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(Chest. 1999;116:46S-54S.)
© 1999 American College of Chest Physicians

Regulation of Neutrophil Activation in Acute Lung Injury*

Gregory P. Downey, MD, FCCP; Qin Dong; Joshua Kruger, BSc; Shoukat Dedhar and Vera Cherapanov

* From the Department of Medicine (Drs. Downey, Dong, Kruger, and Cherapanov), Division of Respirology, The University of Toronto, Toronto, Ontario, Canada; and the British Columbia Cancer Agency (Dr. Dedhar), Jack Bell Research Centre, Vancouver, British Columbia, Canada. Supported by operating grants from the Ontario Thoracic Society, the Medical Research Council of Canada, and the National Institutes of Health. Dr. Downey is the recipient of a Career Scientist Award from the Ontario Ministry of Health.

Correspondence to: Gregory P. Downey, MD, FCCP, Clinical Sciences Division, Room 6264 Medical Sciences Bldg, University of Toronto, 1 Kings College Circle, Toronto, Ontario, Canada, M5S 1A8; e-mail: gregory.downey{at}utoronto.ca

The syndrome of acute lung injury, also known as the ARDS,1 is initiated by a variety of local or systemic insults leading to diffuse damage to the pulmonary parenchyma. The first clinically recognizable consequences of this injury are in large part attributable to an increase in the permeability of the alveolar-capillary membrane with subsequent pulmonary edema.2 The damage to the lung can be the result of direct (toxic) injury to lung parenchymal cells (primarily endothelial and epithelial cells) or indirectly as a consequence of activation of the acute inflammatory response leading to release of cytotoxic leukocyte-derived products, including reactive oxygen species, proteolytic enzymes, cationic proteins, growth factors, eicosanoids, and cytokines. It is important to recognize that even direct injury to the pulmonary parenchyma is frequently complicated by secondary inflammatory damage that is responsible for most of the physiologic abnormalities.3

The Early Phase: Induction of the Acute Inflammatory Response

The histologic appearance of lungs from patients with ARDS defines this as an acute inflammatory response. The findings include increased numbers of neutrophils within the vascular space, the interstitium, and the alveolar space, locations where these itinerant phagocytes are normally found in only very few numbers. Moreover, there is also evidence of injury to the endothelium and epithelium in association with interstitial and alveolar edema indicating that the barrier function of the alveolar capillary membrane is compromised. It is currently believed that an acute inflammatory response in the lung initiates a series of events that culminate in this parenchymal injury. This is to be contrasted to the situation in uncomplicated pneumonia in which inflammation proceeds in a more regulated fashion and resolves once the inciting cause (ie, the bacteria) has been removed, leaving a normal lung.4 It is evident that under most circumstances, counterregulatory mechanisms exist that limit inflammatory damage and allow repair processes to prevail. However, in ARDS and the systemic inflammatory response syndrome (Fig 1) , in which the inflammatory response progresses to become generalized (ie, systemic) and self-propagating despite removal of the inciting cause, these regulatory mechanisms fail.5 6 This highlights one of the main paradoxes in the field of lung injury, that is why neutrophils, which usually serve an important host defense function due to their microbicidal capacity and ability to help resolve an inflammatory response, could under some circumstances be the primary perpetrators of lung injury. One of the main focuses of this review is to attempt to provide insights into the mechanisms responsible for this apparent loss of control.



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  		Figure 1. Mechanisms of leukocyte-mediated lung injury in sepsis. A variety of initiating events leads to activation of the inflammatory response on a systemic level.

