HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:
Guest Access | Sign In via User Name/Password

This Article Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Article Archive Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Strieter, R. M. Articles by Standiford, T. J. Search for Related Content PubMed PubMed Citation Articles by Strieter, R. M. Articles by Standiford, T. J.

Chemokines in Lung Injury^*

Thomas A. Neff Lecture

^* From the Departments of Internal Medicine (Drs. Strieter, Keane, and Standiford) and Pathology (Dr. Kunkel), Division of Pulmonary and Critical Care Medicine, The University of Michigan Medical School, Ann Arbor, MI.

Correspondence to: Robert M. Strieter, MD, FCCP, Department of Internal Medicine, Division of Pulmonary and Critical Care, University of Michigan Medical Center, 6200 MSRB III, 1150 W Medical Center Dr, Ann Arbor, MI 48109-0642; e-mail: rstriete{at}umich.edu

Acute lung injury is due to a variety of direct or indirect insults leading to pulmonary inflammation. Several clinical entities, including trauma, pneumonia/sepsis, and ischemia-reperfusion injury are characterized by varying degrees of pulmonary insult that result in functional impairment of gas transfer in the lung. These events lead to an inflammatory response that is characterized by the following: recognition of the site of injury by inflammatory cells; specific recruitment of subpopulations of leukocytes into tissue; removal of the offending agent and "debridement" of the injured cells/tissue; and repair of the site of injury with attempts to reestablish normal parenchymal, stromal, and extracellular matrix relationship. This is achieved by an orchestrated involvement of both innate and adaptive immunity. In contrast, normal resolution of acute lung injury may not be achieved. This may actually lead to the pathogenesis of pulmonary fibrosis with features of dysregulated repair with exaggerated neovascularization, fibroproliferation, and abnormal deposition of extracellular matrix, leading to progressive fibrosis and loss of lung function. For example, the host response to a bacterial pneumonia is characterized by an acute inflammatory reaction. The histopathology of bacterial pneumonia is composed of proteinaceous exudate and massive neutrophil extravasation leading to consolidation of the lung. Once the inciting agent is cleared, the inflammatory reaction resolves and normal repair and tissue remodeling occurs. This reestablishes normal lung function without the sequela of chronic pulmonary fibrosis. In contrast, the acute inflammatory response associated with ARDS may culminate in severe lung injury, impacting on resolution of inflammation. This injury may ultimately lead to pulmonary fibrosis, impaired gas transfer, and impact on patient survival. The basic mechanisms and mediators that induce acute pulmonary inflammation remain to be fully elucidated. However, it is known that the participation of a variety of factors, produced by both immune and nonimmune cells, is involved in the coordination of these activities, including reactive oxygen metabolites, carbohydrates, lipids, and protein mediators, such as cytokines.

The fidelity of pulmonary inflammation is dependent on cellular communication. Although this is often achieved through direct cell-to-cell adhesive interaction via specific cellular adhesion molecules, cells also signal each other through soluble mediators, such as cytokines. These polypeptide molecules often have pleiotropic effects on a number of biological functions, including recognition, recruitment, removal, and repair. Their actions are mediated through paracrine and autocrine signaling through receptor-ligand interactions on specific cell population targets. Cytokines display concentration-dependent effects. For example, expression in low concentrations occurs during normal homeostasis, with modest increases exerting local effects, and still greater elevations resulting in behavior analogous to hormones resulting in systemic effects. Cytokine research investigating the biology of these proteins has expanded rapidly, and a variety specific cytokines have been isolated and characterized. Individual subpopulations of immune cells possess different capacities to elaborate and secrete specific cytokines in response to particular stimuli. Nonimmune cells, including endothelial cells, fibroblasts, smooth muscle cells, and epithelial cells also demonstrate responses to specific signals resulting in the production of a diversity of cytokines. Furthermore, cell populations vary in their expression of receptors for individual cytokines, and, as a result, differ in their capacity to respond to specific cytokine signals.

Investigations into the interactions between various cell populations have led to the concept of cytokine networking. Simply stated, one population of cells may respond directly to specific stimuli by the elaboration of a particular cytokine to exert distinct effects on another population of cells. The targets respond by producing cytokines that may serve as feedback signals to the primary cell, or alternatively, initiate a cascade of events by affecting yet another array of target cells. Inflammatory effector cells, such as monocytes and neutrophils, may be locally recruited and activated in response to specific chemotactic signals resulting in further amplification of a cytokine cascade. As many of the complexities of the inflammatory cytokine cascade have been elucidated, an increasing amount of evidence now suggests that nonimmune cells play crucial roles in the generation, maintenance, and resolution of both local and systemic inflammatory responses. In this review, we will focus on inflammation research that addresses the interplay of early-response cytokines and CXC chemokine-induced neutrophil recruitment into the lung during the pathogenesis of acute pulmonary inflammation.

Elicitation of Neutrophils Into the Lung: The Role of Cytokines

Cytokines represent a diverse group of biologically active proteins that, in addition to many other activities, are instrumental in the evolution of acute lung injury. To illustrate potentially important cytokine networks operative in pulmonary inflammation that mediate neutrophil recruitment, we will focus our discussion on the early-response cytokines (interleukin-1 [IL-1] and tumor necrosis factor [TNF]) and the CXC chemokine family.

TNF and IL-1
Although biochemically unrelated, TNF and IL-1 demonstrate similar pleiotropic and overlapping effects on a variety cellular functions.^{1 2 3 4 5 6 7 8 9} These cytokines are produced primarily by mononuclear phagocytes and, because of their role for initiating further inflammatory responses, have been termed "early-response cytokines." At sites of local inflammation, modest concentrations are essential and serve to closely regulate cellular function. These early-response cytokines dictate the events leading to recognition, recruitment, removal, and repair of tissue injury in a cytokine cascade. In marked contrast to the controlled events of local production of TNF and IL-1, the exaggerated systemic release of these cytokines can result in a syndrome of multiorgan injury associated with microvascular inflammation leading to increased host morbidity and mortality.

