AM J RESPIR CRIT CARE MED 1999;160:S5−S11.Elucidation of the poorly understood mechanisms by which acute inflammation normally resolves is likely to provide new insights into the pathogenesis of persistent inflammatory states that characterize inflammatory disease and generate new therapeutic targets. We have concentrated on the mechanisms by which granulocytes and their histotoxic contents are cleared from inflamed sites during resolution. Although it had been assumed that extravasated neutrophils disintegrated (undergo necrosis) in situ, we have demonstrated an alternative fate, whereby the cell undergoes apoptosis, a process that has different implications for the control of inflammation. During apoptosis the neutrophil retains its granule contents and loses the ability to secrete them in response to secretagogues. In contrast to necrotic neutrophils, apoptotic neutrophils are ingested by inflammatory macrophages employing novel phagocytic recognition mechanisms that fail to provoke a macrophage proinflammatory response. These recognition mechanisms can be modulated by a number of environmental factors and may represent a pivotal point in the control of inflammation, since if apoptotic granulocytes are not rapidly cleared they undergo secondary necrosis with all the detrimental consequences entailed. The apoptotic clearance pathway is also available to eosinophil granulocytes, but our work suggests that the internal controls may be different from those in neutrophils. For example, corticosteroids delay neutrophil apoptosis but greatly accelerate eosinophil apoptosis, in what may represent a previously unsuspected beneficial mechanism of steroid action in allergic diseases such as bronchial asthma. Furthermore, such differences may lead to novel therapies based on the specific induction of eosinophil apoptosis. Haslett C. Granulocyte apoptosis and its role in the resolution and control of lung inflammation.
Inflammation, and particularly the persistent presence in tissue of granulocytes and the other leukocytes that form the cellular elements of inflammation, is now recognized as a central process in the pathogenesis of chronic obstructive pulmonary disease (COPD), bronchial asthma, and other respiratory diseases that constitute a major health burden in developed societies. Indeed, we could be forgiven for considering inflammation as a detrimental process that inevitably progresses to the tissue injury and scarring that characterize inflammatory diseases, whereas, paradoxically, it evolved as a key host defense mechanism.
In fact, until the last two or three decades, inflammation was regarded as an entirely beneficial host defense response, and it has been recognized for centuries that there exists the potential for complete resolution of inflammation as well as its persistence and progression. Elias Metchnikoff, the father of modern inflammatory cell biology, described inflammation as a “salutory response to some injurious influence” and in the early eighteenth century Sir William Cullen, an Edinburgh physician, recognized that inflammation could cause gangrene (tissue destruction) and scirrhus formation (scarring) but that it could also resolve completely (1), a point that was emphasized by Hurley in his treatise on “acute inflammation” two centuries later (2). So, what can we learn from examples of “beneficial” inflammation, largely ignored of late, which may be helpful in our understanding of the inflammatory diseases that have assumed prominence in developed society?
Perhaps the best example of beneficial inflammation in the lung is the local inflammatory response to streptococcal invasion in the development of lobar pneumonia. During the phase of “red hepatization” there is massive emigration of neutrophil granulocytes and activated monocytes/macrophages into the local air spaces together with an outpouring of protein-rich inflammatory exudate. There is ample scientific evidence from the preantibiotic era that this response was sufficient to protect most patients from a potentially lethal invasion of bacteria (3). One large study of more than 3,000 patients admitted to the Harlem Hospital over a 5-yr period demonstrated a mortality of less than 30% (3). Lobar pneumonia also provides a most dramatic example of the potential for even massive inflammatory responses such as this to resolve completely. Despite what we now know of the destructive and profibrotic capacity of neutrophils and activated macrophages, there is clear evidence from necropsy, and from radiological studies of large series of patients with lobar pneumonia, that in more than 98% of cases the lesions resolve with no destructive or fibrotic sequelae (3, 4). However, it would be inaccurate to suggest that there are no detrimental effects of the inflammatory response—even in streptococcal lobar pneumonia there are examples of “bystander” endothelial injury—yet these must not be sufficiently severe or extensive to preclude rapid and effective reconstitution and repair. Indeed, these observations suggest that the outcome of inflammation can be regarded as the result of a “battle” between mechanisms that would tend to cause injury and amplify inflammation versus those that tend to protect tissues and promote resolution. It is not known why some stimuli (e.g., streptococcus) induce inflammation that tends to be limited in its injurious effects and that resolves completely, whereas others (e.g., staphylococcus, silica, etc.) provoke inflammation that is persistent and associated with destruction of tissue and scarring responses, but the central hypothesis of our research group and its associates is as follows:
The definition of mechanisms responsible for the normal resolution processes of inflammation will lead to new insights into the persistent inflammatory states that characterize diseases such as COPD and asthma, and will open new avenues for therapeutic intervention based on harnessing, or driving, mechanisms that favor resolution and repair.