 
The most proximate signals leading to uncontrolled activation of the acute inflammatory response are not yet understood. It is clear, however, that there is activation of leukocytes resident within the lung (primarily interstitial and alveolar macrophages) as well as of circulating leukocytes, primarily neutrophils. For example, as early as 30 min after an acute insult such as trauma7 or acid aspiration,8 there is increased synthesis and release of interleukin 8 (IL-8), a potent neutrophil chemotactic and activating agent, by alveolar macrophages. Moreover, the level of IL-8 remains elevated in alveolar lining fluid during prolonged acute lung injury and these elevated levels predict a poor prognosis.9 Release of this and similar compounds, including tumor necrosis factor-{alpha} (TNF-{alpha}), and interleukins 1 (IL-1) and 6 (IL-6), into the alveolar space with diffusion to the vascular space in turn triggers pulmonary microvascular sequestration and activation of neutrophils.3 When the primary inciting event is not in the lung (eg, extrapulmonary sepsis, massive transfusions, nonpulmonary trauma), there is systemic release of a plethora of potent "mediators," including lipopolysaccharide and other bacterial products, cytokines such as TNF-{alpha}, IL-1, and IL-6, and lipid mediators such as platelet activating factor (PAF) and eicosanoids.10 11 These have diverse effects, including activation of the endothelium and circulating and resident leukocytes.12

These events lead to a transient leukopenia due to pulmonary microvascular sequestration of the leukocytes.13 14 This occurs very early in the course of ARDS, in fact prior to the onset of hypoxemia and the clinical manifestations of acute lung injury. Not only are the neutrophils present in this strategic location at the right (or wrong) time ("guilt by association"), but there is ample documentation that they are in an activated state as indicated by enhanced production of oxidants, increased release of lysosomal enzymes, and enhanced surface expression of CD11-CD18 and decreased surface expression of L-selectin.15 16 Thus, once sequestered in the pulmonary microvasculature, release of the leukocyte-derived cytotoxic compounds can result in damage to this crucial part of the lung.

Pulmonary Sequestration and Activation of Neutrophils

The mechanisms of this leukocyte sequestration are complex and involve alterations in both cellular biomechanical17 18 and adhesive19 20 properties, the latter attributable to adhesive interactions between cognate receptors on leukocytes and endothelial cells (Table 1) . Even at very early stages of the interaction of leukocytes with the endothelium, leukocytes become activated in part by signals from adhesion receptors21 22 and in part by soluble or membrane-bound chemoattractants such as IL-8 or PAF.23 As a consequence of this activation, the surface expression and avidity of ß2-integrins is increased leading to firm adhesion. The primary endothelial ligand for neutrophil ß2-integrins is intercellular adhesion molecule-1 (ICAM-1), a member of the immunoglobulin superfamily, but fibrinogen and denatured proteins can also serve as ligands.20 In the pulmonary capillaries, where most leukocyte sequestration and transmigration occurs,24 the role of specific adhesion molecules is less certain.25


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  		Table 1. Adhesion Molecules*

 
Signal Transduction Pathways Regulating Neutrophil Activation

To understand the abnormal response of neutrophils in situations such as acute lung injury, it is necessary to review some basic aspects of signal transduction. In the most general paradigm, a ligand interacts with its cognate surface membrane receptor and an intracellular signal is generated. Among the earliest of events is the cleavage of membrane phospholipids by phospholipases with generation of inositol phosphates, leading to changes in intracellular calcium, and diacylglycerols leading to activation of protein kinase C.26 Over the last decade, this field has witnessed an explosion of developments and it has become apparent that complexity exists at many levels of the signaling cascades. For example, there are multiple membrane receptors that include members of the seven transmembrane spanning domain family ("serpentine") (eg, formyl peptide receptors, complement receptors, and chemokine receptors), receptors linked to tyrosine kinases (eg, phagocytic receptors such as Fc receptors), as well as receptors that are themselves primarily tyrosine kinases (eg, growth factor receptors).