TNF and IL-1, which can have a number of effects on endothelial cells that are germane to microvascular inflammation, include the expression of cell surface adhesion molecules for leukocytes (intercellular adhesion molecule-1 [ICAM-1], E-selectin, and P-selectin),^{10 11 12} production of IL-8,^{13 14} induction of a procoagulant surface with the generation of tissue factor,¹⁵ plasminogen activator inhibitor,^{16 17} and a reduction in the cell surface expression of thrombomodulin leading to a decline in thrombomodulin-dependent activation of protein C.^{18 19 20} These cytokines may prime neutrophils in response to specific activating factors with enhanced respiratory burst and release of reactive oxygen metabolites, phagocytosis, and degranulation of specific and azurophilic granules containing a number of proteolytic enzymes.^{1 2 3 4 5 6 7 8 9 21} Thus, these two cytokines act as initiators and promoters, setting into motion an intricate cascade of events leading to microvascular inflammation. The neutrophil-endothelial cell interaction is dynamic, resulting in endothelial injury and migration of neutrophils into the extravascular space.

When endotoxin, IL-1, or TNF is intratracheally injected, these inflammatory mediators induce an intra-alveolar inflammatory response composed of a neutrophilic exudate that peaks at 6 to 12 h, followed by a monocytic and lymphocytic infiltrate peaking at 24 and 48 h, respectively.²² However, IL-1 on a molar basis has been shown to be more potent than TNF. In addition, endotoxin was capable of inducing both TNF and IL-1 gene expression from whole lung homogenates. Interestingly, IL-1 has a naturally occurring competitive antagonist known as IL-1 receptor antagonist (IL-1ra).^{5 8 21 23 24 25 26 27 28} IL-1ra is a 22-kd polypeptide that has 40% homology with IL-1ß and has been shown to be produced by monocytes in response to endotoxin.^{5 8 21 23 24 25 26 27 28} The inhibitory activity of IL-1ra appears to be at the level of competitive occupation of the IL-1 receptor without agonist activity.^{5 8 21 23 24 25 26 27 28} Immunologic effects of IL-1ra have been shown in vitro to inhibit IL-1-induced dermal fibroblast-derived prostaglandin E₂ production and neutrophil adherence to endothelial cells.^{5 8 21 23 24 25 26 27 28} IL-1ra has been shown in vivo to be a potent inhibitor of Escherichia coli-induced septic shock and lung injury in rabbits.²⁹ In addition, IL-1ra was found to have a protective role in the lungs of rats receiving either intratracheal endotoxin or IL-1.³⁰ These findings suggest that IL-1ra has an important immunomodulating influence on IL-1, and its production by mononuclear phagocytes in the lung may impact on the pathogenesis of acute lung injury mediated by IL-1.

In other animal model systems, the systemic administration of TNF induces a similar pathophysiologic effect as either endotoxin or infusion of live Gram-negative bacteria. Animals have metabolic acidosis, elevated body temperature and circulating levels of catecholamines, consumptive coagulopathy, multiorgan dysfunction (renal, hepatic, GI, and pulmonary), alterations in circulating leukocytes, and hypotension leading to shock.^{31 32} The concomitant administration of both TNF and IL-1 can have a synergistic effect in mediating similar pathophysiologic effects.³³ When protein synthesis is inhibited by actinomycin in vivo, the administration of TNF and IL-1 is associated with 100% mortality, whereas all animals survive in the absence of actinomycin.³⁴ These findings suggest that de novo protein synthesis is required to protect against the lethal effects of TNF and IL-1. Inhibition of endogenously produced TNF during bacteria-induced septic shock has been shown to significantly attenuate the pathogenesis of multiorgan injury and mortality. The administration of antihuman TNF antibodies both prior to and after the injection of a LD₁₀₀ dose of live E coli has been found to decrease mortality in nonhuman primate models of bacterial septic shock.^{31 32 35} Interestingly, the endogenous expression and regulation of TNF from a murine model of endotoxemia has shown that TNF is rapidly produced after a LD₁₀₀ infusion of endotoxin.^{36 37} Peak levels of TNF were seen at 1 h, with a rapid decline to relatively undetectable levels by 8 h. Similar findings have been seen in human volunteer subjects injected with low doses of endotoxin.³⁸ Although the pathogenesis of septic shock and the development of acute lung injury are multifactorial, the presence of TNF and IL-1 during septic shock and ARDS has been clearly demonstrated in humans. Several studies have demonstrated that TNF and IL-1 levels correlate with mortality associated with meningococcemia and septic shock.^{39 40} In another study, serum levels of TNF were detected in 33% of the patients with septic shock.⁴¹ TNF levels were elevated with equal frequency in patients with shock due to either Gram-positive or negative bacteria.⁴¹ The magnitude of TNF measured also correlated with a higher incidence and severity of ARDS and mortality.⁴¹ Although the clinical use of antagonists to either TNF or IL-1 has been disappointing, this most likely reflects the logistics of timing of therapy and the rapidity of expression of these cytokines during septic shock. Nevertheless, these cytokines represent pivotal molecules that play a significant role as proximal mediators of proinflammatory cytokine cascades.