For lung tissue to return to normal during the resolution of inflammation, all of the processes involved in the initiation of inflammation must be reversed. Thus, there must be removal of the stimuli responsible for inciting inflammation; dissipation or destruction of proinflammatory mediators; cessation of granulocyte emigration from blood vessels; restoration of normal vascular permeability and removal of extravasated fluids; limitation of granulocyte secretion of proinflammatory and histotoxic agents; cessation of monocyte emigration and their maturation into macrophages; removal of fibrin and protein clots, bacterial and cellular debris, and granulocytes and macrophages; and, finally, repair of any “bystander” injury to constitutive endothelial and epithelial monolayers.
In contrast with initiation and amplification events in inflammation, we know very little about the mechanisms responsible for the preceding processes. However, it is likely that some resolution and repair events occur very early in the evolution of the inflammatory response, e.g., we have found that granulocyte emigration ceases remarkably early (by 6 h) in an experiment model of streptococcal pneumonia in which the histological lesion does not clear for 72 to 96 h (5). By implication, the chronic inflammation that characterizes disease processes is the result of a continuous balance/imbalance between those initiation and proinflammatory mechanisms that tend to injure or scar tissues and those that protect tissues or promote resolution. Although it is often assumed that chronic inflammation occurs as a result of uncontrolled proinflammatory events, it is perhaps equally likely that failure, or inefficiency, of the normal resolution processes is responsible for tipping the balance toward persistent inflammation, tissue injury, and scarring. The following is therefore also hypothesized:
Persistent inflammatory responses may arise from failure or inefficiency of the mechanisms normally responsible for resolution of inflammation and restitution of tissue homeostasis.
The study of the resolution of inflammation is likely to be as complex and difficult as the study of initiation events, but for a number of reasons we have been studying the mechanisms of one important prerequisite for resolution to occur—i.e., how extravasated granulocytes are removed from tissues during the resolution of inflammation. The neutrophil granulocyte is the archetypal acute inflammatory cell. Neutrophils are the first cells to migrate to the inflamed site, and a number of subsequent inflammatory events, including monocyte emigration (6) and the generation of edema (7), appear to depend on this initial response. The neutrophil has been directly implicated in the pathogenesis of a variety of inflammatory diseases (8), including COPD, and it contains a large number of agents with the capacity not only to injure tissues but also to generate further chemotactic agents and to cleave tissue proteins into chemotactic factors (8, 9).
Until very recently, it was assumed that extravasated granulocytes inevitably underwent disintegration (necrosis) at the inflamed site and that their fragments were then cleared by macrophages (2). However, these observations were based on histological studies of diseased tissues, rather than spontaneously resolving beneficial inflammation, and, if this was the rule, healthy tissues would inevitably be exposed to large quantities of disgorged, histotoxic granulocyte products. Furthermore, there is largely forgotten evidence, from Metchnikoff's work, that an alternative fate exists by which intact senescent neutrophils are ingested by macrophages (10). More recently we have shown that purified human neutrophils derived from peripheral blood or inflamed joints undergo apoptosis and that this process determines the rapid clearance of intact senescent neutrophils by macrophages (11). There are now numerous reports of the existence of this process in resolving acute inflammation in the lung and other organs (e.g., 12–14), and there are a number of studies that support the following hypothesis:
In contrast to necrosis, apoptosis provides a granulocyte clearance mechanism that would tend to limit tissue injury and promote resolution, rather than persistence, of inflammation.
There are now several lines of evidence from in vitro experimentation supporting the hypothesis that apoptosis provides an injury-limiting granulocyte clearance mechanism.
1. During apoptosis the neutrophil surface membrane remains intact and continues to exclude vital dyes (11). Macrophages can clear large numbers of apoptotic neutrophils without leakage of potential injurious neutrophil contents into the surrounding milieu (15).
