This study examined the effectiveness of antisense oligonucleotides targeted to intercellular adhesion molecule-1 (ICAM-1) to inhibit endotoxin-induced upregulation of ICAM-1 and neutrophil emigration and compared the apparent role of ICAM-1 when examined using antisense oligonucleotides, anti-ICAM-1 antibodies, and ICAM-1 mutant mice. Antisense oligonucleotides inhibited upregulation of ICAM-1 mRNA at 4 and 24 h after instillation of endotoxin in a dose-dependent manner. Neutrophil emigration into the alveolar spaces at 24 h was inhibited by 59%, similar to inhibition using the anti-ICAM-1 antibodies 3E2 (58%) and YN1/ 1 (75%) .

Neutrophil margination within the pulmonary capillary is due to a delay in their transit compared with that of red blood cells (RBC). This delay has been attributed to the large fraction of capillary segments that are narrower than spherical neutrophils and differences between the time required for deformation of neutrophils and that required for deformation of RBC. This study investigated the characteristics of neutrophil deformation in vivo and the perfusion patterns of segments within capillary pathways. Studies comparing the extraction of neutrophils with that of nondeformable microspheres in one transit through the pulmonary circulation suggest that neutrophils can undergo a rapid deformation from 6.4 to 5.0-5.1 microns, whereas larger deformations require a delay. Effective diameters of the perfused capillary pathways were larger than expected for a random distribution of capillary segment diameters within these pathways. The longer transit times of neutrophils in the upper regions of the lung were associated with a greater fraction of pathways containing narrow segments. These studies suggest that neutrophil deformability and capillary pathway diameters are important in determining the size of the marginated pool of neutrophils within the pulmonary capillaries.

Infusion of complement fragments induces rapid sequestration of neutrophils within pulmonary capillaries. This study examined the mechanisms through which this sequestration occurs, as well as the effect of complement fragments on the expression of L-selectin and CD11/CD18 using ultrastructural immunohistochemistry. Studies using anti-P-selectin antibodies, fucoidin, L-selectin-depleted neutrophils, and anti-CD18 antibodies showed that selectins and CD18 were not required for neutrophil sequestration. However, maintaining the sequestered neutrophils within the pulmonary capillaries required both L-selectin and CD11/CD18. Neutrophils in the pulmonary capillaries of rabbits given complement fragments expressed 72% less L-selectin and 98% more CD11/CD18 than did those in rabbits given saline. Shedding of L-selectin occurred preferentially from the microvillar processes of the plasma membrane rather than from the flat intervening regions. About 28% of L-selectin still remained on intracapillary neutrophil membranes after 15 min and was likely available for binding. Shedding of L-selectin appeared slower in vivo than in vitro. These studies indicate that neutrophil sequestration induced by complement fragments requires at least two sequential steps, one that does not require recognized adhesion molecules followed by a second that requires L-selectin and CD11/ CD18.

Neutrophil emigration in response to acid aspiration does not require the adhesion complex, CD11/ CD18. This study examined the role of CD11b/CD18 using the anti-CD11b F(ab')2, 1B6, in focal HCI-induced intracapillary neutrophil sequestration and edema formation within rat lungs, as well as the effect of pretreatment with endotoxin on this injury. The results show that at the site of aspiration pneumonia, anti-CD11b F(ab')2 did not inhibit neutrophil sequestration or edema formation, either with or without endotoxin pretreatment. In the contralateral lung, focal HCI aspiration induced neutrophil sequestration that was inhibited by the anti-CD11b F(ab')2, but no edema formation. The combined effect of endotoxin pretreatment and HCI aspiration induced CD11b/CD18-independent edema formation in the contralateral lung. These data indicate that CD11b/CD18-independent pathways mediate neutrophil sequestration and edema formation at that pneumonic site with or without pretreatment with endotoxin. CD11b/CD18 mediates neutrophil sequestration at distant sites when no endotoxin is present, although this CD11b/CD18-dependent sequestration is not association with edema formation. The combined effects of endotoxin and HCI aspiration induce edema formation at distant sites that could not be prevented by inhibiting the function of the CD11b/CD18 prior to aspiration.