Chemokines
The hallmark of pulmonary inflammation associated with acute lung injury is the presence of infiltrating leukocytes. Leukocyte recruitment requires intercellular communication between infiltrating leukocytes and the endothelium, resident stromal cells, and parenchyma cells. These events are mediated via the generation of early-response cytokines, the expression of cell-surface adhesion molecules, and the production of chemotactic molecules, such as chemokines. The human CXC, CC, C, and CX₃C chemokines are four closely related polypeptide families that behave, in general, as potent chemotactic factors for leukocytes (Tables 1 2 3) . ^{42 43 44} However, the biological function of these chemokines may well go beyond their role as leukocyte chemoattractants.^{42 43 44} These cytokines in their monomeric form range from 7 to 10 kd and are characteristically basic heparin-binding proteins. The chemokines display highly conserved cysteine amino acid residues: the C, CC, CXC, and CX₃C chemokine designations are based on whether a nonconserved amino acid residue exists between the first two cysteine amino acids of the primary structure of these cytokines.^{42 43 44} CXC chemokines are clustered on human chromosome 4, with the exception SDF-1 which is found on human chromosome 10. The CC chemokines are clustered on human chromosome 17, with the exception of MDC on chromosome 16, MIP-3 on chromosome 2, and MIP-3ß on chromosome 9. The one C chemokine, lymphotactin, is located on human chromosome 1, and the one CX₃C chemokine, fractalkine, is located on human chromosome 16. There is approximately 20 to 50% homology among the members of the four chemokine families.^{42 43 44} Chemokines have been found to be produced by an array of cells, including monocytes, alveolar macrophages, neutrophils, platelets, eosinophils, mast cells, T lymphocytes, natural killer (NK) cells, keratinocytes, mesangial cells, epithelial cells, hepatocytes, fibroblasts, smooth muscle cells, mesothelial cells, and endothelial cells.^{42 43 44} These cells can produce chemokines in response to a variety of factors, including viruses, bacterial products, IL-1, TNF, C5a, leukotriene B₄, and interferons (IFNs).^{42 43 44} The production of chemokines by both immune and nonimmune cells supports the contention that these cytokines may play a pivotal role in orchestrating inflammation. To illustrate the importance of chemokines during the pathogenesis of acute inflammation associated with acute lung injury, we will focus our discussion on the role of CXC chemokines in the lung.

The ELR^- members include platelet factor 4, which was originally described for its ability to bind heparin and inactivate heparin's anticoagulation function.^{42 43 44 45 46 47 48 49 50 51} Other ELR^-, CXC chemokines include monokine induced by IFN- (MIG), interferon--inducible protein (IP-10), stromal cell-derived factor (SDF-1), and beta-R1 interferon-induced T cell alpha chemokine (I-TAC).^{42 43 44 45 46 47 48 49 50 51 58} SDF-1 recently gained notoriety when it was shown that SDF-1 induces lymphocyte migration and prevents infection of T cells by lymphotropic strains of HIV-1.^{42 43 44 45 46 47 48 49 50 51} Despite the name, IP-10 can be induced by all three interferons (IFN-, ß, and ), while beta-R1/I-TAC and MIG appear to be unique in that they are induced only by IFN-ß and IFN-, respectively.^{42 43 44 45 46 47 48 49 50 51 58} Interestingly, although IFN- induces the production of the ELR^- CXC chemokines (ie, IP-10 and MIG), it attenuates expression of the ELR⁺ CXC chemokines molecules IL-8, GRO-, and ENA-78.^{42 43 44 45 46 47 48 49 50 51 52 53 54 55} This differential regulation of ELR⁺ and ELR^- CXC chemokines by IFN- suggests that IFN- may be important in the differential regulation of these chemokines.

The murine homologues to the human CXC chemokine family include KC, macrophage inflammatory protein-2 (MIP-2), crg-2, and MIG, and are structurally homologous to human GRO-, GRO-ß, and GRO-, IP-10, and MIG, respectively.^{42 43 44 45 46 47 48 49 50 51 52 53 54 55} To our knowledge, no murine or rat structural homologue exists for human IL-8.^{42 43 44 45 46 47 48 49 50 51 52 53 54 55} CXC chemokines have been found to be produced by an array of cells, including monocytes, alveolar macrophages, neutrophils, platelets, eosinophils, mast cells, T lymphocytes, NK cells, keratinocytes, mesangial cells, epithelial cells, hepatocytes, fibroblasts, smooth muscle cells, mesothelial cells, and endothelial cells.^{42 43 44 45 46 47 48 49 50 51 52 53 54 55} The production of CXC chemokines by both immune and nonimmune cells within the lung supports the contention that these cytokines may play a pivotal role in orchestrating all of the phases of the pulmonary inflammatory response.

Acute Lung Injury: The Interplay of Early-Response Cytokines, Adhesion Molecules, and CXC Chemokines

During the initiation phase of acute lung inflammation, the movement of neutrophils from the pulmonary vascular compartment to interstitium and alveolar space is an early event in the propagation of further lung inflammation. Inflammatory stimuli from either side of the alveolar-capillary membrane may result in pulmonary microvascular alterations that lead to local increases in neutrophil adhesion. These adhered neutrophils, under the influence of adhesion molecules and chemokines, then undergo directed migration along chemotactic gradients to the inflamed area. During recruitment, these neutrophils also become activated, releasing various proteases, reactive oxygen metabolites, and cytokines, which result in acute lung injury. As the acute inflammatory process changes from the initiation to maintenance and resolution stages, the cellular composition of the inflammatory lesions changes to a predominantly mononuclear cell population. Thus, leukocyte elicitation is dynamic, with specific chemoattractants expressed at specific temporal windows of the inflammatory response. In bacterial infection and other clinical conditions, the recruitment of neutrophils is mediated by a number of biologically active agents, including CXC chemokines.

