efficiently progressing resolution/repair process to regain lung homeostasis. In this line, infection of the lung with S. pneumoniae was found to induce apoptosis/necrosis, particularly in the de novo recruited pool of donor-type macrophages, thus for the first time demonstrating that the early mounted initial donor-type macrophage mobilization toward infected lungs would not participate in, but rather additionally challenge, the later emerging resolution/repair phase. In addition, recipient-type macrophages expected to be among the primary target cells exposed to pneumococcal challenge demonstrated peak apoptosis/necrosis induction in the late phase of pneumococcal lung infection, which again supports the critical necessity of a sustained donor-type macrophage mobilization to compensate for the loss of early recruited donor-type macrophages and at the same time facilitate the removal of apoptotic/necrotic neutrophils and recipient-type macrophages in the later phase of the disease. A detailed knowledge about the fate of alveolar and lung macrophages and the kinetics of their replacement by newly recruited exudate macrophages is an increasingly important aspect in view of emerging pharmacologic intervention strategies. For example, this information is useful in order to inhibit chemokine-dependent effector macrophage mobilization in the treatment of human inflammatory and allergic diseases without perturbing host defense capacities of remote organ systems (6). In another example, as recently shown, inhibition of PI3K During the early phase of pneumococcal lung infection (24 h), numbers of donor-type lung macrophages lagged behind numbers of donor-type alveolar macrophages. This observation may also be influenced by the employed CD11c-based lung macrophage purification technique, which does not allow to collect and analyze both mature CD11cpos resident lung macrophages as well as newly recruited CD11cneg-low lung mononuclear phagocytes still exhibiting a pre-mature phenotype. Recent reports demonstrated that the β2 integrin CD11b, which is normally absent on resident alveolar and lung macrophages but highly expressed on circulating monocytes (13), may be up-regulated on macrophages upon activation, thus representing a macrophage activation marker (14). In the current study, lung parenchymal macrophages of chimeric CD45.1 mice infected with S. pneumoniae for 24 hours were composed of two subsets, one major CD11cpos/CD11blow subset, and a second minor subset defined by its CD11cpos and CD11bhigh β2 integrin expression profile. Interestingly, only the CD11bhigh lung macrophages were (at least partially) newly recruited, donor-type macrophages, as assessed by their CD45.2 alloantigen expression, whereas most of the CD11blow and most of the CD11bhigh lung macrophages were CD45.2neg recipient-type macrophages that apparently up-regulated CD11b as a consequence of cellular activation. Further analysis at Day 7 after infection showed that virtually all of the CD11cpos/CD11bhigh lung macrophages were CD45.2pos, thus reflecting newly recruited, "true" lung exudate macrophages. These data thus illustrate that at least during the early phase of lung bacterial infections, when the inflammatory exchange of recipient-type macrophages against donor-type macrophages is not completed, CD11b may not be an appropriate marker to allow the clear-cut discrimination between resident lung macrophages (which may respond with increased CD11b expression upon activation) and newly recruited monocyte-derived exudate lung macrophages exhibiting a strong CD11b expression. Therefore, additional activation-independent markers such as the currently employed stable CD45 alloantigen expression system are required to make a clear-cut distinction between the pool of resident but "activated" (CD11cpos and CD11blow-high) lung macrophages and the pool of newly recruited, monocyte-derived (CD11cpos/CD11bhigh) exudate lung macrophages. Collectively, the current study for the first time provides a detailed insight into the kinetics of inflammatory macrophage turnover triggered in the lungs of mice in response to the prototype gram-positive bacterial pathogen, S. pneumoniae. The data show that low-dose infection of mice with S. pneumoniae is sufficient to trigger a brisk replacement of recipient-type macrophages against donor-type macrophages both in the alveolar compartment and the lung parenchymal tissue, which in turn appear to primarily mediate the later developing resolution/repair phase to regain alveolar and lung homeostasis.
This study was supported by the German Research Foundation, grant 587 "Immune reactions of the lung to allergy and infection" (U.A.M., T.W). Originally Published in Press as DOI: 10.1165/rcmb.2007-0132OC on August 20, 2007 Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript. Received in original form April 18, 2007 Accepted in final form May 24, 2007
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Abstract
CLINICAL RELEVANCE
90%) preparations of CD11cpos lung mononuclear phagocytes, according to recent reports (
