Partitioning of respiratory mechanics in mechanically ventilated patients.

In ten mechanically ventilated patients, six with chronic obstructive pulmonary disease (COPD) and four with pulmonary edema, we have partitioned the total respiratory system mechanics into the lung (l) and chest wall (w) mechanics using the esophageal balloon technique together with the airway occlusion technique during constant-flow inflation (J. Appl. Physiol. 58: 1840-1848, 1985). Intrinsic positive end-expiratory pressure (PEEPi) was present in eight patients (range 1.1-9.8 cmH2O) and was due mainly to PEEPi,L (80%), with a minor contribution from PEEPi,w (20%), on the average. The increase in respiratory elastance and resistance was determined mainly by abnormalities in lung elastance and resistance. Chest wall elastance was slightly abnormal (7.3 +/- 2.2 cmH2O/l), and chest wall resistance contributed only 10%, on the average, to the total. The work performed by the ventilator to inflate the lung (WL) averaged 2.04 +/- 0.59 and 1.25 +/- 0.21 J/l in COPD and pulmonary edema patients, respectively, whereas Ww was approximately 0.4 J/l in both groups, i.e., close to normal values. We conclude that, in mechanically ventilated patients, abnormalities in total respiratory system mechanics essentially reflect alterations in lung mechanics. However, abnormalities in chest wall mechanics can be relevant in some COPD patients with a high degree of pulmonary hyperinflation.     

Nonlinearity of respiratory mechanics during bronchoconstriction in mice with airway inflammation.

Respiratory system resistance (R) and elastance (E) are commonly estimated by fitting the linear equation of motion P = EV + RV + P0 (Eq. 1) to measurements of respiratory pressure (P), lung volume (V), and flow (V). However, the respiratory system is unlikely to behave linearly under many circumstances. We determined the importance of respiratory system nonlinearities in two groups of mechanically ventilated Balb/c mice [controls and mice with allergically inflamed airways (ova/ova)], by assessing the impact of the addition of nonlinear terms (E2V2 and R2V(V)) on the goodness of model fit seen with Eq. 1. Significant improvement in fit (51.85 +/- 4.19%) was only seen in the ova/ova mice during bronchoconstriction when the E2V2 alone was added. An improvement was also observed with addition of the E2V2 term in mice with both low and high lung volumes ventilated at baseline, suggesting a volume-dependent nonlinearity of E. We speculate that airway closure in the constricted ova/ova mice accentuated the volume-dependent nonlinearity by decreasing lung volume and overdistending the remaining lung.     

Hyperoxia-induced changes in mouse lung mechanics: forced oscillations vs. barometric plethysmography.

Hyperoxia-induced lung damage was investigated via airway and respiratory tissue mechanics measurements with low-frequency forced oscillations (LFOT) and analysis of spontaneous breathing indexes by barometric whole body plethysmography (WBP). WBP was performed in the unrestrained awake mice kept in room air (n = 12) or in 100% oxygen for 24 (n = 9), 48 (n = 8), or 60 (n = 9) h, and the indexes, including enhanced pause (Penh) and peak inspiratory and expiratory flows, were determined. The mice were then anesthetized, paralyzed, and mechanically ventilated. Airway resistance, respiratory system resistance at breathing frequency, and tissue damping and elastance were identified from the LFOT impedance data by model fitting. The monotonous decrease in airway resistance during hyperoxia correlated best with the increasing peak expiratory flow. Respiratory system resistance and tissue damping and elastance were unchanged up to 48 h of exposure but were markedly elevated at 60 h, with associated decreases in peak inspiratory flow. Penh was increased at 24 h and sharply elevated at 60 h. These results indicate no adverse effect of hyperoxia on the airway mechanics in mice, whereas marked parenchymal damage develops by 60 h. The inconsistent relationships between LFOT parameters and WBP indexes suggest that the changes in the latter reflect alterations in the breathing pattern rather than in the mechanical properties. It is concluded that, in the presence of diffuse lung disease, Penh is inadequate for characterization of the mechanical status of the respiratory system.     

Flow and volume dependence of expiratory resistance in anesthetized cats

In five anesthetized paralyzed cats, mechanically ventilated with tidal volumes of 36-48 ml, the isovolume pressure-flow relationships of the lung and respiratory system were studied. The expiratory pressure was altered between 3 and -12 cmH2O for single tidal expirations. Isovolume pressure-flow plots for three lung volumes showed that the resistive pressure-flow relationships were curvilinear in all cases, fitting Rohrer's equation: P = K1V + K2V2, where P is the resistive pressure loss, K1 and K2 are Rohrer's coefficients, and V is flow. Values of K1 and K2 declined with lung inflation, consistent with the volume dependence of pulmonary (RL) and respiratory system resistances (Rrs). During lung deflation against atmospheric pressure, RL and Rrs tended to remain constant through most of expiration, resulting in a nearly linear volume-flow relationship. In the presence of a fixed respiratory system elastance, the shape of the volume-flow profile depended on the balance between the volume and the flow dependence of RL and Rrs. However, the flow dependence of RL and Rrs indicates that their measured values will be affected by all factors that modify expiratory flow, e.g., respiratory system elastance, equipment resistance, and the presence of respiratory muscle activity.     