The importance of cytokine networks between immune and nonimmune cells of the alveolar-capillary membrane or airway of the lung is necessary for cellular communication during inflammation. The subsequent events of these cellular/cytokine interactions are crucial to initiating and propagating the inflammatory response that leads to pulmonary injury. Both TNF and IL-1 are early-response cytokines that are necessary not only for the initiation of acute inflammation, but also are required for persistence of the inflammatory response, leading to chronic inflammation. The production of CXC chemokines by the major cellular components of the alveolar-capillary membrane or airway of the lung, and their participation in the inflammatory response, may be critical for the orchestration of the directed migration of leukocytes into the lung. The alveolar-capillary membrane has traditionally been viewed only as a structure for gas exchange, but an understanding of a more complex role has emerged with advances in molecular biological techniques and investigations of individual cell components. The alveolar-capillary membrane can now be viewed as a dynamic assembly of immune and nonimmune cells that, through cytokine networking, can generate significant quantities of CXC chemokines. Importantly, the expression of CXC chemokines by the major cellular constituents of the lung is stimulus specific. Neutrophils, mononuclear phagocytes, and endothelial cells produce CXC chemokines in response to lipopolysaccharide, TNF, or IL-1, but not to IL-6. Pulmonary fibroblasts and epithelial cells express CXC chemokines in response to specific host-derived signals, such as TNF or IL-1. These findings are significant since cells once thought of as "targets" of the inflammatory response can actively participate as effector cells in the production of potent neutrophil chemoattractants. Thus, during acute inflammation, the production of TNF and IL-1 can act in either an autocrine or paracrine fashion to stimulate contiguous cells, both immune and nonimmune, to express CXC chemokines.

Cytokine networks between immune and nonimmune cells of the alveolar-capillary membrane are necessary for cellular communication during pulmonary inflammation. The subsequent events of these cellular/humoral interactions are pivotal to the initiation and propagation of the inflammatory response leading to pulmonary injury. The interrelationship of early-response cytokines, adhesion molecules, and the CXC chemokines orchestrate the recruitment of neutrophils into the lung. The paradigm for neutrophil extravasation is likely operative in the microvasculature of the lung, and consists of four or more steps. First, lung injury results in the activation of microvascular endothelium in response to the local generation of TNF or IL-1, leading to expression of endothelial cell-derived E- and P-selectins and ICAM-1. The constitutive presence of neutrophil-derived L-selectin and other lectin moieties allows for the initial adhesive interaction of these cells with endothelial cell selectins leading to the "rolling" effect. Second, generation of either CXC chemokines leads to the activation of neutrophils in the vascular compartment and expression of ß₂-integrins, while L-selectin is concomitantly shed. Third, the interaction of the neutrophil ß₂-integrins, with their receptor/ligand, ICAM-1, results in the rapid arrest of neutrophils on the endothelium. Fourth, the subsequent events leading to neutrophil extravasation beyond the vascular compartment are dependent on haptotaxis (ie, migration in response to an insoluble gradient), the continued expression of ß₂-integrins on neutrophils and ICAM-1 on nonimmune cells, and the maintenance of a CXC chemokine-specific neutrophil chemotactic gradient. The participation of CXC chemokines in the inflammatory response appears to be critical for the orchestration of the directed migration of neutrophils into the lung. After arriving in the lung, these activated leukocytes can further respond to noxious or antigenic stimuli and induce pulmonary injury through the release of reactive oxygen metabolites, proteolytic enzymes, and additional cytokines.

The Role of CXC Chemokines in Pulmonary Inflammation

Clinical studies examining elevations in pulmonary IL-8 levels and the development and mortality of ARDS have conflicted; however, most have suggested a strong correlation.^{59 60 61 62 63} Of particular interest are the findings of Donnelly and colleagues,⁶⁴ which correlated early increases in BAL fluid IL-8 content of patients at risk for subsequent development of ARDS and, importantly, also demonstrated that the alveolar macrophage is an important cellular source of IL-8 prior to neutrophil influx. High concentrations of IL-8 were found in the BAL fluid from trauma patients, some within 1 h of injury and prior to any evidence of significant neutrophil influx. Patients who progressed to ARDS had significantly greater BAL fluid levels of IL-8 than those patients who failed to develop ARDS. Interestingly, plasma levels of IL-8 from these patients were not found to be significantly different from patients who developed ARDS as compared to those who did not develop ARDS.

Recent investigations have also shown that anoxia/hyperoxia simulating an ischemia-reperfusion or hyperoxia environment can lead to an induction of IL-8 gene expression with a significant increase in IL-8 production by mononuclear cells and endothelial cells.^{65 66} IL-8 gene induction was associated with the presence of increased binding activity in nuclear extracts from hypoxic endothelial cells for the nuclear factor-kappa B site.^{65 66} Of further clinical significance, endotoxin was found to further potentate this hyperoxic response.^{65 66} While these in vitro studies suggested that IL-8 may be a major neutrophil chemotaxin produced in the context of simulated ischemia-reperfusion, Sekido and associates,⁶⁷ demonstrated that IL-8 significantly contributed to reperfusion lung injury using a rabbit model of lung ischemia-reperfusion injury. Reperfusion of the ischemic lung resulted in the production of IL-8 that correlated with maximal pulmonary neutrophil infiltration. Passive immunization of the animals with neutralizing antibodies to IL-8, prior to reperfusion of the ischemic lung, prevented neutrophil extravasation and tissue injury, suggesting a causal role for IL-8 in this model. In another model of ischemia-reperfusion injury demonstrating the importance of cytokine cascades between the liver and lung, Colletti and colleagues^{68 69 70 71} demonstrated that hepatic ischemia-reperfusion injury and the generation of TNF can result in pulmonary-derived ENA-78. The production of ENA-78 in the lung was correlated with the presence of neutrophil-dependent lung injury, and passive immunization with neutralizing ENA-78 antibodies resulted in significant attenuation of lung injury.

CXC chemokines have also been found to play a significant role in mediating neutrophil infiltration in the lung parenchyma and pleural space in response to endotoxin and bacterial challenge. Frevert and associates^{72 73} passively immunized rats with neutralizing KC (homologous to human GRO-) antibodies prior to intratracheal lipopolysaccharide and found a 71% reduction in neutrophil accumulation within the lung. Boylan et al⁷⁴ and Broaddus and associates,⁷⁵ found that passive immunization with neutralizing IL-8 antibodies blocked 77% of endotoxin-induced neutrophil influx in the pleura of rabbits. Standiford and colleagues,^{76 77 78} using a murine model of Klebsiella pneumonia, demonstrated that neutralization of MIP-2 (murine homologue of human GRO-ß/) results in both a reduction in the recruitment of neutrophils to the lung and pulmonary clearance of bacteria. Interestingly, the depletion of MIP-2 in this model during bacterial pneumonia was associated with a higher early mortality. Furthermore, these same investigators have found that lung-specific transgenic expression of KC enhances resistance to Klebsiella pneumonia and improves survival in mice.^{79 80} These studies support the notion that CXC chemokines are important in the elicitation of neutrophils in the lung under conditions of acute inflammation. Furthermore, under conditions of bacterial pneumonia leading to acute lung injury, the expression of CXC chemokines may be beneficial to both the eradication of the organism and host survival.