2. In their physiological state, neutrophils normally release a proportion of their potentially injurious granule contents on external stimulation with inflammatory mediators such as formylated bacteria-derived peptides, e.g., fMLP. However, during apoptosis, neutrophils lose this ability to degranulate on deliberate external stimulation (16) as well as a number of other functions, including phagocytosis. The mechanisms responsible for rapid shutdown of neutrophil function during apoptosis are poorly understood, but apoptosis is associated with specific alterations in the surface expression of a number of receptors that are related to effective neutrophil function, including partial loss of fMLP receptors (17) and greater than 90% loss of others including the IgG receptor FcR III or CD16 (17, 18). Although the precise mechanisms responsible for receptor dysregulation during apoptosis are unclear, there are striking parallels with activation-induced changes in receptor expression. Notably, those receptors that are shed by a proteolytic cleavage mechanism during neutrophil activation, e.g., CD16, L-selectin, p55 and p75 tumor necrosis factor (TNF) receptors, and CD43, all show marked reduction in surface expression during early apoptosis (18), suggesting that part of the activation program may be engaged during apoptosis. Since free apoptotic cells are seen at inflamed sites this mechanism could be important in the control of local tissue injury before apoptotic neutrophils are cleared by macrophages. However, it is unlikely that isolated apoptotic neutrophils remain “inert” for long periods because in vitro experiments suggest that in the absence of macrophages, apoptotic neutrophils undergo secondary necrosis after a few hours, and later disintegrate and disgorge their own contents.
3. Macrophages normally release large quantities of proinflammatory mediators such as leukotriene products, cytokines, etc., in response to the ingestion of particles. However, the uptake of large numbers of apoptotic granulocytes, in contrast to the uptake of opsonized zymosan or opsonized erythrocytes, fails to stimulate the release of proinflammatory agents by human monocyte-derived macrophages (18, 19). Moreover, the ingestion of apoptotic neutrophils that have been further cultured in vitro to a point at which the cells begin to undergo necrosis, or the uptake of apoptotic cells that have been opsonized does stimulate major release of inflammatory mediators by macrophages. These observations suggest that the lack of release of proinflammatory agents by macrophages is not due to a toxic effect of the apoptotic cell per se and that this lack of macrophage response is determined by the specific mechanisms that macrophages use to ingest apoptotic cells (18, 19). Important recent work by Fadok and colleagues suggests that the macrophage response is not entirely “silent” and that the uptake of apoptotic neutrophils may not only suppress the release of proinflammatory agents such as interleukin (IL)-1β, granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-8, TNF, etc., but increase macrophage release of agents such as transforming growth factor β (TGF-β) and prostaglandin E2 (PGE2) (20) that have suppressive influences on the inflammatory response.
Early work on human monocyte-derived macrophage recognition of apoptotic human neutrophils suggested a novel mechanism rather than utilization of one of the receptors previously ascribed to the phagocytosis of particles. These experiments also demonstrated that recognition of apoptotic neutrophils could be markedly inhibited by cationic molecules and by conditions of low pH. This may be of considerable relevance to the control of inflammation since conditions known to exist in the chronic inflammatory microenvironment would have detrimental influences on this clearance pathway. For example, a number of granulocyte enzymes are highly cationic and have been demonstrated extracellularly in tissues in inflammatory diseases, e.g., asthma; and, in abscesses or at sites of chronic inflammation, the tissue pH may be very low (21). We have now shown that the novel macrophage recognition mechanism employed in the recognition of apoptotic granulocytes involves the vitronectin receptor αvβ3 and the thrombospondin receptor CD36 (22), perhaps acting in concert via thrombospondin as a “molecular bridge” to ligate an as yet unidentified site on the apoptotic neutrophil surface. Other candidate mechanisms have been suggested whereby macrophages recognize phosphatidylserine residues that become exposed on the surface of apoptotic cells (23). However, the in vivo significance of the various candidate mechanisms remains uncertain (24).
It has become clear that the constitutive rate of apoptosis in neutrophils is under different controls than those described in stimulated lymphocytes and thymocytes. Hence, cycloheximide enhances the constitutive rate of apoptosis in neutrophils (25), and agents that elevate extracellular calcium delay neutrophil apoptosis (26). A range of inflammatory agents including lipopolysaccharide (LPS) and GM-CSF also inhibit neutrophil apoptosis and, in parallel, greatly enhance and preserve a number of neutrophil functions (27). Indeed, it now seems clear that apoptosis is the major mechanism controlling the “functional longevity” of neutrophils at inflamed sites. Human eosinophil granulocytes also constitutively undergo apoptosis but at a much slower rate than neutrophils (28). As in neutrophils, GM-CSF profoundly inhibits the rate of eosinophil apoptosis, whereas IL-5, which has no influence on neutrophil apoptosis, specifically inhibits eosinophil apoptosis (28), perhaps providing part of the explanation for the differential accumulation of eosinophils in allergic tissues. Hypoxic conditions, which are observed in diseased tissues at chronically inflamed sites, also inhibit granulocyte apoptosis.
