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Adhesion Molecules: The Path to a New Understanding of Acute Inflammation

Barbara Walzog and Peter Gaehtgens

B. Walzog and P. Gaehtgens are in the Department of Physiology, Freie Universität Berlin, Arnimallee 22, D-14195 Berlin, Germany.

	Abstract

 
About 100 years after the definition of the basic principles of inflammation, the identification of the underlying molecular mechanisms provides a new understanding of the inflammatory response. The specificity and diversity of the adhesion molecules involved in leukocyte extravasation account for the ordered leukocyte recruitment and activation in inflammation.

	Introduction

Top Introduction How are leukocytes made... How do leukocytes penetrate... How is the inflammatory... References

 
At the end of the last century, Elie Metchnikoff laid the foundation for the biological theory of inflammation by realizing that the acute inflammatory response "consists in a reaction of phagocytes against a harmful agent" (8). In the following 100 years, this theory was consolidated and extended by recognizing the molecular mechanisms that underlie the activation and recruitment of the leukocytes from the circulation and their trafficking through the body. The identification of the nature of adhesion molecules and inflammatory mediators involved not only expanded our knowledge of the molecular mechanisms but also provided the basis for a new understanding of the inflammatory response and its role in tissue homeostasis. This review focuses on the importance of adhesion molecules in the control of acute inflammation, which is characterized by immediate infiltration of polymorphonuclear neutrophils (PMN) at sites of lesion, followed by monocytes and eventually lymphocytes.

Human host defense includes physical and chemical barriers, e.g., skin and mucous membranes as well as gastric acidity or secretory and excretory flow, and so forth. Agents that overcome these barriers are faced with the innate and/or acquired defense mechanisms designed to recognize and eliminate foreign materials. These mechanisms, which are based on the sophisticated functions of the leukocytes, are also responsible for the elimination of old, damaged, or "unwanted" cells and thereby contribute to the maintenance of tissue homeostasis. Thus host defense mechanisms not only protect the organism from infection but also allow the removal of cell debris and destroyed tissue components that may result, for example, from ischemia or trauma. As a part of the innate defense, the acute inflammatory response that is elicited on these biological, chemical, or physical noxae allows leukocyte recruitment, i.e., the rapid and site-directed traveling of leukocytes to their target regions within the body, the first of four prerequisites for an effective host defense at sites of lesion. In a second step, leukocytes develop specific instruments that are responsible for the elimination of foreign materials or damaged tissue cells. This destructive potential of the leukocytes is prevented from causing uncontrolled tissue damage by containment mechanisms allowing graduation and finally resolution of the acute inflammatory response. Finally, inflammation gives rise to the process of repair and wound healing, which permits restitutio ad integrum.

	How are leukocytes made to leave the circulation? The multistep paradigm of leukocyte recruitment

Top Introduction How are leukocytes made... How do leukocytes penetrate... How is the inflammatory... References

 
Metchnikoff (8) was convinced that leukocyte recruitment represents an active process that is managed by the leukocytes alone, whereas Cohnheim (4) and other investigators had the idea that leukocyte emigration depends on the properties of the vessel wall. The identification of the molecules involved in this recruitment process showed that emigration depends on sophisticated interaction between leukocytes and endothelial cells, to which both cell types actively contribute by expressing adhesion molecules on their surfaces and secreting soluble mediators. The sequence of events that allows the traveling of leukocytes to sites of host defense is designated the multistep paradigm of leukocyte recruitment (10). It involves margination and capturing of free-flowing leukocytes, leukocyte rolling, activation, firm adhesion, and spreading, transendothelial diapedesis, and chemotactic migration of the leukocytes (Fig. 1). The prerequisite for all of these steps is the activation of the endothelial cell monolayer by tissue-derived signals that induce the expression of endothelial adhesion molecules and trigger the secretion of inflammatory mediators by endothelial cells.

View larger version (37K): [in this window] [in a new window]   FIGURE 1. The multistep paradigm of leukocyte recruitment. PMN, polymorphonuclear neutrophils; EC, endothelial cells.