In summary, the complete manifestation of acute lung injury is dependent on the elicitation and activation of inflammatory cells into the lung leading to tissue injury. This is underscored by the important interaction of early-response cytokines, adhesion molecules, and chemokines in the orchestration of the recruitment of neutrophils into the lung. The discovery of the CXC chemokine supergene family has greatly enhanced our understanding of the biology of leukocyte recruitment to the lung. These protein mediators of inflammation play an important role during the recognition, recruitment, removal, and repair phases of pulmonary inflammation.

Footnotes

Supported in part by National Institutes of Health grants HL50057, CA66180, and P50HL60289 (R.M.S.), HL57243, HL58200, and P50HL60289 (T.J.S.), and HL35276, HL31237, and P50HL60289 (S.L.K.).

References

1. Larrick, JW, Kunkel, SL (1988) The role of tumor necrosis factor and interleukin-1 in the immunoinflammatory response. Pharmacol Res 5,129-139[CrossRef][ISI][Medline]
2. Kunkel, SL, Remick, DG, Strieter, RM, et al (1989) Mechanisms that regulate the production and effects of tumor necrosis factor . Crit Rev Immunol 9,93-117[ISI][Medline]
3. Le, J, Vilcek, J (1987) Tumor necrosis factor and interleukin 1: cytokines with multiple overlapping biological activities. Lab Invest 56,234-248[ISI][Medline]
4. Sherry, B, Cerami, A (1988) Cachectin/tumor necrosis factor exerts endocrine, paracrine, and autocrine control of the inflammatory responses. J Cell Biol 107,1269-1277[Free Full Text]
5. Dinarello, CA (1996) Biologic basis for interleukin-1 in disease. Blood 87,2095-2147[Abstract/Free Full Text]
6. Dinarello, CA (1988) Biology of interleukin 1. FASEB J 2,108-115[Abstract]
7. Dinarello, CA, Cannon, JG, Wolff, SM, et al (1986) Tumor necrosis factor (cachectin) is an endogenous pyrogen and induces production of interleukin 1. J Exp Med 163,1433-1450[Abstract/Free Full Text]
8. Dinarello, CA (1989) Interleukin-1 and its biologically related cytokines. Adv Immunol 44,153-205[ISI][Medline]
9. Cerami, A (1992) Inflammatory cytokines. Clin Immunol Immunopathol 62,S3-S10[CrossRef][ISI][Medline]
10. Springer, TA (1990) Adhesion receptors of the immune system. Nature 346,425-434[CrossRef][Medline]
11. Butcher, EC (1991) Leukocyte-endothelial cell recognition: three (or more) steps to specificity and diversity. Cell 67,1033-1035[CrossRef][ISI][Medline]
12. Bevilacqua, MP, Stengelin, S, Gimbrone, MA, Jr, et al (1989) Endothelial leukocyte adhesion molecule 1: an inducible receptor for neutrophils related to complement regulatory proteins and lectins. Science 243,1160-1165[Abstract/Free Full Text]
13. Strieter, RM, Kunkel, SL, Showell, HJ, et al (1988) Monokine-induced gene expression of human endothelial cell-derived neutrophil chemotactic factor. Biochem Biophys Res Commun 156,1340-1345[CrossRef][ISI][Medline]
14. Strieter, RM, Kunkel, SL, Showell, HJ, et al (1989) Endothelial cell gene expression of a neutrophil chemotactic factor by TNF-alpha, LPS, and IL-1-beta. Science 243,1467-1469[Abstract/Free Full Text]
15. Bevilacqua, MP, Pober, JS, Majeau, GR, et al (1986) Recombinant tumor necrosis factor induces procoagulant activity in cultured human vascular endothelium: characterization and comparison with the actions of interleukin 1. Proc Natl Acad Sci USA 83,4533-4537[Abstract/Free Full Text]
16. Stern, DM, Kaiser, E, Nawroth, PP (1988) Regulation of the coagulation system by vascular endothelial cells. Haemostasis 18,202-214[ISI][Medline]
17. Crutchley, DJ, Conanan, LB (1986) Endotoxin induction of an inhibitor of plasminogen activator in bovine pulmonary artery endothelial cells. J Biol Chem 261,154-159[Abstract/Free Full Text]
18. Esmon, CT (1987) The regulation of natural anticoagulant pathways. Science 235,1348-1352[Abstract/Free Full Text]
19. Clouse, LH, Comp, PC (1986) The regulation of hemostasis: the protein C system. N Engl J Med 314,1298-1304[ISI][Medline]
20. Moore, KL, Andreoli, SP, Esmon, NL, et al (1987) Endotoxin enhances tissue factor and suppresses thrombomodulin expression of human vascular endothelium in vitro. J Clin Invest 79,124-130
21. Dinarello, CA (1991) Interleukin-1 and interleukin-1 antagonism. Blood 77,1627-1635[Abstract/Free Full Text]
22. Ulich, TR, Watson, LR, Yin, SM, et al (1991) The intratracheal administration of endotoxin and cytokines: I. Characterization of LPS-induced inflammatory infiltrate. Am J Pathol 138,1485-1496[Abstract]
23. Eisenberg, SP, Brewer, MT, Verdeber, E, et al (1991) IL-1 receptor antagonist (IL-1ra) is a member of the IL-1 gene family: evolution of a cytokine control mechanism. Proc Natl Acad Sci USA 88,5232-5236[Abstract/Free Full Text]
24. Eisenberg, SP, Evans, RJ, Arend, WP, et al (1990) Primary structure and functional expression from complementary DNA of a human interleukin-1 receptor antagonist. Nature 343,343-346
25. Mazzei, GJ, Seckinger, PL, Dayer, JM, et al (1990) Purification and characterization of a 26-kDa competitive inhibitor of interleukin-1. Eur J Immunol 20,683-689[ISI][Medline]