Low-volume ventilation causes peripheral airway injury and increased airway resistance in normal rabbits.

Lung mechanics and morphometry of 10 normal open-chest rabbits (group A), mechanically ventilated (MV) with physiological tidal volumes (8-12 ml/kg), at zero end-expiratory pressure (ZEEP), for 3-4 h, were compared with those of five rabbits (group B) after 3-4 h of MV with a positive end-expiratory pressure (PEEP) of 2.3 cmH(2)O. Relative to initial MV on PEEP, MV on ZEEP caused a progressive increase in quasi-static elastance (+36%) and airway (Rint; +71%) and viscoelastic resistance (+29%), with no change in the viscoelastic time constant. After restoration of PEEP, quasi-static elastance and viscoelastic resistance returned to control levels, whereas Rint remained elevated (+22%). On PEEP, MV had no effect on lung mechanics. Gas exchange on PEEP was equally preserved in groups A and B, and the lung wet-to-dry ratios were normal. Both groups had normal alveolar morphology, whereas only group A had injured respiratory and membranous bronchioles. In conclusion, prolonged MV on ZEEP induces histological evidence of peripheral airway injury with a concurrent increase in Rint, which persists after restoration of normal end-expiratory volumes. This is probably due to cyclic opening and closing of peripheral airways on ZEEP.     

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.     

Choosing the frequency of deep inflation in mice: balancing recruitment against ventilator-induced lung injury

Low tidal volume (Vt) ventilation is protective against ventilator-induced lung injury but can promote development of atelectasis. Periodic deep inflation (DI) can open the lung, but if delivered too frequently may cause damage via repeated overdistention. We therefore examined the effects of varying DI frequency on lung mechanics, gas exchange, and biomarkers of injury in mice. C57BL/6 males were mechanically ventilated with positive end-expiratory pressure (PEEP) of 2 cmH2O for 2 h. One high Vt group received a DI with each breath (HV). Low Vt groups received 2 DIs after each hour of ventilation (LV) or 2 DIs every minute (LVDI). Control groups included a nonventilated surgical sham and a group receiving high Vt with zero PEEP (HVZP). Respiratory impedance was measured every 4 min, from which tissue elastance (H) and damping (G) were derived. G and H rose progressively during LV and HVZP, but returned to baseline after hourly DI during LV. During LVDI and HV, G and H remained low and gas exchange was superior to that of LV. Bronchoalveolar lavage fluid protein was elevated in HV and HVZP but was not different between LV and LVDI. Lung tissue IL-6 and IL-1beta levels were elevated in HVZP and lower in LVDI compared with LV. We conclude that frequent DI can safely improve gas exchange and lung mechanics and may confer protection from biotrauma. Differences between LVDI and HV suggest that an optimal frequency range of DI exists, within which the benefits of maintaining an open lung outweigh injury incurred from overdistention.     

Respiratory mechanics and lung development in the rat from early age to adulthood.

The purpose of the present study was to establish how the dependence of respiratory mechanics on lung inflation changes during development. We studied seven groups of rats from 10 days to 3 mo of age at five levels of positive end-expiratory pressure (PEEP) from 0 to 7 hPa (1 hPa = 0.1 kPa approximately 1 cmH(2)O). At each PEEP level, we measured respiratory system resistance and elastance at both 0.9 and 4.8 Hz to partition the mechanical properties into its airway and tissue components. Elastance increased more rapidly with PEEP in the younger animals, which we interpret as reflecting a more pronounced strain stiffening of the younger parenchyma. However, the decrease in airway resistance with PEEP was more pronounced in the older animals. Morphometric analysis showed that mean tissue density decreased and total alveolar surface area increased with age. Our data suggest that the mechanical interdependence between airways and parenchyma is weaker in very young animals compared with mature animals. This may play a role in the hyperresponsiveness of immaturity.     

