Tissue Specific Expression of AMs in the Lung Microvasculature

The aforementioned sequence of events and mechanisms leading to the transmigration of leukocytes out of the circulation has been shown to occur in vitro and in vivo in tissues such as the mesentery. However, several recent studies have shown differences in leukocyte trafficking characteristics in the pulmonary circulation when compared to the systemic circulation [1]. The location of leukocyte extravasation and the requirements for AM expression have also proven to be different, possibly because of the unique structural features of the lung microcirculation [7]. This suggests that tissue-specific leukocyte trafficking and differential expression of AMs exist in the lung, and thus, the mechanisms of leukocyte trafficking must not be thought of as a generalized set of occurrences. We have recently developed a rat model of intravital microscopy in the airway circulation or tracheal microcirculation [8] and demonstrated that leukocyte recruitment in the circulation of the trachea is similar to the systemic circulation. Other intravital microscopy techniques to study microvessel behavior and leukocyte trafficking in the pulmonary circulation have been created. One utilized an implanted window in the thoracic wall of rabbits and dogs. In addition, transplantation of neonatal lung into skin folds of nude mice has been used to examine leukocyte recruitment in revascularized lung tissues [9].

Margination and Migration in the Pulmonary Circulation

In the systemic circulation of the airways and other tissues, migration occurs in postcapillary venules, following the typical sequence of leukocyte trafficking described previously. However, several distinct characteristics are seen in the pulmonary circulation. For example, leukocytes marginate and transmigrate in alveolar capillaries, rather than the normal site of migration, the postcapillary venule. Many leukocyte-EC interactions take place in the pulmonary capillary bed via a process known as sequestration. Here, the network consists of capillary segments that connect several alveolar walls and generally contain many more leukocytes compared to other tissue vascular beds. In fact, the concentration of leukocytes (neutrophils or polymorphonuclear [PMN] cells in this case) in pulmonary capillary blood is 35 to 100 times more than that of systemic vessels. This could be an active process, or simply due to small capillary diameters (2 to 5 mm). Leukocytes are approximately 8 mm in diameter, so they would need to deform to squeeze through such small vessels, taking more time to travel through this microcirculation. Although selectin-mediated rolling occurs in pulmonary postcapillary venules, most migrated neu-trophils (97%) are found in the capillary network, where rolling does not occur, as the leukocyte arrests without rolling because of the size of the capillaries. Similarly, leukocytes transmigrate out of the capillary network in the lung, because of their slow transit and interaction with the capillary EC, possibly independent of PECAM-1.

Selectins

Due to the small diameters of pulmonary capillaries, arrest and migration in the pulmonary circulation can occur without rolling. P-selectin is expressed on pulmonary venu-

lar and arteriolar EC, but not capillary EC in rabbits, whereas in the rat, P-selectin is completely nonexpressed. Thus, it can be proposed that in this case, selectins are not required for leukocyte trafficking in the pulmonary circulation. Further, from experiments using E-selectin and P-selectin-deficient mice, pulmonary migration to Streptococcus pneumoniae, a Gram-positive bacterium (see next section), was increased, indicating that selectin expression actually suppresses leukocyte migration out of the pulmonary circulation. This contrasts with other, allergen-driven cell recruitment models, where selectin deficiency or blockade reduces T cell and eosinophil recruitment. The depletion of L-selectin from neutrophils does not affect the rate and response of sequestration in the lung induced by complement fragments. This suggests that selectins may not be required for migration to Grampositive bacteria. However, selectin-mediated processes are involved in migration to Gram-negative bacteria or endotoxin (Escherichia coli, LPS), where selectin deficiency protects against endotoxin-induced septicemia, lung injury, and death.

During acute lung injury, blockage of all selectins can result in approximately 40 percent inhibition of leukocyte infiltration and vascular permeability. High tidal volume ventilation activates lung microvessels in a P-selectin-dependent process. Furthermore, E-selectin is upregulated in lungs of fatal acute respiratory distress patients infected with Gram-negative bacteria. Thus the role of selectins in acute respiratory distress and acute lung injury appears somewhat variable depending on the inflammatory condition.