26. Hannum, CH, Wilcox, CJ, Arend, WP, et al (1990) Interleukin-1 receptor antagonist activity of a human interleukin-1 inhibitor. Science 343,336-340
27. Carter, DB, Deibel, MR, Dunn, CJ, et al (1990) Purification, cloning, expression, and biological characterization of an interleukin-1 receptor antagonist protein. Nature 344,633-638[CrossRef][Medline]
28. Arend, WP (1991) Interleukin-1 receptor antagonist—a new member of the interleukin-1 family. J Clin Invest 88,1445-1451
29. Ohlsson, K, Bjork, P, Bergenfeldt, M, et al (1990) IL-1ra reduces mortality from endotoxin shock. Nature 348,550-552[CrossRef][Medline]
30. Ulich, TR, Yin, SM, Guo, KZ, et al (1991) The intratracheal administration of endotoxin and cytokines: III. The interleukin-1 (IL-1) receptor antagonist inhibits endotoxin- and IL-1-induced acute inflammation. Am J Pathol 138,521-524[Abstract]
31. Tracey, KJ, Fong, Y, Hesse, DG (1987) Anti-cachectin/INF monoclonal antibodies prevent septic shock during lethal bacteremia in baboons. Nature 330,662-666[CrossRef][Medline]
32. Tracy, KJ, Lowry, SF (1990) The role of cytokine mediators in septic shock. Adv Surg 23,21-56[Medline]
33. Sipe, JD (1989) The molecular biology of interleukin 1 and the acute phase response. Adv Intern Med 34,1-20[Medline]
34. Shalaby, MR, Halgunset, J, Haugen, OA, et al (1991) Cytokine-associated tissue injury and lethality in mice: a comparative study. Clin Immunol Immunopathol 61,69-82[CrossRef][ISI][Medline]
35. Hinshaw, LB, Telcamp-Olson, P, Chang, ACK, et al (1990) Survival of primates in LD₁₀₀ septic shock following therapy with antibody to tumor necrosis factor (INF-alpha). Circ Shock 30,279-292[ISI][Medline]
36. Remick, DG, Strieter, RM, Eskandari, MK, et al (1990) Role of tumor necrosis factor- in lipopolysaccharide-induced pathologic alterations. Am J Pathol 136,49-60[Abstract]
37. Remick, DG, Strieter, RM, Lynch, JP, III, et al (1989) In vivo dynamics of murine tumor necrosis factor- gene expression: kinetics of dexamethasone-induced suppression. Lab Invest 60,766-771[ISI][Medline]
38. Michie, HR, Mangue, KR, Spriggs, DR, et al (1988) Detection of circulating tumor necrosis factor after endotoxin administration. N Engl J Med 318,1481-1484[Abstract]
39. Waage, A, Halstensen, A, Espevik, T (1987) Association between tumor necrosis factor in serum and fatal outcome in patients with menigococcal disease. Lancet 2,355-357
40. Girardin, E, Grau, GE, Dayer, JM, et al (1988) Tumor necrosis factor and interleukin-1 in the serum of children with severe infectious purpura. N Engl J Med 319,397-400[Abstract]
41. Marks, JD, Marks, CB, Luce, JM, et al (1990) Plasma tumor necrosis in patients with septic shock: mortality rate, incidence of adult respiratory distress syndrome. Am Rev Respir Dis 141,94-97[ISI][Medline]
42. Strieter RM, Kunkel SL. Chemokines and the lung. In: Crystal R, West J, Weibel E, et al, eds. Lung: scientific foundations. 2nd ed. Raven Press, New York, NY: 1997; 155–186
43. Rollins, BJ (1997) Chemokines. Blood 90,909-928[Free Full Text]
44. Luster, AD (1998) Chemokines—chemotactic cytokines that mediate inflammation. N Engl J Med 338,436-445[Free Full Text]
45. Baggiolini, M, Walz, A, Kunkel, SL (1989) Neutrophil-activating peptide-1/interleukin-8, a novel cytokine that activates neutrophils. J Clin Invest 84,1045-1049
46. Oppenheim, JJ, Zachariae, OC, Mukaida, N, et al (1991) Properties of the novel proinflammatory supergene `intercrine' cytokine family. Annu Rev Immunol 9,617-648[ISI][Medline]
47. Miller, MD, Krangel, MS (1992) Biology and biochemistry of the chemokines: a family of chemotactic and inflammatory cytokines. Crit Rev Immunol 12,17-46[ISI][Medline]
48. Baggiolini, M, Dewald, B, Moser, B (1994) Interleukin-8 and related chemotactic cytokines—CXC and CC chemokines. Adv Immunol 55,97-179[ISI][Medline]
49. Taub D. C-C chemokines: an overview. In: Koch A, Strieter R, eds. Chemokines in disease. Austin, TX: RG Landes, Co, 1996; 27–54
50. Taub, DD, Oppenheim, JJ (1994) Chemokines, inflammation and immune system. Ther Immunol 1,229-246[Medline]
51. Farber, JM (1997) Mig and IP-10: CXC chemokines that target lymphocytes. J Leukoc Biol 61,246-257[Abstract]
52. Walz, A, Kunkel, SL, Strieter, RM (1996) CXC chemokines—an overview. Strieter, RM eds. Chemokines in disease ,1-26 RG Landes Co Austin, TX.
53. Walz, A, Strieter, RM, Schnyder, S (1993) Neutrophil-activating peptide ENA-78. Adv Exp Med Biol 351,129-137[Medline]
54. Walz, A, Burgener, R, Car, B, et al (1991) Structure and neutrophil-activating properties of a novel inflammatory peptide (ENA-78) with homology to interleukin-8. J Exp Med 174,1355-1362[Abstract/Free Full Text]
55. Proost, P, Wolf-Peeters, CD, Conings, R, et al (1993) Identification of a novel granulocyte chemotactic protein (GCP-1) from human tumor cells: in vitro and in vivo comparison with natural forms of GRO, IP-10, and IL-8. J Immunol 150,1000-1010[Abstract]
