Quantitative evaluation of pulmonary stretch receptor activity during high-frequency ventilation.

The purpose of this study was to determine the neural output of pulmonary stretch receptors (PSRs) in response to conditions that, in previous studies (J. Appl. Physiol. 65: 179-186, 1988 and Respir. Physiol. 80: 307-322, 1990), produced apnea in anesthetized cats. These conditions included changes in airway pressure (Paw; 2 or 6 cmH2O), stroke or tidal volume (1-4 ml/kg), frequency [conventional mechanical ventilation (CMV) vs. high-frequency ventilation (HFV) at 10, 15, and 20 Hz], and levels of inspired CO2 (0, 2, and 5%). These data were needed to assess properly the specific contribution of the PSRs to the apnea found with certain combinations of the above variables. Each PSR was subjected to HFV over a range of mechanical and chemical settings, and its activity was recorded. PSRs exhibited continuous activity associated with pump stroke in 11 of 12 fibers tested. PSRs fired more rapidly when mean Paw was 6 cmH2O [45.3 +/- 0.8 (SE) impulses/s] than when it was 2 cmH2O (31.7 +/- 0.9 impulses/s, P = 0.0001). At both pressures, PSR activity increased as the volume of inflation, or tidal volume, was increased from 1 to 4 ml/kg. At Paw of 2 cmH2O, the number of impulses per second for HFV was not different from that for CMV (averaged over the respiratory cycle), under conditions previously demonstrated as apneogenic for both modes of ventilation. Therefore the absolute amount of information being sent to the brain stem processing centers via PSRs during HFV did not differ from that during CMV. Thus any PSR contribution to HFV-induced apnea must have been the result of changes in the pattern of the signal or the central nervous system's processing of it rather than an increase in the amount of inhibitory afferent signal.     

Effect of pulmonary arterial PCO2 on slowly adapting pulmonary stretch receptors

We recorded pulmonary stretch receptor (PSR) activity in anesthetized dogs and examined the effect of varying pulmonary arterial PCO2 (PpCO2) in both the naturally perfused and vascularly isolated pulmonary circulations while ventilating the lungs with room air. Steady-state increases in PpCO2 from approximately 25 to 50 Torr and from 50 to 70 Torr decreased PSR activity (impulses/ventilatory cycle) by 15 and 9%, respectively (P less than 0.001). Rapid increases in PpCO2 from approximately 50 to 80 Torr in a right-heart bypass preparation (with pulmonary blood flow constant) decreased PSR activity by 27%. Depression of firing, which was proportionately greater in deflation, was not dependent on changes in lung mechanics. Results show that loading CO2 intravascularly depresses PSR activity, the effects extending above as well as below resting PpCO2. Rapidly increasing PpCO2 above the resting level markedly depresses PSR activity during the transient. We conclude that PSRs may contribute to altered breathing resulting from changes in mixed venous PCO2 over the physiological range.     

Mitigation of pulmonary hyperoxic injury by administration of exogenous surfactant

We studied the effects of surfactant supplementation on the progression of lung injury in rabbits exposed to 100% O2 for 64 h and returned to room air for 24 h. At this time, rabbits not treated with surfactant exhibit a severe lung injury with hypoxemia, increased alveolar premeability to solute, decreased total lung capacity (TLC) and lung edema. For surfactant treatment, 125 mg of calf lung surfactant extract (CLSE), suspended in 6-8 ml of normal saline, were instilled intratracheally at 0 and 12 h posthyperoxic exposure. At 24 h postexposure, these CLSE-treated rabbits compared with saline controls had significantly higher amounts of lung phospolipids (34 +/- 4 vs. 4.5 +/- 0.6 mumol/kg body wt) and increased TLC (42 +/- 2 vs. 27 +/- 1 ml/kg), with significantly lower amounts of alveolar protein (36 +/- 3 vs. 56 +/- 3 mg/kg) and decreased lung wet weight-to-dry weight ratios (5.6 +/- 0.1 vs. 6.3 +/- 0.3). Surfactant supplementation also decreased the degree of lung atelectasis as reflected by the increase in arterial O2 partial pressure (PaO2) after breathing 100% O2 for 20 min (PaO2 = 460 +/- 31 vs. 197 +/- 52 Torr). These findings indicate that instillation of exogenous surfactant mitigates the progression of hyperoxic lung injury in rabbits.     