Perhaps surprisingly, given that the physiological half-life of the neutrophil in the circulation is only 6 h, the constitutive rate of neutrophil apoptosis can also be accelerated. TNF-α accelerates the rate of neutrophil apoptosis, particularly in the first 10 h of culture (29). Nitric oxide donors also induce neutrophil apoptosis (30), perhaps explaining part of the beneficial influence of NO on inflammation. Ligation of Fas on the neutrophil or eosinophil surface can promote apoptosis (31), an observation repeated in our laboratory, and Fas ligand appears to induce granulocyte apoptosis in vivo (32).
The mechanisms whereby some inflammatory mediators exert their powerful effects on the rate of neutrophil apoptosis are poorly understood. However, many chemotactic peptides signal by an elevation of intracellular calcium, which itself exerts a major inhibitory effect on neutrophil apoptosis (33). Receptor-directed stimuli (such as the prostaglandins) and pharmacological agents, e.g., dibutyryl-cyclic AMP (db-cAMP) and forskolin, that elevate intracellular cAMP have also been shown to inhibit neutrophil apoptosis by a protein kinase A (PKA)- dependent mechanism (34). The observation that GM-CSF requires protein synthesis led to a search for neutrophil apoptosis-inhibitory agents. Proteins such as Bcl-2 were possible candidates since they inhibit apoptosis in myeloid cell lines (35). However, despite studies in a number of laboratories, there is, as yet, no definitive mechanism for these effects.
Although we did not expect to find major differences between the apoptotic control mechanisms of neutrophils and eosinophils, which are closely related in ontogeny, corticosteroids acting directly on the same receptor clearly accelerate eosinophil apoptosis while profoundly inhibiting neutrophil apoptosis (36). The identification of intracellular mechanisms governing such divergent responses should provide new therapeutic targets for selective induction of eosinophil apoptosis in allergic disease (see below).
We have described factors in the chronic inflammatory microenvironment that might inhibit the normal recognition mechanisms whereby monocyte-derived macrophages engulf apoptotic neutrophils, but it is also clear that important inflammatory mediators and therapeutic agents can accelerate macrophage clearance of apoptotic neutrophils.
In vitro experiments showed that a number of inflammatory mediators (37) and agents that modulate macrophage cAMP (38) can produce a modest enhancement of macrophage ingestion of apoptotic granulocytes. More recently we have shown much more impressive augmentation by corticosteroids (39) and by ligation of CD44 on the macrophage surface (40).
We have now described a pathway for granulocyte removal from inflamed tissues that, in contrast to the deleterious effects of its alternative, necrosis, would tend to limit inflammatory tissue injury and favor resolution of inflammation and restitution of normal tissue homeostasis. Apoptosis is a highly controlled process, modulated by extracellular and intracellular mechanisms, that is responsible for the shutdown of granulocyte secretory processes and removal of the intact senescent cell by macrophages utilizing novel phagocytic recognition mechanisms. These do not trigger the release of proinflammatory mediators but do stimulate macrophage release of mediators that suppress the inflammatory response. Finally, we have shown that granulocyte apoptosis is a central mechanism in the resolution of experimental streptococcal pneumonia (Figures 1A–1C).
The existence of highly effective resolution mechanisms suggests that some inflammatory diseases could arise from the failure, or inefficiency, of such mechanisms. For example, it can be seen (Figure 2) that there are a number of hypothetical steps in the “ideal” clearance pathway (Pathway 1) at which dysregulation could tip the balance in favor of excessive tissue injury and chronic inflammation. Some examples are as follows.
1. There may be a “primary” imbalance between the ideal pathway and the necrotic “detrimental” pathway (Pathway 2). Even at sites of beneficial inflammation, e.g., streptococcal pneumonia, some necrotic cells are seen on ultrastructural examination. However, it is difficult to determine how much necrosis might be necessary to tip the balance in vivo because we lack truly specific markers of apoptotic and necrotic cells.
