C-reactive protein inhibits increased pulmonary vascular permeability induced by fMLP in isolated rabbit lungs.

Increased serum concentrations of C-reactive protein (CRP) have previously been shown to downregulate neutrophil (PMN) influx and vascular permeability changes in models of localized inflammation such as alveolitis [R. M. Heuertz, D. Xia, D. Samols, and R. O. Webster, Am. J. Physiol. 266 (Lung Cell. Mol. Physiol. 10): L649-L654, 1994]. Experiments in isolated, buffer-perfused rabbit lungs were used to determine whether CRP attenuates vascular lung injury induced by PMNs stimulated with the chemotactic peptide N-formylmethionyl-leucyl-phenylalanine (fMLP). Peritoneal PMN were added to the perfusate of lungs from PMN-depleted rabbits. Stimulation with fMLP produced an immediate and transient rise in pulmonary artery pressure that peaked at 35-40 cmH2O. An increase in permeability occurred 60 min after fMLP, which was marked by a 70% increase (P < 0.05) in filtration coefficient and bronchoalveolar lavage (BAL) protein concentration. CRP pretreatment of PMNs prevented fMLP-induced increases in permeability and significantly reduced the BAL protein below levels in control lungs (P < 0.05). CRP pretreatment of PMNs did not alter the pulmonary arterial pressor response to fMLP and had no effect on the production of leukotrienes, thromboxane, prostacyclin, or superoxide anion induced by fMLP. The mechanism by which CRP protects lung tissue from vascular injury induced by activation of PMNs remains unclear.

Noninvasive measures of radiolabeled dextran transport in in situ rabbit lung.

UNLABELLED: Dextrans are nontoxic and can be obtained in a wide variety of molecular weights. The purpose of this study was to label 6-kDa and 40-kDa dextrans with gamma- (99mTc) and positron- (18F) emitting radioisotopes and monitor their transport across the pulmonary microvascular barrier. METHODS: External scan measurements for radiolabeled uncharged dextrans, albumin and red blood cells were obtained in eight blood-perfused in situ rabbit lung preparations. After 3 hr of external scanning, the lungs were removed for postmortem and extravascular distribution volume calculations. Extravascular distribution volumes were obtained in six additional rabbits following 4 hr of dextran perfusion to compare the effect of time. The normalized slope index (NSI), a measure of transvascular transport rate, was calculated for each diffusible tracer. RESULTS: The mean NSI for albumin (0.001676 +/- 0.000537 min-1) was significantly lower than NSI for the 40-kDa dextran (0.002303 +/- 0.0005426 min-1) as well as the 6-kDa dextran (0.004312 +/- 0.001134 min-1). The difference between the 6-kDa and the 40-kDa dextrans was also significant. After 4 hr of equilibration, distribution volumes were not significantly different than those obtained at 3 hr. CONCLUSION: Dextrans can be radiolabeled with gamma and positron emitters and small dextrans traverse the lung microvascular barrier more rapidly than albumin. Our results suggest that the use of small dextrans rather than albumin can reduce scan times in clinical applications and minimize motion artifact associated with the noninvasive gamma detection method.

Noninvasive measurements of albumin flux into lung interstitium with increased microvascular pressure.

The purpose of this study was to determine the effect of increasing left atrial pressure on noninvasive measurements of radiolabeled albumin normalized slope index (NSI). Using portable gamma scintillation detectors, we monitored radioactivities of 131I-labeled albumin and 51Cr-labeled red blood cells in the blood and over the lung of six anesthetized sheep before and 2 h after a 9- to 14-Torr increase in left atrial pressure. Measurements of NSI for 131I-albumin decreased > 50% after a step increase in left atrial pressure. We interpreted the data using a model that has been used to successfully describe unsteady-state lymph flow and protein concentrations after vascular pressure increases in sheep. Model predictions strongly suggest that the reduction in NSI is due to rapid fluid and solute removal from the interstitium via the lymphatics. The theoretical model was able to predict external scan data and lung lymph protein concentrations only when a change in lymphatic conductance (LI) or initial lymphatic pressure (P0) was imposed at the time of increased pressure. On average, model-predicted increases in LI were sevenfold, whereas predicted decreases in P0 were four- to fivefold. Imposed changes in LI and P0 opposed increases in interstitial fluid volume after increased pressure. This was consistent with normal-to-low postmortem measurements of bloodless wet-to-dry lung weight ratios. In summary, these results indicate that changes in the rate of fluid removal from the interstitium can significantly alter NSI, and in this case, NSI does not reflect pulmonary microvascular permeability. In sheep, increases in the lymphatics' ability to remove interstitial fluid may occur with relatively small increases in microvascular pressure.

Evaluation of perilla ketone-induced unilateral lung injury using external gamma scanning.

We used a modified external gamma scanning technique to quantitate right and left lung permeability changes to iodinated sheep albumin before and after perilla ketone (PK)-mediated unilateral lung injury in seven anesthetized sheep. Three portable gamma scintillation probes containing 2-in. NaI crystals detected radioactivities of 51Cr-labeled red blood cells and 125I-labeled albumin over the right and left lungs and blood, respectively. Radioactivities were monitored for 1 h before and 3 h after infusion of 25 mg/kg PK into a single lung. Calculation of normalized slope index (NSI) (Roselli and Riddle, J. Appl. Physiol. 67: 2343-2350, 1989) over the 30-min interval before PK and over the 60- to 90-min interval after PK for each lung revealed a four- to five-fold NSI increase in lungs receiving PK (0.00237 +/- 0.00065 to 0.0109 +/- 0.0016 min-1) and no increase in contralateral control lungs (0.00214 +/- 0.00065 to 0.00201 +/- 0.00032 min-1). Observed changes in NSI were consistent with postmortem evaluations of each lung. Lungs receiving PK had significantly higher wet-to-dry lung weight ratios and extravascular lung water volumes than contralateral control lungs. Measured bloodless wet-to-dry lung weight ratios were 5.68 +/- 0.39 and 3.27 +/- 0.27 (P < 0.05) for PK and control lungs, respectively.

Effects of Perilla ketone on the in situ sheep lung.

We studied the effects of three different doses (15, 20, and 25 mg/kg) of Perilla ketone (PK) on the blood-perfused in situ sheep lung while obtaining external measurements of lung transvascular protein flux. Lymph flow and lymphatic protein clearance increased significantly after all doses of PK. Severe pulmonary edema was confirmed by high postmortem wet-to-dry lung weight ratios and increased extravascular lung water from multiple indicator-dilution studies. Urea permeability-surface area product and effective diffusivity from multiple indicator-dilution studies also increased after PK infusion. Because we observed no evidence of increased capillary pressure or increased microvascular surface area after PK, we conclude that PK significantly increased pulmonary microvascular permeability. Certain aspects of the in situ PK response appeared to be dose dependent. The lungs responded rather quickly to high doses of PK, but an apparent latency period was noted with low doses of PK. Postmortem wet-to-dry lung weight ratios were always high but did not suggest dose dependence. However, times of postmortem measurements were not the same for all doses of PK. The external scan technique appeared to be sensitive to changes that occurred in the lung after PK. Externally detected albumin interstitial-to-plasma mass (mass I/P) ratios were substantially higher after PK than during control in situ studies. In some experiments, final mass I/P ratios increased above 4 approximately 2.0 h after PK compared with control values of 0.2 and 0.4. A delay time between injection and change in mass I/P slope was also observed, which decreased with increasing dose of PK. PK causes a permeability injury in the in situ sheep lung and provides a useful model for studying the sensitivity of permeability measurement techniques such as the external gamma-ray detection method.