Surfactant aggregation in rat lungs: influence of temperature and ventilation

We examined the effect of the ventilatory rate and the temperature of excised lungs and of increased body temperature of anesthetized spontaneously breathing rats on the centrifugal sedimentation of disaturated phosphatidylcholine (DSPC) present in lung lavage returns. More DSPC sedimented from lungs ventilated at low than at high rates, and sedimentation of DSPC and lung volume loss were temperature dependent, 41 greater than 37 greater than 4 degrees C. Most of the noncellular sedimented material was tubular and common myelin; these had diminished ability to lower surface tension rapidly compared with less-aggregated surfactant. More aggregated DSPC accumulated and lung volume decreased more in spontaneously breathing rats anesthetized for 30 min than in rats killed immediately after being anesthetized; these changes were greater after 30 min of anesthesia in hyperthermic rats (40.4 +/- 0.3 degrees C) than in normothermic rats (37.4 +/- 0.1 degrees C). These studies have shown a correlation between the increased accumulation of surfactant as large aggregates and the loss of alveolar stability; however, a cause and effect between these events has not yet been shown.     

Altered lung phospholipid metabolism in mice with targeted deletion of lysosomal-type phospholipase A2

Lung surfactant dipalmitoylphosphatidylcholine (DPPC) is endocytosed by alveolar epithelial cells and degraded by lysosomal-type phospholipase A2 (aiPLA2). This enzyme is identical to peroxiredoxin 6 (Prdx6), a bifunctional protein with PLA2 and GSH peroxidase activities. Lung phospholipid was studied in Prdx6 knockout (Prdx6-/-) mice. The normalized content of total phospholipid, phosphatidylcholine (PC), and disaturated phosphatidylcholine (DSPC) in bronchoalveolar lavage fluid, lung lamellar bodies, and lung homogenate was unchanged with age in wild-type mice but increased progressively in Prdx6-/- animals. Degradation of internalized [3H]DPPC in isolated mouse lungs after endotracheal instillation of unilamellar liposomes labeled with [3H]DPPC was significantly decreased at 2 h in Prdx6-/- mice (13.6 +/- 0.3% vs. 26.8 +/- 0.8% in the wild type), reflected by decreased dpm in the lysophosphatidylcholine and the unsaturated PC fractions. Incorporation of [14C]palmitate into DSPC at 24 h after intravenous injection was decreased by 73% in lamellar bodies and by 54% in alveolar lavage surfactant in Prdx6-/- mice, whereas incorporation of [3H]choline was decreased only slightly. Phospholipid metabolism in Prdx6-/- lungs was similar to that in wild-type lungs treated with MJ33, an inhibitor of aiPLA2 activity. These results confirm an important role for Prdx6 in lung surfactant DPPC degradation and synthesis by the reacylation pathway.     

High tidal volume upregulates intrapulmonary cytokines in an in vivo mouse model of ventilator-induced lung injury.