Downstream of the receptors are complex and interconnected signaling pathways. Figure 2 illustrates some of the signaling pathways that have been described recently. Although at first glance these pathways appear complex, it is helpful to think of them as being grouped in several levels or tiers of signaling molecules (enzymes and adapters). Serpentine family receptors (eg, receptors for N-formyl-methionyl-leucyl-phenylalanine [fMLP], C5a, PAF, leukotriene ß4), are linked to heterotrimeric guanosine triphosphate binding proteins that confer some specificity and amplification to a signal resulting from receptor occupation. Members of the Src family of tyrosine kinases, including include Hck, Fgr, and Src itself are activated very early after neutrophil activation by phagocytic receptors and appear to be involved in activation of subsequent microbicidal responses. A variety of intermediary "adapter" molecules such as Shc and Grb-2 serve to transmit signals by protein-protein interactions. Somewhat downstream of these juxtamembrane events lie small GTPases such as Ras and a series of enzymes such as Raf leading to the canonical MEK (mitogen-activated protein kinase [MAP] or extracellular signal-related kinase [Erk] kinase)-MAP kinase signaling pathway.27 In addition, recent evidence suggests that Ras is also located upstream of Rac, a small GTPase of the Rho subfamily, which also regulates protein kinases, including the p21-activated kinases (PAKs) and two other members of the MAP kinase family, Jun N-terminal kinase (JNK) and p38 MAP kinase.28 Although the relevant targets of these MAP kinase family members are not completely understood, it is well described that certain transcription factors (eg, Elk-1, c-Fos, c-Jun) as can be phosphorylated by MAP kinases leading to gene transcription.



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  		Figure 2. Divergent protein kinase cascades link plasma membrane receptors to the nucleus. Parallel kinase cascades control the activity of members of the MAP kinase superfamily family of serine-threonine kinases that include Erk, C-Jun kinases (JNKs), and p38 MAP. The pathway connecting G protein-coupled receptors to low-molecular weight GTP-binding proteins and to additional members of the MAP kinase superfamily are outlined and shown in tiers of signaling molecules.

 
In human neutrophils, activation of the Erk family of MAP kinases is prominent after a stimulation of a variety of soluble agonists including the formyl peptide fMLP, PAF, and phorbol myristate acetate (PMA). A new and expanding family of soluble pharmacologic inhibitors targeting specific enzymes in these signaling pathway is being developed. One of these compounds, PD98059, is a potent and selective inhibitor of MEK, the enzyme directly upstream of and responsible for the activation of Erks. Pretreatment of neutrophils with this compound essentially abrogates agonist-induced stimulation of Erks. To determine the role of Erks in neutrophil effector responses, neutrophils were pretreated with PD98059 and several parameters were monitored, including the oxidative burst, phagocytosis, chemotaxis, and regulation of apoptosis. Figure 3 illustrates that in neutrophils pretreated with a PD98059 compound, the fMLP-induced oxidative burst is substantially inhibited. Pretreatment of neutrophils with PD98059 also resulted in a smaller but significant diminution of phagocytosis of opsonized yeast particles. To examine the role of Erks in regulation of neutrophil apoptosis, neutrophils were first pretreated with the PD98059 compound and then apoptosis was assessed by propidium iodide staining and measured by flow cytometry. Figure 4 illustrates that in neutrophils pretreated with the growth factor granulocyte-macrophage colony-stimulating factor (GM-CSF), there is diminished apoptosis, which corresponds to a prolonged survival of neutrophils. Pretreatment of these cells with PD98059 reversed some of this effect, indicating a role for Erks in the regulation of apoptosis. These latter observations are important because part of the control of an inflammatory response includes regulation of life span of inflammatory cells.



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  		Figure 3. Effect of PD098059 (PD) on NADPH oxidase activity, as determined by cytochrome C reduction, in cells stimulated with fMLP. Cells pretreated with vehicle (dimethyl sulfoxide [DMSO]) or PD098059 (50 µM) prior to stimulation with fMLP (0.1 µM). PD098059 was present throughout the assay. A representative experiment, illustrating the increase in absorbance after fMLP stimulation, is shown.

 


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  		Figure 4. Effect of PD098059 on apoptosis. Neutrophils were pretreated with the indicated dose of PD098059 (PD) or DMSO for 1 h, followed by stimulation with GM-CSF (200 pM for 10 min). The cells were next incubated for 24 h and the extent of apoptosis was determined by propidium iodide staining. The percentage of apoptotic cells, determined using a FACScan, is shown. Data are means ± SE of three experiments.