56. Strieter, RM, Kunkel, SL, Shanafelt, AB, et al (1996) CXC chemokines in regulation of angiogenesis. Koch, AE Strieter, RM eds. Chemokines in disease ,195-210 RG Landes Austin, TX.
57. Strieter, RM, Polverini, PJ, Kunkel, SL, et al (1995) The functional role of the ELR motif in CXC chemokine-mediated angiogenesis. J Biol Chem 270,27348-27357[Abstract/Free Full Text]
58. Rani, MRS, Foster, GR, Leung, S, et al (1996) Characterization of beta-R1, a gene that is selectively induced by interferon beta (IFN-beta) compared with IFN-alpha. J Biol Chem 271,22878-22884[Abstract/Free Full Text]
59. Jorens, PG, VanDame, J, DeBecker, W, et al (1992) Interleukin-8 in the bronchoalveolar lavage fluid from patients with the adult respiratory distress syndrome (ARDS) and patients at risk for ARDS. Cytokine 4,592-597[CrossRef][ISI][Medline]
60. Miller, EJ, Cohen, AB, Nago, S, et al (1992) Elevated levels of NAP-1/Interleukin-8 are present in the airspaces of patients with the adult respiratory distress syndrome and are associated with increased mortality. Am Rev Respir Dis 146,427-432[ISI][Medline]
61. Hack, CE, Hart, M, Strack-vanSchijindel, RJM, et al (1992) Interleukin-8 in sepsis: relation to shock and inflammatory mediators. Infect Immun 60,2835-2842[Abstract/Free Full Text]
62. Chollet-Martin, S, Montravers, P, Gilbert, C, et al (1993) High levels of interleukin-8 in the blood and alveolar spaces of patients with pneumonia and adult respiratory distress syndrome. Infect Immun 61,4553-4559[Abstract/Free Full Text]
63. Donnelly, TJ, Meade, P, Jagels, M, et al (1994) Cytokine, complement, and endotoxin profiles associated with the development of the adult respiratory distress syndrome after severe injury. Crit Care Med 22,768-776[ISI][Medline]
64. Donnelly, SC, Strieter, RM, Kunkel, SL, et al (1993) Interleukin-8 and development of adult respiratory distress syndrome in at-risk patient groups. Lancet 341,643-647[CrossRef][ISI][Medline]
65. Metinko, AP, Kunkel, SL, Standiford, TJ, et al (1992) Anoxia-hyperoxia induces monocyte derived interleukin-8. J Clin Invest 90,791-798
66. Karakurum, M, Shreeniwas, R, Chen, J, et al (1994) Hypoxia induction of interleukin-8 gene expression in human endothelial cells. J Clin Invest 93,1564-1570
67. Sekido, N, Mukaido, N, Harada, A, et al (1993) Prevention of lung reperfusion injury by a monoclonal antibody against interleukin-8. Nature 365,654-657[CrossRef][Medline]
68. Colletti, LM, Kunkel, SL, Walz, A, et al (1995) Chemokine expression during hepatic ischemia/reperfusion-induced lung injury in the rat: the role of epithelial neutrophil activating protein. J Clin Invest 95,134-141
69. Colletti, LM, Kunkel, SL, Green, M, et al (1996) Hepatic inflammation following 70% hepatectomy may be related to up-regulation of epithelial neutrophil activating protein-78 [see comments]. Shock 6,397-402[ISI][Medline]
70. Colletti, LM, Kunkel, SL, Green, M, et al (1996) Post-ischemic shunt following hepatic ischemia/reperfusion does not affect tissue chemokine levels of tissue injury. Shock 5,371-377[CrossRef][ISI][Medline]
71. Colletti, LM, Kunkel, SL, Walz, A, et al (1996) The role of cytokine networks in the local liver injury following hepatic ischemia/reperfusion in the rat. Hepatology 23,506-514[CrossRef][ISI][Medline]
72. Frevert, CW, Farone, A, Danaee, H, et al (1995) Functional characterization of rat chemokine macrophage inflammatory protein-2. Inflammation 19,133-142[CrossRef][ISI][Medline]
73. Frevert, CW, Huang, S, Danaee, H, et al (1995) Functional characterization of the rat chemokine KC and its importance in neutrophil recruitment in a rat model of pulmonary inflammation. J Immunol 154,335-344[Abstract]
74. Boylan, AM, Hebert, CA, Sadick, M, et al (1994) Interleukin-8 is a major component of pleural liquid chemotactic activity in a rabbit model of endotoxin pleurisy. Am J Physiol 267,L137-L144[Abstract/Free Full Text]
75. Broaddos, VC, Boylan, AM, Hoeffel, JM, et al (1994) Neutralization of IL-8 inhibits neutrophil influx in a rabbit model of endotoxin-induced pleurisy. J Immunol 152,2960-2667[Abstract]
76. Standiford, TJ, Kunkel, SL, Greenberger, MJ, et al (1996) Expression and regulation of chemokines in bacterial pneumonia. J Leukoc Biol 59,24-28[Abstract]
77. Greenberger, MJ, Strieter, RM, Kunkel, SL, et al (1996) Neutralization of macrophage inflammatory protein-2 attenuates neutrophil recruitment and bacterial clearance in murine Klebsiella pneumonia. J Infect Dis 173,159-165[ISI][Medline]
78. Standiford, TJ, Strieter, RM, Greenberger, MJ, et al (1996) Expression and regulation of chemokines in acute bacterial pneumonia. Biol Signals 5,203-208[ISI][Medline]
79. Tsai, WC, Strieter, RM, Wilkowski, JM, et al (1998) Lung-specific transgenic expression of KC enhances resistance to Klebsiella pneumonia in mice. J Immunol 161,2435-2440[Abstract/Free Full Text]
80. Lira, SA, Fuentes, ME, Strieter, RM, et al (1997) Transgenic methods to study chemokine function in lung and central nervous system. Methods Enzymol 287,304-318[ISI][Medline]