Mechanical ventilation has been demonstrated to exacerbate lung injury, and a sufficiently high tidal volume can induce injury in otherwise healthy lungs. However, it remains controversial whether injurious ventilation per se, without preceding lung injury, can initiate cytokine-mediated pulmonary inflammation. To address this, we developed an in vivo mouse model of acute lung injury produced by high tidal volume (Vt) ventilation. Anesthetized C57BL6 mice were ventilated at high Vt (34.5 +/- 2.9 ml/kg, mean +/- SD) for a duration of 156 +/- 17 min until mean blood pressure fell below 45 mmHg (series 1); high Vt for 120 min (series 2); or low Vt (8.8 +/- 0.5 ml/kg) for 120 or 180 min (series 3). High Vt produced progressive lung injury with a decrease in respiratory system compliance, increase in protein concentration in lung lavage fluid, and lung pathology showing hyaline membrane formation. High-Vt ventilation was associated with increased TNF-alpha in lung lavage fluid at the early stage of injury (series 2) but not the later stage (series 1). In contrast, lavage fluid macrophage inflammatory protein-2 (MIP-2) was increased in all high-Vt animals. Lavage fluid from high-Vt animals contained bioactive TNF-alpha by WEHI bioassay. Low-Vt ventilation induced minimal changes in physiology and pathology with negligible TNF-alpha and MIP-2 proteins and TNF-alpha bioactivity. These results demonstrate that high-Vt ventilation in the absence of underlying injury induces intrapulmonary TNF-alpha and MIP-2 expression in mice. The apparently transient nature of TNF-alpha upregulation may help explain previous controversy regarding the involvement of cytokines in ventilator-induced lung injury.     

Exercise response after rapid intravenous infusion of saline in healthy humans.

Patients with chronic heart failure have an abnormal pattern of exercise ventilation (Ve), characterized by small tidal volumes (Vt), increased alveolar ventilation, and elevated physiological dead space (Vd/Vt). To investigate whether increased lung water in isolation could reproduce this pattern of exercise ventilation, 30 ml/kg of saline were rapidly infused into nine normal subjects, immediately before a symptom-limited incremental exercise test. Saline infusion significantly reduced forced vital capacity, 1-s forced expiratory volume, and alveolar volume (P < 0.01 for all). After saline, exercise ventilation assessed by the Ve/Vco(2) slope increased from 24.9 +/- 2.4 to 28.0 +/- 2.9 l/l, (P < 0.0002), associated with a small decrease in arterial Pco(2), but without changes in Vt, Vd/Vt, or alveolar-arterial O(2) difference. A reduction in maximal O(2) uptake of 175 +/- 184 ml/min (P < 0.02) was observed in the postsaline infusion exercise studies, associated with a consistent reduction in maximal exercise heart rate (8.1 +/- 5.9 beats/min, P < 0.01), but without a change in the O(2) pulse. Therefore, infusion of saline to normal subjects before exercise failed to reproduce either the increase in Vd/Vt or the smaller exercise Vt described in heart failure patients. The observed increase in Ve can be attributed to dilution acidosis from infusion of the bicarbonate-free fluid and/or to afferent signals from lung and exercising muscles. The reduction in maximal power output, maximal O(2) uptake, and heart rate after saline infusion may be linked to accumulation of edema fluid in exercising muscle, impairing the diffusion of O(2) to muscle mitochondria.     

Variable ventilation induces endogenous surfactant release in normal guinea pigs

Variable or noisy ventilation, which includes random breath-to-breath variations in tidal volume (Vt) and frequency, has been shown to consistently improve blood oxygenation during mechanical ventilation in various models of acute lung injury. To further understand the effects of variable ventilation on lung physiology and biology, we mechanically ventilated 11 normal guinea pigs for 3 h using constant-Vt ventilation (n = 6) or variable ventilation (n = 5). After 3 h of ventilation, each animal underwent whole lung lavage for determination of alveolar surfactant content and composition, while protein content was assayed as a possible marker of injury. Another group of animals underwent whole lung lavage in the absence of mechanical ventilation to serve as an unventilated control group (n = 5). Although lung mechanics did not vary significantly between groups, we found that variable ventilation improved oxygenation, increased surfactant levels nearly twofold, and attenuated alveolar protein content compared with animals ventilated with constant Vt. These data demonstrate that random variations in Vt promote endogenous release of biochemically intact surfactant, which improves alveolar stability, apparently reducing lung injury.     