 
Studies of this nature from several laboratories have demonstrated the importance of Erks in a variety of important neutrophil functions, including activation of the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, chemotaxis, apoptosis, as well as more minor roles in adhesion and activation of phospholipase A2.29 Analogous studies investigating the physiologic importance of P38 MAP kinase using other pharmacologic inhibitors (eg, SK&F 86002 and SB203580) have demonstrated the importance of this MAP kinase family member in activation of the NADPH oxidase, chemotaxis, adhesion, and regulation of stress-induced apoptosis.30 31 32

Activation of Leukocytes by Adhesion
A pivotal concept in the understanding of leukocyte-mediated tissue injury is that neutrophils do not cause damage while suspended in the bloodstream; rather release of cytotoxic compounds occurs primarily while neutrophils are adherent to endothelium or epithelium or in contact with extracellular matrix proteins in the interstitium. Thus, it is the behavior of adherent cells that is most germane to inflammatory tissue injury. In this regard, it has become apparent that in addition to functioning in attachment of leukocytes to surfaces, adhesion receptors also participate in cell activation. Indeed, adhesion can greatly potentiate the effects of soluble mediators on activation of the respiratory burst and release of granule contents by neutrophils.21 33 34 As is illustrated in Figure 5 , the amount of oxidant production by neutrophils adherent to a substrate can be increased from 50-fold up to 1,000 (!!)-fold when compared with cells stimulated in suspension. Signals from integrins are primarily responsible for this enhanced activation during adhesion because the effect can be blocked by antibodies to CD11b/CD1835 and is absent in neutrophils from patients deficient in ß2-integrins.36 In addition, signals from other adhesion molecules such as L-selectin can also enhance the oxidative burst of neutrophils22 37 38 indicating that signaling and activation occur even during the earliest adhesive interactions.



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  		Figure 5. Effect of adhesion on the neutrophil oxidative burst. Left: 7.5 x 106 human neutrophils were stimulated in suspension with 10-6M fMLP, 10-7 M PMA, or DMSO and incubated for 120 min. The production of H2O2 was monitored by measurement of the reduction of scopoletin. Right: 7.5 x 106 human neutrophils were first allowed to adhere to tissue culture plastic coated with fetal bovine serum then stimulated with 10-6M fMLP, 10-7 M PMA, or DMSO and incubated for an additional 120 min. Data are means ± SE of four experiments. Note the pronounced amplification of the oxidative burst in response to fMLP stimulation in the cells adherent to the serum-coated surface.

 
Elucidation of the molecular signals from adhesion receptors is important in understanding this hyperactivatible state of adherent neutrophils. One of the ways of dissecting the importance of various adhesion receptors and signaling pathways involved in these processes is by the use of monoclonal antibodies directed at specific adhesion receptors. When these antibodies are allowed to bind to the cell surface followed by the addition of a secondary ("cross-linking") antibody that leads to clustering of receptors, intracellular signals are generated. This is thought to model some of the events that occur when leukocytes bind to adhesive ligands bound to substrates. Using this model system, we and others have demonstrated that signals from ß2-integrins and L-selectin can activate a variety of intracellular signaling pathways, including cleavage of membrane polyphosphoinositides with release of Ca2+ from intracellular stores, activation of cytosolic tyrosine kinases, tyrosine phosphorylation, and activation of the Erk and JNK members of MAP kinase family.39 40 41 42 Importantly, cross-linking either ß2-integrins or L-selectin leads to activation of physiologically important responses, including alterations in the actin cytoskeleton, decreases in cell deformability, enhanced adhesivity, potentiation of the oxidative burst, and cytokine (eg, TNF-{alpha}) gene expression.22 37 43 44