Ig Superfamily and Integrin Ligands

ICAM-1 is expressed at constitutively high levels on pulmonary capillary and venular ECs, and at low levels on ECs in the systemic circulation [10]. This could be one reason why activated leukocytes (with increased expression of activated b2 integrins) are sequestered in the lungs. However, pulmonary migration of granulocytes can occur independently of b2 integrins depending on the inflammatory stimuli. Using neutralizing antibodies to CD18, leukocyte migration from activation by Gram-negative bacteria (Pseudomonas aeruginosa and E. coli), IL-1, LPS, and phorbol esters can induce CD18-dependent lung migration pathways, involving ICAM-1, while Gram-positive bacteria (S. pneumoniae) and complement products induce CD18-independent pulmonary recruitment. Accordingly, ICAM-1 expression (as high as it is on pulmonary ECs) is further upregulated by Gram-negative bacteria and LPS, but not by Gram-positive bacteria in these animal models. Interestingly, expression of CD18 and L-selectin in neutrophils exposed to E. coli was altered only after migration and not while in the circulation. In contrast, in response to S. pneu-moniae, CD18 and L-selectin levels were increased and reduced, respectively, before migration, indicating their involvement. In these cases, the expression and requirement for CD18 before and during migration is inversely corre lated and the limiting factor could be the increased expression of ICAM-1. In patient samples of sepsis-induced lung injury, ICAM-1 as well as VCAM-1 expression is highly upregulated. Hydrochloric acid instillation into the trachea, an animal model of gastric acid inspiration, causes lung injury and endothelial activation. It does not require CD18 for leukocyte accumulation, but subsequent lung injury and injury to other organs is CD18 dependent. It is possible that VCAM-1 or other AMs can be involved in Gram-positive bacterial infections. The mechanism underlying CD 18-independent leukocyte recruitment in the pulmonary circulation is still unknown.

Migration in the Systemic Bronchial Circulation

Leukocyte trafficking and endothelial migration in the systemic circulation of the lungs is not well studied. Only 1 percent of the cardiac output is directed to the airway circulation to supply the central airways and bronchi. These vessels form a plexus network around the airways, supplied by the bronchial artery, sending branches into the muscle and submucosa. It remains unknown whether leukocyte infiltration close to the bronchi is occurring from the bronchial circulation or the pulmonary circulation. It seems unlikely that tissue-infiltrating leukocytes such as eosinophils found in and around the bronchi in airway conditions such as asthma exit through the pulmonary circulation. Thus, it is important to know the recruitment properties of this circulation. As mentioned previously, we have developed a model of intravital microscopy in the upper airways to address this issue [8]. Although this model uses the tracheal circulation, the function and regulation of tracheal muscle and tissue mirror the smaller airways. Leukocyte-endothelial rolling and adhesion induced by Gram-negative bacterial LPS and the leukocyte-activating bacterial peptide fMLP (formyl-methionyl-leucyl-phenylalanine) occurred in postcapillary venules, with parameters similar to that of the systemic circulation. Furthermore, using the same model, high-pressure mechanical ventilation induced EC activation and leukocyte recruitment in tracheal microvessels, which was sensitive to selectin blockage. In a lung transplant model [9], where intravital microscopy was done in revascularized vessels of the lung, TNF-induced leukocyte rolling and adhesion occurred in the venules and arterioles, and this, too, was dependent on selectins. It was interesting that no arrest or sequestration was seen in the capillaries. However, rolling leukocytes in the postcapillary venules were elongated, perhaps because of shape change from traversing through the capillary network. It is possible that because these are newly revascularized vessels, it may be a model of angiogenesis rather than pulmonary circulation per se. In any case, this indicates that selectins are likely important in the recruitment of leukocytes in the airways. Similarly, other studies have observed that lymphocyte homing to the bronchial endothelium is P-selectin-PSGL-1 mediated, and VCAM-1, E-selectin, and CD18 independent. Furthermore, strong expression of P-selectin and ICAM-1 was found on bronchial ECs, with low or negligible expression of E-selectin.

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