Quantification of surfactant pool sizes in rabbit lung during perinatal development

Methods are presented for the quantitative isolation of surfactants from fetal and newborn rabbit alveolar lavage returns and post-lavaged lung tissue homogenates. The phospholipid content of both fractions progressively increased between 27 days gestation and term (31 days). The tissue-stored fraction increased approximately 16-fold (from 0.48 +/- 0.13 to 7.83 +/- 0.86 mg/g dry lung) and the alveolar fraction more than 30-fold (from 0.08 +/- 0.02 to 2.69 +/- 0.52 mg/g dry lung). Developmental changes in phospholipid composition were also observed. Tissue-stored surfactant was prepared using differential and density gradient centrifugation. Alveolar surfactant was isolated during fetal development as a high-speed pellet following a one-step differential centrifugation. There was little change in the phospholipid content of fetal alveolar lavage supernatant (range 0.12 +/- 0.04 to 0.28 +/- 0.09 mg/g dry lung). By the first postnatal day the phospholipid content of both lavage fractions significantly increased (pellet, 7.51 +/- 1.79; supernatant, 4.01 +/- 1.36 mg/g dry lung) and both were identified as surfactant. This increase in alveolar surfactant was accompanied by an approximately twofold decrease (to 3.81 +/- 1.1 mg/g dry lung) in the tissue-stored fraction. These data provide a quantitative profile of surfactant accumulation and secretion in developing rabbit lung.     

Inhibition of breathing after surfactant depletion is achieved at a higher arterial PCO2 during ventilation with liquid than with gas

Background

Inhibition of phrenic nerve activity (PNA) can be achieved when alveolar ventilation is adequate and when stretching of lung tissue stimulates mechanoreceptors to inhibit inspiratory activity. During mechanical ventilation under different lung conditions, inhibition of PNA can provide a physiological setting at which ventilatory parameters can be compared and related to arterial blood gases and pH.

Objective

To study lung mechanics and gas exchange at inhibition of PNA during controlled gas ventilation (GV) and during partial liquid ventilation (PLV) before and after lung lavage.

Methods

Nine anaesthetised, mechanically ventilated young cats (age 3.8 ± 0.5 months, weight 2.3 ± 0.1 kg) (mean ± SD) were studied with stepwise increases in peak inspiratory pressure (PIP) until total inhibition of PNA was attained before lavage (with GV) and after lavage (GV and PLV). Tidal volume (V_t), PIP, oesophageal pressure and arterial blood gases were measured at inhibition of PNA. One way repeated measures analysis of variance and Student Newman Keuls-tests were used for statistical analysis.

Results

During GV, inhibition of PNA occurred at lower PIP, transpulmonary pressure (Ptp) and Vt before than after lung lavage. After lavage, inhibition of inspiratory activity was achieved at the same PIP, Ptp and Vt during GV and PLV, but occurred at a higher PaCO₂ during PLV. After lavage compliance at inhibition was almost the same during GV and PLV and resistance was lower during GV than during PLV.

Conclusion

Inhibition of inspiratory activity occurs at a higher PaCO₂ during PLV than during GV in cats with surfactant-depleted lungs. This could indicate that PLV induces better recruitment of mechanoreceptors than GV.     

Cardiorespiratory and lactate responses to a 1-hour submaximal running at the lactate threshold

Cardiorespiratory and blood lactate (La) responses to prolonged submaximal running at an intensity relative to lactate threshold (LT) were examined in 15 recreational runners, aged 19 to 32. In test 1 where treadmill speed was progressively incremented by 10-20m/min until exhaustion, oxygen uptake at the LT (VO2 @ LT: 2.34 +/- 0.331/min or 41.6 +/- 5.7 ml/kg/min) and VO2max (3.58 +/- 0.341/min or 63.6 +/- 5.5 ml/kg/min) were measured. In test 2, the subject was required to run on the treadmill for 1 hour at a fixed velocity (Vt) which corresponded to his Vt @ LT. As expected, mean VO2 ranged during the 1-h submaximal running from 2.31 +/- 0.411/min or 63.0 +/- 7.8% VO2max at min 10-20 to 2.52 +/- 0.351/min or 69.2 +/- 6.2% VO2max at min 50-60, both of which were close to VO2 @ LT (65.2 +/- 4.4% VO2max). The slight decrease in blood La was found from min 20 to min 60, and this was accompanied by a parallel decline in respiratory exchange ratio. Shifts in the energy substrate toward a reliance on fat oxidation may occur during the course of 1-h running at Vt @t LT. The small oxygen debt observed after the 1-h running may confirm the assumption that prolonged running at Vt at LT would be performed in an almost fully aerobic steady state. We conclude that prolonged running at Vt @ LT may possibly maximize health-related benefits in the healthy adult.     