2. Secondary necrosis (Pathway 3) of apoptotic cells is likely to occur if the downstream phagocytic clearance mechanism is ineffective for any reason, e.g.,
a. Monocyte-derived macrophages have not had time to mature fully into inflammatory macrophages capable of ingesting apoptotic neutrophils.
b. The macrophage clearance system is overwhelmed by massive waves of apoptosis, e.g., in vivo triggering of Fas ligand (41).
c. The surface recognition mechanisms by which macrophages recognize apoptotic granulocytes could be inhibited by cationic proteins, low pH, autoantibodies, etc., in diseased tissues.
Secondary necrosis of granulocytes would then exacerbate the inflammatory response and by releasing more cationic proteins would further inhibit macrophage clearance of apoptotic cells, thus setting up a vicious cycle of further waves of secondary necrosis, etc.
Regardless of whether the preceding hypotheses prove to be true in the pathogenesis of inflammatory disease, it should be possible to harness the apoptotic mechanisms involved in the resolution of acute inflammation and “drive” granulocyte death down the beneficial pathway that “nature intended” for the physiological clearance of unwanted cells. This could be done by activating “death receptors” on the cell surface, but it may also be necessary to overcome the effects of powerful survival factors, e.g., GM-CSF (Figure 3). It may also be possible to selectively induce apoptosis in some types of granulocytes, e.g., corticosteroids induce eosinophil apoptosis but inhibit neutrophil apoptosis. Evidence in support of such an approach is provided by experimental models in which Fas ligation attenuates inflammation (32), and in the treatment of human asthma with corticosteroids a recent study showed that clinical improvement was associated with an increased proportion of apoptotic eosinophils and apoptotic bodies within macrophages in airway secretions (42). Thus, it is possible that the beneficial effects of corticosteroids in asthma may occur partly as a result of previously unexpected influences on eosinophil apoptosis and subsequent clearance by macrophages.
Any highly effective therapy that induces massive waves of granulocyte apoptosis could overwhelm macrophage clearance mechanisms (e.g., excessive Fas ligation in vivo; Reference 41) and lead to secondary necrosis of apoptotic granulocytes with all the obvious adverse sequelae. Therefore, any such approach is likely to require a parallel strategy to accelerate the phagocytic clearance of apoptotic cells before secondary necrosis occurs. It has been shown that the macrophage phagocytosis of apoptotic cells can be augmented nonspecifically by some cytokines and agents that influence macrophage levels of cAMP, but more recently we have shown that corticosteroids (39) and ligation of macrophage surface CD44 (40) significantly accelerate macrophage clearance of apoptotic granulocytes. Finally, other cells, e.g., fibroblasts (43), appear to be able to act as semiprofessional phagocytes and it may be possible to provide these cells with the receptors necessary for clearance of apoptotic granulocytes in a gene therapy strategy that could augment the “professional” macrophage clearance system.
The definition of key resolution mechanisms will lead to new therapeutic opportunities to harness and promote them in order to shift the balance of inflammation in favor of resolution and restitution of tissue homeostasis. Whether such approaches are feasible in diseases with the chronicity of COPD remains to be established.
The author thanks Mrs. Heather Chisholm for typing the manuscript, Peter Henson for suggesting this research track in 1982, and the following coworkers and colleagues for scientific stimulation: John Savill (in particular), Ian Dransfield, Adriano Rossi, Andrew Wyllie, Edwin Chilvers, Moira Whyte, Geoff Bellingan, Myra Stern, Valerie Fadok, Simon Hart, Jo Murray, and Carol Ward (all of whom made major contributions to the incomplete picture presented in this article).