Although leukocyte recruitment generally follows these basic principles, the underlying molecular mechanisms show great versatility in detail. Depending on the inflammatory stimulus, the leukocyte population recruited, the tissue, and the context of activation, different adhesion molecules and inflammatory mediators are involved. This allows the temporal and spatial regulation of targeting distinct leukocyte populations to distinct destinations within the body. During acute inflammation, PMN are mobilized within minutes to hours upon stimulation, whereas monocytes accumulate at sites of lesion with a time lag of approximately one day. PMN (and monocytes) emigrate from postcapillary venules, and naive lymphocytes emigrate preferentially from venules in secondary lymphoid organs, which, due to their characteristic endothelial lining, are called high-endothelial venules (HEV). Lymphocytes reenter the blood stream and recirculate with preference for a specific tissue (homing). Memory lymphocytes are known to emigrate primarily from post-capillary venules and enter "their" secondary lymphoid organ via the afferent lymph.

	How do leukocytes penetrate tissue in a targeted fashion? A pivotal role for adhesion molecules

Top Introduction How are leukocytes made... How do leukocytes penetrate... How is the inflammatory... References

 
In inflammation, soluble mediators initiate cellular activation of leukocytes and endothelial cells, whereas adhesion molecules allow the interaction of free-flowing leukocytes with the vessel wall and all subsequent adhesive interactions that are required for emigration into the tissue. The diversity and specificity of the engaged adhesion molecules account for the ordered leukocyte recruitment, which allows that leukocytes meet and finally eliminate foreign particles with great efficiency within a reasonable time.

Various families of adhesion molecules are involved in leukocyte-endothelial cell interactions. These include selectins, integrins, immunoglobulins, and other molecules as listed in Table 1. Expressed on the cell surface, adhesion molecules recognize and bind specific ligands, e.g., other adhesion molecules or extracellular matrix proteins, and thereby mediate cell-cell and cell-substrate interactions. All adhesion molecules show a characteristic cellular distribution. Variations are due, for example, to the level of expression, posttranslational modification of the molecules, differential splicing, constitutive and/or inducible expression following cellular activation, and so forth.

View larger version (17K): [in this window] [in a new window]   FIGURE 2. Structure of adhesion molecules involved in leukocyte recruitment. ICAM, intercellular adhesion molecule; VCAM, vascular adhesion molecule; PECAM, platelet endothelial cell adhesion molecule.

P-selectin and E-selectin also contribute to leukocyte rolling on the activated endothelial surface. P-selectin is stored in the Weibel-Palade bodies of endothelial cells and in the -granules of platelets. On activation of endothelial cells, P-selectin is rapidly recruited to the cell surface, whereas E-selectin expression requires de novo synthesis induced by several inflammatory mediators. Both P- and E-selectin bind carbohydrate ligands on leukocytes and thereby mediate leukocyte rolling on activated endothelial cells. The major ligand of P-selectin on leukocytes is PSGL-1, which also shows some affinity for E-selectin. E-selectin recognizes ESL-1 on leukocytes. Similar to L-selectin, the extracellular portions of P- and E-selectin, sP-selectin, and sE-selectin, are present in the plasma.

Besides direct interactions with endothelial cells, leukocytes are also conducted to the endothelial monolayer by platelets, forming a bridge while binding, for example, to peripheral node addressin (PNAd) via P-selectin. Leukocytes that adhere to the vessel wall can also capture free-flowing leukocytes from the circulation. Thus a broad variety of cellular and molecular mechanisms contribute to the initial contact between leukocytes and endothelial cells.

Integrins.
Integrins mediate the firm adhesion of leukocytes by binding members of the immunoglobulin family of adhesion molecules expressed on endothelial cells. Integrins are heterodimeric molecules consisting of an -subunit and a noncovalently-bound ß-subunit. They represent a large protein family that is classified by the ß-subunits. ß₁- (CD29), ß₂- (CD18), ß₃- (CD61), and ß₇-integrins are engaged in leukocyte recruitment, with ß₂-integrins playing the key role in mediating firm adhesion of human PMN subsequent to selectin-mediated rolling. Leukocyte rolling constitutes a prerequisite for ß₂-integrin-mediated firm adhesion in vivo, since ß₂-integrins are not able to bind their ligands unless the velocity of passing leukocytes is slowed down to a critical value by selectin-based rolling.