Cytokine release, small airway injury, and parenchymal damage during mechanical ventilation in normal open-chest rats.

Lung morpho-functional alterations and inflammatory response to various types of mechanical ventilation (MV) have been assessed in normal, anesthetized, open-chest rats. Measurements were taken during protective MV [tidal volume (Vt) = 8 ml/kg; positive end-expiratory pressure (PEEP) = 2.6 cmH(2)O] before and after a 2- to 2.5-h period of ventilation on PEEP (control group), zero EEP without (ZEEP group) or with administration of dioctylsodiumsulfosuccinate (ZEEP-DOSS group), on negative EEP (NEEP group), or with large Vt (26 ml/kg) on PEEP (Hi-Vt group). No change in lung mechanics occurred in the Control group. Relative to the initial period of MV on PEEP, airway resistance increased by 33 +/- 4, 49 +/- 9, 573 +/- 84, and 13 +/- 4%, and quasi-static elastance by 19 +/- 3, 35 +/- 7, 248 +/- 12, and 20 +/- 3% in the ZEEP, NEEP, ZEEP-DOSS, and Hi-Vt groups. Relative to Control, all groups ventilated from low lung volumes exhibited histologic signs of bronchiolar injury, more marked in the NEEP and ZEEP-DOSS groups. Parenchymal and vascular injury occurred in the ZEEP-DOSS and Hi-Vt groups. Pro-inflammatory cytokine concentration in the bronchoalveolar lavage fluid (BALF) was similar in the Control and ZEEP group, but increased in all other groups, and higher in the ZEEP-DOSS and Hi-Vt groups. Interrupter resistance was correlated with indexes of bronchiolar damage, and cytokine levels with vascular-alveolar damage, as indexed by lung wet-to-dry ratio. Hence, protective MV from resting lung volume causes mechanical alterations and small airway injury, but no cytokine release, which seems mainly related to stress-related damage of endothelial-alveolar cells. Enhanced small airway epithelial damage with induced surfactant dysfunction or MV on NEEP can, however, contribute to cytokine production.     

Continuous tracheal gas insufflation during partial liquid ventilation in juvenile rabbits with acute lung injury.

To examine the hypothesis that combined treatment with tracheal gas insufflation (TGI) and partial liquid ventilation (PLV) may improve pulmonary outcome relative to either treatment alone in acute lung injury (ALI), saline lavage lung injury was induced in 24 anesthetized, ventilated juvenile rabbits that were then randomly assigned to receive (n = 6/group) 1) conventional mechanical ventilation (CMV) alone, 2) continuous TGI at 0.5 l/min, 3) PLV with perfluorochemical liquid, and 4) combined TGI and PLV (TGI + PLV), and subsequently ventilated with minimized pressures and tidal volume (Vt) to keep arterial Po(2) (Pa(O(2))) >100 Torr and arterial Pco(2) (Pa(CO(2))) at 45-60 Torr for 4 h. Gas exchange, lung mechanics, myeloperoxidase, IL-8, and histomorphometry [including expansion index (EI)] were assessed. The CMV group showed no improvement in lung mechanics and gas exchange; all treated groups had significant increases in compliance, Pa(O(2)), ventilation efficacy index (VEI), and EI, and decreases in PaCO(2), oxygenation index, physiological dead space-to-Vt ratio (Vd/Vt), myeloperoxidase, and IL-8, relative to the CMV group. TGI resulted in lower peak inspiratory pressure, Vt, Vd/Vt, and greater VEI vs. PLV group; PLV resulted in greater compliance, Pa(O(2)), and EI vs. TGI. TGI + PLV resulted in decreased peak inspiratory pressure, Vt, Vd/Vt, and increased VEI compared with TGI, improved compliance and EI compared with PLV, and a further increase in Pa(O(2)) and oxygenation index and a decrease in PaCO(2) vs. either treatment alone. These results indicate that combined treatment of TGI and PLV results in improved pulmonary outcome than either treatment alone in this animal model of ALI.     