|1.||Cullen, Sir William. The Practice of Physic, 2nd ed. Edinburgh. 1778– 1784.|
|2.||Hurley, J. V. 1983. Termination of acute inflammation: 1. Resolution. In Acute Inflammation, 2nd ed. Churchill Livingstone, London. 109.|
|3.||Heffron, R. 1939. Pneumonia: With Special Reference to Pneumococcus Lobar Pneumonia, Vol. xvii. Commonwealth Fund. 1086.|
|4.||Robertson O. H., Uhley C. G.Changes occurring in the macrophage system of the lungs in Pneumococcus lobar pneumonia. J. Clin. Invest.151935115|
|5.||Jones H. A., Clark R. J., Rhodes C. G., Schofield J. B., Krausz T., Haslett C.In vivo measurement of neutrophil activity in experimental lung inflammation. Am. J. Respir. Crit. Care Med.149199416351639|
|6.||Doherty D. E., Worthen G. S., Haslett C., Henson P. M.Monocyte accumulation at acutely inflamed sites in the rabbit lung is dependent upon initial neutrophil accumulation. Lab. Invest.591988200213|
|7.||Wedmore C. V., Williams T. J.Control of vascular permeability by polymorphonuclear leukocytes in inflammation. Nature (London)2891981646650|
|8.||Haslett C., Jose P. J., Giclas P. C., Williams T. J., Henson P. M.Cessation of neutrophil influx in C5a-induced acute experimental arthritis is associated with loss of chemotractant activity from joint spaces. J. Immunol.142198935103517|
|9.||Spitznagel J. K.Antibiotic proteins of neutrophils. J. Clin. Invest.86199418511854|
|10.||Metchnikoff, E. 1891. Lecture VII. In F. A. Starling and E. H. Starling, translators. Lectures on the Comparative Pathology of Inflammation. Delivered at the Pasteur Institute in 1891. Dover, New York.|
|11.||Savill J. S., Wyllie A. H., Henson J. E., Walport M. J., Henson P. M., Haslett C.Macrophage phagocytosis of aging neutrophils in inflammation: programmed cell death in the neutrophil leads to its recognition by macrophages. J. Clin. Invest.831989865875|
|12.||Grigg J. M., Savill J. S., Sarraf C., Haslett C., Silverman M.Neutrophil apoptosis and clearance from neonatal lungs. Lancet3381991720722|
|13.||Cox G., Crossley J., Xing Z.Macrophage engulfment of apoptotic neutrophils contributes to the resolution of acute pulmonary inflammation in vivo. Am. J. Respir. Cell Mol. Biol.121995232237|
|14.||Savill J. S., Smith J., Ren Y., Sarraf C., Abbot F., Rees A. J.Glomerular mesangial cells and inflammatory macrophages ingest neutrophils undergoing apoptosis. Kidney Int.421992924936|
|15.||Kar S., Ren Y., Savill J. S., Haslett C.Inhibition of macrophage phagocytosis in vitro of aged neutrophils increases release of neutrophil contents. Clin. Sci.85199527p|
|16.||Whyte M. K. B., Meagher L. C., MacDermot J., Haslett C.Impairment of function in aging neutrophils is associated with apoptosis. J. Immunol.150199351245134|
|17.||Meagher L. C., Savill J. S., Baker A., Haslett C.Phagocytosis of apoptotic neutrophils does not induce macrophage release of thromboxane B2. J. Leukocyte Biol.521992269273|
|18.||Dransfield I., Stocks S. C., Haslett C.Regulation of cell adhesion molecule expression and function associated with neutrophil apoptosis. Blood85199532643273|
|19.||Stern M., Savill J., Haslett C.Human monocyte-derived macrophage phagocytosis of senescent eosinophils undergoing apoptosis: mediation by αvβ3/CD36/thrombospondin recognition mechanism and lack of phlogistic response. Am. J. Pathol.1491996911921|
|20.||Fadok V. A., Bratton D. L., Konowal A., Freed P. W., Westcott J. Y., Henson P. M.Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-β, PGE2 and PAF. J. Clin. Invest.90199815131522|
|21.||MenkinBiology of inflammation: chemical mediators and cellular injury. Science1231956527534|
|22.||Savill J. S., Hogg N., Haslett C.Thrombospondin co-operates with CD36 and the vitronectin receptor in macrophage recognition of aged neutrophils. J. Clin. Invest.90199215131529|
|23.||Fadok V. A., Savill J. S., Haslett C.Different populations of macrophages use either the vitronectin receptor or the phosphatidylserine receptor to recognise and remove apoptotic cells. J. Immunol.149199240294035|