This article has been cited by other articles:

				F. J. Jacono, Y.-J. Peng, D. Nethery, J. A. Faress, Z. Lee, J. A. Kern, and N. R. Prabhakar Acute lung injury augments hypoxic ventilatory response in the absence of systemic hypoxemia J Appl Physiol, December 1, 2006; 101(6): 1795 - 1802. [Abstract] [Full Text] [PDF]

				S. Perkowski, A. Scherpereel, J.-C. Murciano, E. Arguiri, C. C. Solomides, S. M. Albelda, V. Muzykantov, and M. Christofidou-Solomidou Dissociation between alveolar transmigration of neutrophils and lung injury in hyperoxia Am J Physiol Lung Cell Mol Physiol, November 1, 2006; 291(5): L1050 - L1058. [Abstract] [Full Text] [PDF]

				R Mehta and A Petrova Intrauterine neutrophil activation is associated with pulmonary haemorrhage in preterm infants Arch. Dis. Child. Fetal Neonatal Ed., November 1, 2006; 91(6): F415 - F418. [Abstract] [Full Text] [PDF]

				R. Rodrigo, S. Trujillo, and C. Bosco Biochemical and Ultrastructural Lung Damage Induced by Rhabdomyolysis in the Rat Experimental Biology and Medicine, September 1, 2006; 231(8): 1430 - 1438. [Abstract] [Full Text] [PDF]

				A. Pirat, P. Zeyneloglu, D. Aldemir, M. Yucel, O. Ozen, S. Candan, and G. Arslan Pretreatment with Simvastatin Reduces Lung Injury Related to Intestinal Ischemia-Reperfusion in Rats Anesth. Analg., January 1, 2006; 102(1): 225 - 232. [Abstract] [Full Text] [PDF]

				M. A. Matthay and G. A. Zimmerman Acute Lung Injury and the Acute Respiratory Distress Syndrome: Four Decades of Inquiry into Pathogenesis and Rational Management Am. J. Respir. Cell Mol. Biol., October 1, 2005; 33(4): 319 - 327. [Full Text] [PDF]

				X. Lin, H. Yang, T. Sakuragi, M. Hu, L. L. Mantell, S. Hayashi, Y. Al-Abed, K. J. Tracey, L. Ulloa, and E. J. Miller {alpha}-Chemokine receptor blockade reduces high mobility group box 1 protein-induced lung inflammation and injury and improves survival in sepsis Am J Physiol Lung Cell Mol Physiol, October 1, 2005; 289(4): L583 - L590. [Abstract] [Full Text] [PDF]

				J. L. Lomas-Neira, C.-S. Chung, D. E. Wesche, M. Perl, and A. Ayala In vivo gene silencing (with siRNA) of pulmonary expression of MIP-2 versus KC results in divergent effects on hemorrhage-induced, neutrophil-mediated septic acute lung injury J. Leukoc. Biol., June 1, 2005; 77(6): 846 - 853. [Abstract] [Full Text] [PDF]

				J. L. Lomas-Neira, C.-S. Chung, P. S. Grutkoski, E. J. Miller, and A. Ayala CXCR2 inhibition suppresses hemorrhage-induced priming for acute lung injury in mice J. Leukoc. Biol., July 1, 2004; 76(1): 58 - 64. [Abstract] [Full Text] [PDF]

				W. S. Madorin, T. Rui, N. Sugimoto, O. Handa, G. Cepinskas, and P. R. Kvietys Cardiac Myocytes Activated by Septic Plasma Promote Neutrophil Transendothelial Migration: Role of Platelet-Activating Factor and the Chemokines LIX and KC Circ. Res., April 16, 2004; 94(7): 944 - 951. [Abstract] [Full Text] [PDF]

				R. D. Sue, J. A. Belperio, M. D. Burdick, L. A. Murray, Y. Y. Xue, M. C. Dy, J. J. Kwon, M. P. Keane, and R. M. Strieter CXCR2 Is Critical to Hyperoxia-Induced Lung Injury J. Immunol., March 15, 2004; 172(6): 3860 - 3868. [Abstract] [Full Text] [PDF]

				J. C. Leemans, A. A. te Velde, S. Florquin, R. J. Bennink, K. de Bruin, R. A. W. van Lier, T. van der Poll, and J. Hamann The Epidermal Growth Factor-Seven Transmembrane (EGF-TM7) Receptor CD97 Is Required for Neutrophil Migration and Host Defense J. Immunol., January 15, 2004; 172(2): 1125 - 1131. [Abstract] [Full Text] [PDF]

				Z. H. Nemeth, E. A. Deitch, Q. Lu, C. Szabo, and G. Hasko NHE blockade inhibits chemokine production and NF-kappa B activation in immunostimulated endothelial cells Am J Physiol Cell Physiol, August 1, 2002; 283(2): C396 - C403. [Abstract] [Full Text] [PDF]

A. BOKER, M. RUTH GRAHAM, K. R. WALLEY, B. M. MCMANUS, L. G. GIRLING, E. WALKER, G. R. LEFEVRE, and W.A. C. MUTCH Improved Arterial Oxygenation with Biologically Variable or Fractal Ventilation Using Low Tidal Volumes in a Porcine Model of Acute Respiratory Distress Syndrome Am. J. Respir. Crit. Care Med., Febru