Since neither integrins nor selectins possess enzymatic activity, studies on adhesion receptor signaling have focused on proteins that interact with the cytoplasmic domains of the receptors. The intracellular domain of L-selectin is very short (18 amino acids) and while it has not been shown to bind directly to any "signaling molecules," it is known to bind to {alpha}-actinin,45 a cytoskeletal protein, which may provide a link to intracellular signaling pathways.46 The cytoplasmic domain of the ß-chain of integrins also interacts directly with cytoskeletal elements such as {alpha}-actinin47 and talin.48 However, in contrast to L-selectin, the ß-chain of integrins is known to bind signaling molecules, including integrin-associated protein (CD47),49 focal adhesion kinase,50 51 cytohesin-1,52 and the integrin-linked kinase (ILK).53 These molecules are presumably involved in regulation of the affinity state of the receptor ("inside-out signaling") or of signals emanating from the receptors ("outside-in signaling"). Calreticulin binds to the integrin {alpha}-chain and participates in regulation of Ca2+-dependent events during adhesion.54 55 In addition, association of integrins with other membrane proteins such as Fc receptors and transmembrane-4 superfamily proteins56 57 may participate in transmission of intracellular signals. Lastly, cytosolic factors such as integrin modulating factor-1 can increase the avidity of the ß2-integrin CD11b/CD18.58

Our recent studies have focused on the ILK, a serine/threonine kinase that was identified in a yeast 2-hybrid screen using the cytoplasmic domain of ß1-integrin as "bait."53 ILK has been shown to bind directly to the cytoplasmic domain of ß1-integrins in vitro, indicating that the kinase may function at a very proximal (if not the first) step in transmission of signals from integrins. The substrate(s) of ILK are, at present, incompletely characterized, although protein kinase B (PKB/AKT) and glycogen synthase kinase 3 (GSK-3) can be phosphorylated and activated by ILK.59 In epithelial cell lines, overexpression of ILK resulted in profound alterations in cell morphology, diminished adhesion to the substratum, enhanced deposition of extracellular matrix, and anchorage-independent proliferation.53 Taken together, these results imply that ILK regulates both inside-out and outside-in integrin signals. We undertook studies to determine if ILK (or a related kinase) participated in adhesion-dependent signaling in leukocytes. Western blotting demonstrated that neutrophilic polymorphonuclear leukocyte (PMN) and leukocyte cell lines express a prominent immunoreactive band at 56 kd, the predicted molecular radius of ILK (Fig 6) , and immunofluorescence studies demonstrated that ILK was localized diffusely in the cytosol of quiescent PMNs in suspension (not shown). Importantly, when PMNs were adhered to a surface coated with fibrinogen (a ß2-integrin ligand), a fraction of ILK migrated to the basal (adherent) surface and co-localized with CD18, the common ß2-chain. This adhesion-dependent co-localization suggests an important link between ILK and ß2-integrins. Also, given the profound influence that adhesion has on PMN function, and the range of important functions influenced by ILK in epithelial cells, by analogy we believe that ILK will play a pivotal role in adhesion-dependent signaling pathways in PMNs.



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  		Figure 6. Expression of the ILK in myeloid cells and human neutrophils. 5 x 105 cells (human neutrophils, HL-60 cells, PLB cells, and U937 cells) were boiled in Laemli sample buffer, subjected to sodium dodecyl polyacrylamide gel electrophoresis, transferred to Immobilon membranes, and blotted with affinity-purified polyclonal anti-ILK antibodies. A single immunoreactive band is apparent at the predicted molecular weight of ILK (56 kd). Representative of three experiments. Blotting antibody: affinity-purified rabbit anti-ILK. PMN = neutrophils; HL-60 = promyelocytic cell line; PLB = myeloid cell line; and U937 = myelomonocytic cell line.

 
Conclusion

The syndrome of acute lung injury and ARDS is the end result of a wide variety of initiating events. The clinical picture is rather stereotypical, implying that the pathways leading to injury converge to a final common pathway leading to lung injury. This concept holds out the possibility that selective intervention may be possible to ameliorate the lung damage. It is our belief that, in the vast majority of cases, acute lung injury is the end result of an acute inflammatory response that has become unregulated because of the overwhelming nature of the insult and an inappropriate host response to the inciting event. We have described how inflammation may spiral out of control and have focused on the potential mechanisms by which neutrophil activation may become unregulated. The challenge for the next decade will be to unravel at the cellular and molecular level the complexities of the inflammatory response and regulation of neutrophil function in order to target our therapeutic interventions so that they will lessen the injurious consequences of inflammation while leaving the beneficial effects intact.

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