There exist four different ß₂-integrins (CD11/CD18) designated according to the -subunit: lymphocyte function-associated antigen 1 or LFA-1 (CD11a/CD18), Mac-1 (CD11b/CD18), gp150/95 (CD11c/CD18), and CD11d/CD18. ß₂-integrins mediate firm adhesion of leukocytes to endothelial cells by binding to intercellular adhesion molecules (ICAMs), members of the immunoglobulin superfamily that are expressed by endothelial cells. The most important ß₂-integrin that mediates firm adhesion is LFA-1, which is constitutively expressed on virtually all leukocytes. LFA-1 exerts its function primarily by binding ICAM-1, which is upregulated on the inflamed endothelium. Mac-1 also has some affinity for ICAM-1, but its role in mediating adhesion is thought to be less important. LFA-1 also binds to ICAM-2, which is constitutively expressed by endothelial cells. Moreover, LFA-1 recognizes ICAM-3, which is expressed on leukocytes and mediates leukocyte-leukocyte interaction. Besides the affinity for ICAM-1, Mac-1 shows affinity for ligands such as fibrinogen, factor X, and C3bi. gp150/95 binds ICAM-1, fibrinogen, and C3bi. CD11d/CD18 is a receptor for VCAM-1 and ICAM-3. ß₂-integrins as well as other integrins are physically linked to the integrin-associated protein IAP (CD47), which is thought to contribute to the regulation of integrin function.

The ß₁-integrins are primarily expressed on lymphocytes and monocytes. Very late antigen 4 (VLA-4, ₄/ß₁, CD49d/CD29) plays a major role in mediating monocyte extravasation by binding to inducible vascular adhesion molecule 1 (VCAM-1, CD106). ß₁-integrins have a subordinate function in extravasation of PMN, which show only minimal expression of this integrin. The _v/ß_3-integrin (CD51/CD61) serves as a receptor for the extracellular matrix protein vitronectin and plays a role in migration of PMN. The ₄/ß₇-integrin (CD49d/ß₇) binds MAdCAM-1 and VCAM-1 and mediates lymphocyte homing to Peyer's patches and the lamina propria.

Immunoglobulins.
The most important adhesion molecules of the immunoglobulin superfamily that serve as ligands for the integrins during leukocyte-endothelial cell interactions are the ICAMs termed ICAM-1 (CD54), ICAM-2 (CD102), ICAM-3 (CD50), and VCAM-1 (CD106). ICAM-1 is strongly upregulated on endothelial cells upon activation by inflammatory mediators such as TNF-. ICAM-1 binds LFA-1 with strong affinity, shows some affinity for Mac-1, and putatively binds gp150/95. As mentioned above, ICAM-1 serves as the major endothelial ligand that mediates firm adhesion of PMN to inflamed endothelial cells and therefore plays a central role in PMN recruitment to sites of inflammation. In contrast to ICAM-1, ICAM-2 is constitutively expressed on endothelial cells and its expression is virtually unaffected by inflammatory mediators. ICAM-2, which binds LFA-1 with high affinity, is also expressed on some leukocyte populations but is absent on PMN. ICAM-2 is considered to be involved primarily in lymphocyte homing. ICAM-3 (CD50) is highly expressed on leukocytes but absent on endothelial cells. ICAM-3 binds LFA-1 with high affinity and thereby mediates leukocyte-leukocyte interactions. VCAM-1 (CD106) is expressed primarily on endothelial cells and is upregulated upon stimulation by various inflammatory mediators, especially cytokines. VCAM-1 plays a role in mediating leukocyte-endothelial interactions by binding to the ₄/ß₁ and the ₄/ß₇-integrins as well as to the ß₂-integrin CD11d/CD18. Platelet endothelial cell adhesion molecule (PECAM-1) (CD31), another member of the immunoglobulin family, is highly expressed on PMN and monocytes as well as on endothelial cells, exerts homotypic interactions, and binds to _v/ß₃. CD31 is considered to mediate leukocyte-endothelial cell interactions as well as transendothelial migration of leukocytes.

Other adhesion molecules.
Cadherins represent another family of adhesion molecules that is primarily characterized by exerting homotypic adhesion. E-cadherin is expressed on endothelial cells at close cellular contacts in the adherens junctions. Dissociation of the E-cadherin interactions is currently considered to occur during transendothelial migration of leukocytes. E-cadherin also binds E/ß₇ and may contribute to lymphocyte homing to intestinal epithelium. Besides this, other molecules, such as CD44 and vascular adhesion protein 1 (VAP-1), may be involved in leukocyte trafficking, but the biological significance of these are still under investigation.

