Intravascular infusion of inflammatory mediators causes a sudden neutropenia due to the sequestration of polymorphonuclear leukocytes (PMN) within the microvasculature of the lung and other organs. This sequestration could be due to a decrease in the ability of PMN to deform and pass through the narrow capillary bed. The purpose of this study was to determine if the complement fragments present in zymosan-activated plasma (ZAP) caused a rapid stiffening of PMN. The PMN deformability was determined by measuring the pressure required to pass PMN through a polycarbonate filter containing 5-micron pores at a constant flow rate as well as the extraction of PMN compared with red blood cells and 125I-labeled albumin by the filter. The role of the cytoskeleton in PMN deformation was examined in studies where F-actin formation was inhibited using cytochalasin B or microtubule assembly was inhibited using colchicine. The results showed that treatment with ZAP induced a rapid decrease in PMN deformability. Inhibiting the formation of F-actin made the unstimulated PMN more deformable and reduced the stiffening induced by ZAP. In contrast, inhibition of microtubule reassembly did not alter either normal deformability or the ZAP-induced decrease in deformability. In vivo, colchicine increased normal PMN margination but did not inhibit the rapid sequestration of PMN induced by infusion of ZAP. These studies indicate that ZAP induces a rapid decrease in PMN deformability that is mediated through the cytoskeleton. They suggest that this decrease is due to the polymerization of F-actin.
It has been demonstrated that methacholine (MCh) challenge produces a greater increase in lung resistance in immature than in mature rabbits (R. S. Tepper, X. Shen, E. Bakan, and S. J. Gunst. J. Appl. Physiol. 79: 1190-1198, 1995). To determine whether this maturational difference in the response to MCh was primarily related to changes in airway resistance (Raw) or changes in tissue resistance, we assessed airway narrowing in 1-, 2-, and 6-mo-old rabbits during intravenous MCh challenge (0.01-5.0 mg/kg). Airway narrowing was determined from measurements of Raw in vivo and from morphometric measurements on lung sections obtained after rapidly freezing the lung after the MCh challenge. The fold increase in Raw was significantly greater for 1- and 2-mo-old animals than for 6-mo-old animals. Similarly, the degree of airway narrowing assessed morphometrically was significantly greater for 1- and 2-mo-old animals than for 6-mo-old animals. The fold increase in Raw was highly correlated with the degree of airway narrowing assessed morphometrically (r2 = 0.82, P < 0.001). We conclude that the maturational difference in the effect of MCh on lung resistance is primarily caused by greater airway narrowing in the immature rabbits.
When O2 delivery (blood flow X arterial O2 content) is reduced, many tissues respond by increasing perfused capillary density. This facilitates the increase in O2 extraction required to maintain tissue O2 consumption in the face of limited O2 supply. In a previous study of isolated canine small intestine (J. Appl. Physiol. 64: 2410-2419, 1988), endotoxin administration was associated with an impaired ability to increase O2 extraction in response to progressive reductions in O2 delivery. The aim of the present study was to determine whether reductions in perfused capillary density occur after endotoxin administration. Fourteen male dogs were anesthetized with chloralose (150 mg/kg iv) and urethan (750 mg/kg iv), and a segment of small intestine was exteriorized through a midline laparotomy. The segment was isolated vascularly, autoperfused, and maintained at body temperature. Escherichia coli endotoxin (5 mg/kg) or sham challenge was administered, and the animals were allowed to stabilize. Blood flow and arterial and gut venous blood O2 contents were measured after 3 h. Perfused vessels were then labeled by injecting colloidal carbon (less than 0.8 microns) through the arterial cannula and clamping the artery and vein as the bolus passed through the tissue. In some of the experiments a second gut segment was successfully obtained within 1 h of the first, yielding a total of 14 gut segments in nine endotoxin animals and nine segments in five control animals. Morphological analysis of capillary surface density in mucosal villi and crypts showed a significantly higher perfused capillary density in control tissue blocks (77.8 +/- 9.2%) than in blocks from endotoxin-treated animals (68.8 +/- 8.0%, P less than 0.04).(ABSTRACT TRUNCATED AT 250 WORDS)
The circulating neutrophils must slow down, adhere to the vessel walls, and migrate out of the microvasculature into the tissue and air spaces to defend the lung against microorganisms. The present study was designed to provide quantitative information about each of these steps. Streptococcus pneumoniae was instilled into the left lower lobe of New Zealand White rabbits to induce a pneumonia, and this lobe was compared with the same region of the opposite lung. The distribution of blood flow was determined by using radiolabeled macroaggregated albumin, and the patterns of perfusion within the capillary bed were quantitated using Monastral blue. The number of neutrophils delivered to the pneumonic site was determined by multiplying the circulating neutrophil count and blood flow. The results show that retention of 51Cr-labeled neutrophils was increased in the pneumonic region 2, 4, and 8 h after instillation of the organisms. The number of intracapillary neutrophils was increased in the pneumonic regions at all time points and in the control regions at 1 and 4 h. Neutrophil migration occurred in the pneumonic site, but only 1-2% of the total neutrophils delivered to the region migrated out of the pulmonary vessels into the air space. We conclude that the circulating neutrophils undergo a generalized response that increases their margination throughout the lung, that increased margination in the pneumonic site changes the distribution of capillary flow, and that the majority of neutrophils delivered to a pneumonic site are returned to the circulation without migrating into the air space.
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