|24.||Savill J. S., Fadok V. A., Henson P. M., Haslett C.Phagocyte recognition of cells undergoing apoptosis. Immunol. Today141993131136|
|25.||Whyte M. K. B., Meagher L. C., Lee A., Haslett C.Coupling of neutrophil apoptosis to recognition by macrophages: co-ordinated acceleration by protein synthesis inhibitors. J. Leukocyte Biol.621997195202|
|26.||Whyte M. K. B., Meagher L. C., Hardwick S. J., Savill J. S., Haslett C.Transient elevations of cytosolic free calcium retard subsequent apoptosis in neutrophils in vitro. J. Clin. Invest.921993446455|
|27.||Lee A., Whyte M. K. B., Haslett C.Prolonged in vitro lifespan and functional longevity of neutrophils induced by inflammatory mediators acting through inhibition of apoptosis. J. Leukocyte Biol.541993283288|
|28.||Stern M., Meagher L., Savill J. S., Haslett C.Apoptosis in human eosinophils: programmed cell death in the eosinophil leads to phagocytosis by macrophages and is modulated by IL-5. J. Immunol.148199235433549|
|29.||Murray J., Barbara J. A. J., Lopez A. F., Ostade X. F., Condliffe A. M., Dransfield I., Haslett C., Chilvers E. R.Regulation of neutrophil apoptosis by tumour necrosis factor a requirement for CD120a (TNFR-55) and CD120b (TNFR-75) for induction of apoptosis in vitro. Blood90199727722783|
|30.||Chilvers, E. R., T. H. Wong, I. Rahman, C. Haslett, and A. G. Rossi. 1997. Nitric oxide stimulates neutrophil apoptosis via a cyclic-GMP-independent mechanism. Keystone Symposia: apoptosis and programmed cell death. A109.|
|31.||Matsumoto K., Schleimet R. P., Saito H., Iikura Y., Bochner B. S.Induction of apoptosis in human eosinophils by anti-Fas antibody treatment in vitro. Blood86199514371443|
|32.||Tsuyuki S., Bertrand C., Erard F., Trifilieff A., Tsuyki J., Wesp M., Anderson G. P.Activation of the Fas receptor on lung eosinophils leads to apoptosis and the resolution of inflammation of the airways. J. Clin. Invest.96199529242931|
|33.||Whyte M. K. B., Meagher L. C., Hardwick S. J., Savill J. S., Haslett C.Transient elevations of cytosolic free calcium retard subsequent apoptosis in neutrophils in vitro. J. Clin. Invest.921993446455|
|34.||Rossi A. G., Cousin J. M., Dransfield I., Lawson M. F., Chilvers E. R., Haslett C.Agents that elevate cAMP inhibit human neutrophil apoptosis. Biochem. Biophys. Res. Commun.2171995892899|
|35.||Delia D., Aiello A., Soligo D., Fontanella E., Melani C., Pezzella F., Pierolli M. A., Delia G., Portabcl-2 proto-oncogene expression in normal and neoplastic human myeloid cells. Blood79199212911298|
|36.||Meagher L., Cousin J. M., Seckl J. R., Haslett C.Opposing effects of glucocorticoids on the rate of apoptosis in neutrophilic and eosinophilic granulocytes. J. Immunol.156199644224428|
|37.||Ren Y., Savill J.Pro-inflammatory cytokines potentiate thrombospondin-mediated phagocytosis of neutrophils undergoing apoptosis. J. Immunol.154199523662374|
|38.||Rossi A. G., McCutcheon J. C., Roy N., Chilvers E. R., Haslett C., Dransfield I.Regulation of macrophage phagocytosis of apoptotic cells by cAMP. J. Immunol.160199835623568|
|39.||Liu Y., Cousin J. M., Hughes J., van Damme J., Seckl J. R., Haslett C., Dransfield I., Savill J., Rossi A. G.Glucocorticoids promote non-phlogistic phagocytosis of apoptotic leukocytes. J. Immunol.162199936393646|
|40.||Hart S. P., Dougherty G. J., Haslett C., Dransfield I.CD44 regulates phagocytosis of apoptotic neutrophil granulocytes, but not apoptotic lymphocytes, by human macrophages. J. Immunol.1591974919925|
|41.||Ogasawara J., Watanabe-Fukanaga R., Adachi M., Matsuzawa A., Kasugai T., Kitiamura Y., Itoh N., Suda T., Nagata S.Lethal effect of the anti-Fas antibody in mice. Nature (London)36464401993806809|
|42.||Wooley K. L., Gibson P. G., Carty K., Wilson A. J., Twaddel S. H., Wooley M. J.Eosinophil apoptosis and the resolution of airway inflammation in asthma. Am. J. Respir. Crit. Care Med.1541996237243|
|43.||Hall S., Savill J., Henson P., Haslett C.Apoptotic neutrophils are phagocytosed by fibroblasts with participation of the fibroblast vitronectin receptor and involvement of a mannose/fucose-specific lectin. J. Immunol.153199432183227|