	How is the inflammatory cascade initiated? Insights from the molecular mechanisms of leukocyte-endothelial cell interactions

Top Introduction How are leukocytes made... How do leukocytes penetrate... How is the inflammatory... References

 
Adhesion and emigration.
The acute inflammatory response elicited upon invasion of microorganisms or upon tissue damage is associated with the release of proinflammatory mediators by tissue macrophages, mast cells, or other tissue cells such as damaged fibroblasts. Soluble mediators like histamine, interleukin 1, and TNF- activate the endothelium lining postcapillary venules, i.e., they induce the expression of adhesion molecules and the secretion of soluble mediators, which in turn allow the leukocyte-endothelial cell interactions. The diversity and specificity of the adhesion molecules expressed constitute the molecular basis for the site-directed traveling of leukocytes during inflammation (2). The sequence of molecular mechanisms during PMN recruitment in acute inflammation is shown in Fig. 3. The induction of the L-selectin ligand on the microvascular endothelium by tissue-derived proinflammatory mediators allows initial capture and rolling of PMN via L-selectin. Rolling is also supported by upregulation of endothelial P- and E-selectin, which serve as receptors for PSGL-1 and ESL-1. PMN recruitment subsequent to rolling critically requires ß₂-integrin-mediated firm adhesion of the PMN to the endothelial cells. Patients suffering from leukocyte adhesion deficiency type I, an inheritable defect of the CD18 gene of the ß₂-integrins, show a lack of inflammatory response: PMN extravasation does not occur despite the presence of inflammatory agents (6). This is consistent with the finding that gene-targeted CD18-deficient mice show impaired PMN recruitment. In contrast, extravasation of monocytes that predominantly emigrate via ß₁-integrin-dependent mechanisms is not diminished in the absence of ß₂-integrins (15). The dependence of PMN emigration on ß₂-integrins is thought to result from their ability to bind ICAM-1 on activated endothelial cells. Adhesive interactions of the ß₂-integrins require integrin activation, i.e., functional upregulation of their ligand-binding affinity by a process termed inside-out signaling. It is elicited by soluble inflammatory mediators from activated endothelial cells to which the PMN are exposed while rolling on the inflamed vessel wall. Thus substantial PMN recruitment from the circulating blood can only occur if endothelial cells are sufficiently activated to stimulate the PMN to activate ß₂-integrins and firmly adhere to the vessel wall. Besides soluble mediators, engagement of L-selectin and PSGL-1 is also considered to trigger the functional upregulation of ß₂-integrins and thereby support firm adhesion. Adherent PMN spread on the endothelium transmigrate through the intercellular junctions of the endothelial cells and finally penetrate the basement membrane. Recent data suggest that adhesion preferentially occurs near the margins of the endothelial cells and thus in the vicinity of the endothelial junctions, through which the PMN eventually escape.

View larger version (34K): [in this window] [in a new window]   FIGURE 3. Molecular events of PMN-endothelial cell interactions in inflammation. PSGL, P-selectin ligand; ESL, E-selectin ligand.

Chemoattractants that guide PMN during inflammation include classical inflammatory mediators such as platelet-activating factor (PAF), leukotriene B4 (LTB4), chemoattractant cytokines such as interleukin-8 (which are also designated as chemokines), the complement factor C5a, and exogenous components like bacteria-derived peptides such as the N-formylated tripeptide Met-Leu-Phe. Chemoattractants exert their effects by binding to specific receptors on the leukocyte surface that share common features: they are heptahelical molecules with seven transmembrane domains that activate intracellular signal transduction cascades via GTP-binding proteins (G proteins). Some of these receptors, including that for interleukin 8, show promiscuous ligand binding by exerting affinity to other structurally related chemoattractants, i.e., the chemokines epithelial-derived neutrophil attractant-78 (ENA-78), neutrophil activating peptide 2 (NAP-2), and melanoma growth-stimulating activity (GRO). Moreover, some chemoattractants bind to different receptors, whereas one type of receptor is often expressed by more than one leukocyte population: bacteria-derived N-formyl-peptides, for example, are chemoattractants for both PMN and monocytes. Other mediators, like secondary lymphoid tissue chemokine (SCL), which attracts T cells, or B lymphocyte chemoattractant (BCL), which is chemotactic for B cells, act primarily on lymphocytes.