Neutrophil defensins mediate acute inflammatory response and lung dysfunction in dose-related fashion

High concentrations of neutrophil defensins from airway and blood have been reported in patients with inflammatory lung diseases, but their exact role is unclear. We investigated the direct effect of defensins on the lungs of mice. Intratracheal instillation of purified defensins (5-30 mg/kg) induced a progressive reduction in peripheral arterial O(2) saturation, increased lung permeability, and enhanced the lung cytochrome c content. These indexes of acute lung dysfunction were associated with an increased total cell number and a significant neutrophil influx into the lung [5.1 +/- 0.04% in control vs. 48.6 +/- 12.7% in the defensin (30 mg/kg) group, P < 0.05]. Elastase concentrations in the bronchoalveolar lavage (BAL) fluids increased from 38 +/- 11 ng/ml (control) to 80 +/- 4 ng/ml (defensins, P < 0.05). Five hours after defensin instillation, concentrations of tumor necrosis factor-alpha and macrophage inflammatory protein-2 in BAL fluid were significantly increased. High levels of monocyte chemoattractant protein-1 in BAL fluid and plasma were also found after defensin stimulation. We conclude that intratracheal instillation of defensins causes acute lung inflammation and dysfunction, suggesting that high concentrations of defensins in the airways may play an important role in the pathogenesis of inflammatory lung diseases.     

Alveolar macrophage depletion is associated with increased surfactant pool sizes in adult rats.

Pulmonary surfactant is a lipid-protein material that is essential for normal lung function. Maintaining normal and consistent alveolar amounts of surfactant is in part dependent on clearance of surfactant by alveolar macrophages (AM). The present study utilized a rat model of AM depletion to determine the impact on surfactant pool sizes and function over time. Male Sprague-Dawley rats were anesthetized and intratracheally instilled with PBS-liposomes (PBS-L) or dichloromethylene diphosphonic acid (DMDP) containing liposomes (DMDP-L) and were killed at various time points up to 21 days for compliance measurements, AM cell counts, and surfactant analysis. AM numbers were significantly decreased 1, 2, and 3 days after instillation in DMDP-L vs. PBS-L, with 72% depletion at 3 days. AM numbers returned to normal levels by 5 days. In DMDP-L rats, there was a rapid increase in surfactant-phospholipid pools, showing a ninefold increase in the amount of surfactant in the lavage 3 days after liposome instillation. Surfactant accumulation progressed up to 7 days, with pools normalizing by 21 days. The increase in surfactant was due to increases in both subfractions of surfactant, the large aggregates (LA) and small aggregates. Surfactant protein A levels, relative to LA phospholipids, were not increased. There was a decreased extent of surfactant conversion in vitro for LA from DMDP-L rats compared with controls. It is concluded that the procedure of AM depletion significantly affects surfactant metabolism. The increased endogenous surfactant must be considered when utilizing the AM depletion model to study the role of these cells during lung insults.     