How is the activation of PMN controlled and prevented from exploding? Development of weaponry and mechanisms of containment
The pattern of adhesion molecules expressed represents the critical checkpoint for leukocyte extravasation in inflammation by determining the quantity and quality of leukocyte-endothelium interactions as well as its time course. This has unequivocally been shown by the use of monoclonal antibodies or by gene disruption in experimental animals. But adhesion molecules also play a important role subsequent to PMN emigration. Severe inflammatory responses are eventually accompanied by plasma exudation, which allows clotting in the extravascular space. This provides an appropriate matrix for ß₂-integrin-mediated adhesion of emigrated PMN. By serving as receptor for C3bi-opsonized material, the ß₂-integrin Mac-1 also facilitates phagocytosis and thereby promotes clearance of the tissue from foreign particles. PMN destroy ingested material by reactive oxygen metabolites, which are produced upon activation of NADPH oxidase. The destructive potential of PMN is further due to the contents of granules, i.e., enzymes such as elastase and cathepsin G, myeloperoxidase, and others, which can be released from the cells by exocytosis and contribute to tissue damage in inflammation.

But adhesion molecules not only mediate interaction of PMN with the environment: Upon ligand binding, several adhesion molecules, such as integrins, transduce signals into the cell that control adhesion-related processes, including firm attachment and spreading and, moreover, contribute to the activation of cellular functions (3). Thus integrins as well as other adhesion molecules integrate ligand-dependent, i.e., site-specific, and signaling functions at the molecular level. Early studies revealed that ß₂-integrins initiate intracellular signal transduction processes and serve as costimulators, e.g., upon activation of PMN by soluble mediators such as TNF- (9). This functional cooperation between locally released soluble mediators and integrins provides a site-specific extracellular signal pattern and may help to control PMN activation in inflammation. Tissue cells in inflamed areas are known to upregulate ICAM-1, the counterreceptor for ß₂-integrins, which allows adhesive interaction between tissue cells and emigrated PMN. Since ß₂-integrin engagement induces and/or promotes several biological responses of PMN, including degranulation and production of reactive oxygen metabolites, this may increase the efficiency of host defense. By precisely directing the destructive material to the target area, i.e., an injured tissue cell, this mechanism prevents the uncontrolled release of the histotoxic contents of PMN that could otherwise result in excessive tissue damage. The engagement of ß₂-integrins upon costimulation by TNF- even triggers the activation of apoptosis, the programmed cell death, of human PMN (14). Thus integrins not only contribute to the control of PMN recruitment from the circulation and to the ordered activation of their defense functions in the tissue but also mediate their final elimination. Since apoptotic PMN are specifically recognized and engulfed by macrophages and tissue cells such as fibroblasts, apoptosis of PMN is currently discussed as a key mechanism that allows the resolution of acute inflammation.

How is the process of repair and tissue remodeling initiated? Toward a new definition of inflammation
Although the mechanisms of inflammation described above are still within the framework of Metchnikoff's concept, growing evidence implies that the inflammatory response must be placed into a greater context of tissue homeostasis. Beyond its immediate physiological function, the inflammatory reaction seems to cover more than an effective host defense mechanism. Patients suffering from leukocyte adhesion deficiency type I not only show compromised leukocyte recruitment due to the absence of ß₂-integrins but also show impaired wound healing. Thus inflammatory leukocyte infiltration seems to give rise to wound repair and tissue remodeling, which eventually allows restitutio ad integrum. On the molecular and cellular levels, this requires production and reconstitution of extracellular matrix, cell proliferation and differentiation, as well as more complex processes such as induction of angiogenesis and vascularization. Growing evidence suggests that these processes can be initiated or promoted by inflammatory cytokines such as interleukin-1, which induces, for example, proliferation of fibroblasts and matrix production. The present evidence that the inflammatory response does not end with the elimination of foreign particles may imply the requirement of a novel definition of inflammation. However, the biological significance of these findings remains to be proven and further investigations are required to provide the molecular basis for the understanding of the mechanisms by which inflammation may integrate host defense, wound repair, and tissue remodeling.

	References

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