Protective effects of elevated endogenous surfactant pools to injurious mechanical ventilation

Depletion of alveolar macrophages (AM) leads to an increase in endogenous surfactant that lasts several days beyond the repletion of AM. Furthermore, impairment to the endogenous pulmonary surfactant system contributes to ventilation-induced lung injury. The objective of the current study was to determine whether increased endogenous surfactant pools induced via AM depletion was protective against ventilation-induced lung injury. Adult rats were intratracheally instilled with either control or dichloromethylene diphosphonic acid (DMDP) containing liposomes to deplete AMs and thereby increase endogenous surfactant pools. Either 3 or 7 days following instillation, rats were exposed to 2 h of injurious ventilation using either an ex vivo or in vivo ventilation protocol and were compared with nonventilated controls. The measured outcomes were oxygenation, lung compliance, lavage protein, and inflammatory cytokine concentrations. Compared with controls, the DMDP-treated animals had significantly reduced AM numbers and increased surfactant pools 3 days after instillation. Seven days after instillation, AM numbers had returned to normal, but surfactant pools were still elevated. DMDP-treated animals at both time points exhibited protection against ventilation-induced lung injury, which included superior physiological parameters, lower protein leakage, and lower inflammatory mediator release into the air space, compared with animals not receiving DMDP. It is concluded that DMDP-liposome administration protects against ventilation-induced lung injury. This effect appears to be due to the presence of elevated endogenous surfactant pools.     

Altered function of pulmonary surfactant in fatty acid lung injury

To determine whether acute fatty acid lung injury impairs pulmonary surfactant function, we studied anesthetized ventilated rabbits given oleic acid (55 mg/kg iv, n = 11) or an equivalent volume of saline (n = 8). Measurements of pulmonary mechanics indicated a decrease in dynamic compliance within 5 min of injury and a decrease in lung volume that was disproportionately large at low pressures, consistent with diminished surfactant activity in vivo. Bronchoalveolar lavage fluid obtained 1 h after injury had significantly increased erythrocytes and total leukocytes, largely polymorphonuclear cells. The phospholipid content and composition of the cell-free fraction had only minor changes from those of controls, but the protein content was increased 35-fold. Measurements of lavage surface activity in vitro showed an increase in average minimum surface tension from 1.3 +/- 0.4 (SE) dyn/cm in controls to 20.2 +/- 3.9 dyn/cm in injured animals. The alterations in static pressure-volume curves and decrease in lavage surface activity suggest a severe alteration of surfactant function in this form of lung injury that occurs despite the presence of normal amounts of surfactant phospholipids.     

Acute lung injury augments hypoxic ventilatory response in the absence of systemic hypoxemia.

The objective of the present study was to examine the impact of early stages of lung injury on ventilatory control by hypoxia and hypercapnia. Lung injury was induced with intratracheal instillation of bleomycin (BM; 1 unit) in adult, male Sprague-Dawley rats. Control animals underwent sham surgery with saline instillation. Five days after the injections, lung injury was present in BM-treated animals as evidenced by increased neutrophils and protein levels in bronchoalveolar lavage fluid, as well as by changes in lung histology and computed tomography images. There was no evidence of pulmonary fibrosis, as indicated by lung collagen content. Basal core body temperature, arterial Po(2), and arterial Pco(2) were comparable between both groups of animals. Ventilatory responses to hypoxia (12% O(2)) and hypercapnia (7% CO(2)) were measured by whole body plethysmography in unanesthetized animals. Baseline respiratory rate and the hypoxic ventilatory response were significantly higher in BM-injected compared with control animals (P = 0.003), whereas hypercapnic ventilatory response was not statistically different. In anesthetized, spontaneously breathing animals, response to brief hyperoxia (Dejours' test, an index of peripheral chemoreceptor sensitivity) and neural hypoxic ventilatory response were augmented in BM-exposed relative to control animals, as measured by diaphragmatic electromyelograms. The enhanced hypoxic sensitivity persisted following bilateral vagotomy, but was abolished by bilateral carotid sinus nerve transection. These data demonstrate that afferent sensory input from the carotid body contributes to a selective enhancement of hypoxic ventilatory drive in early lung injury in the absence of pulmonary fibrosis and arterial hypoxemia.