Role of the Fas/FasL system in a model of RSV infection in mechanically ventilated mice

Infection with respiratory syncytial virus (RSV) in children can progress to respiratory distress and acute lung injury necessitating mechanical ventilation (MV). MV enhances apoptosis and inflammation in mice infected with pneumonia virus of mice (PVM), a mouse pneumovirus that has been used as a model for severe RSV infection in mice. We hypothesized that the Fas/Fas ligand (FasL) system, a dual proapoptotic/proinflammatory system involved in other forms of lung injury, is required for enhanced lung injury in mechanically ventilated mice infected with PVM. C57BL/6 mice and Fas-deficient ("lpr") mice were inoculated intratracheally with PVM. Seven or eight days after PVM inoculation, the mice were subjected to 4 h of MV (tidal volume 10 ml/kg, fraction of inspired O(2) = 0.21, and positive end-expiratory pressure = 3 cm H(2)O). Seven days after PVM inoculation, exposure to MV resulted in less severe injury in lpr mice than in C57BL/6 mice, as evidenced by decreased numbers of polymorphonuclear neutrophils in the bronchoalveolar lavage (BAL), and lower concentrations of the proinflammatory chemokines KC, macrophage inflammatory protein (MIP)-1α, and MIP-2 in the lungs. However, when PVM infection was allowed to progress one additional day, all of the lpr mice (7/7) died unexpectedly between 0.5 and 3.5 h after the onset of ventilation compared with three of the seven ventilated C57BL/6 mice. Parameters of lung injury were similar in nonventilated mice, as was the viral content in the lungs and other organs. Thus, the Fas/FasL system was partly required for the lung inflammatory response in ventilated mice infected with PVM, but attenuation of lung inflammation did not prevent subsequent mortality.     

Improvement of respiratory function by bosentan during endotoxic shock in the pig.

We evaluated the role of endothelin-1 (ET-1) and the involvement of nitric oxide in cardiovascular and respiratory dysfunction, during endotoxic shock, in 18 anaesthetised, mechanically ventilated pigs, divided into three groups. Group 1 was i.v. infused with LPS (20 microg/Kg/h for 240 min). Group 2 was pre-treated with bosentan, a dual inhibitor of ET-1 receptors, and at 180 min of endotoxic shock, L-NAME (N(G)-nitro-L-arginine methyl ester, 10 mg/Kg), a non-selective inhibitor of NO synthases, was i.v. administered. Group 3 was infused with LPS and L-NAME was administered similarly to group 2. Results show that LPS caused systemic hypotension, pulmonary biphasic hypertension, decrease in compliance (C(rs)) and increase in resistance (R(max,rs)) of respiratory system. Bosentan completely abolished the pulmonary hypertension and the changes in C(rs)and R(max,rs). L-NAME does not affect the LPS-dependent changes in respiratory mechanics, but it worsens the cardiovascular effects, causing death of pigs. Pre-treatment with bosentan prevents this deleterious effect.Our study demonstrates that the LPS-dependent respiratory effects are mediated by ET-1, which, probably causing pulmonary oedema, is responsible for the decrease in C(rs)and the increase of R(max,rs).     

Tracking of airway and tissue mechanics during TLC maneuvers in mice.

A tracking impedance estimation technique was developed to follow the changes in total respiratory impedance (Zrs) during slow total lung capacity maneuvers in six anesthetized and mechanically ventilated BALB/c mice. Zrs was measured with the wave-tube technique and pseudorandom forced oscillations at nine frequencies between 4 and 38 Hz during inflation from a transrespiratory pressure of 0-20 cmH2O and subsequent deflation, each lasting for approximately 20 s. Zrs was averaged for 0.125 s and fitted by a model featuring airway resistance (Raw) and inertance, and tissue damping and elastance (H). Lower airway conductance (Glaw) was linearly related to volume above functional residual capacity (V) between 0 and 75-95% maximum V, with a mean slope of dGlaw/dV = 13.6 +/- 4.6 cmH2O-1. s-1. The interdependence of Raw and H was characterized by two distinct and closely linear relationships for the low- and high-volume regions, separated at approximately 40% maximum V. Comparison of Raw with the highest-frequency resistance of the total respiratory system revealed a marked volume-dependent contribution of tissue resistance to total respiratory system resistance, resulting in the overestimation of Raw by 19 +/- 8 and 163 +/- 40% at functional residual capacity and total lung capacity, respectively, whereas the lowest frequency reactance was proportional to H; these findings indicate that single-frequency resistance values may become inappropriate as surrogates of Raw when tissue impedance is changing.     

Effects of longitudinal laparotomy on respiratory system, lung, and chest wall mechanics.

In six sedated, anesthetized, paralyzed, and mechanically ventilated guinea pigs, total respiratory system (RT,rs), lung, and chest wall resistances and respiratory system (Est,rs), lung, and chest wall (Est,w) elastances were determined before and after longitudinal laparotomy. Furthermore the resistances were also split into their initial and difference components, with the former reflecting the Newtonian resistances and the latter representing the viscoelastic/inhomogeneous pressure dissipations in the system. For such purpose the end-inflation occlusion during constant inspiratory flow method was used. During laparotomy, a statistically significant increase in respiratory system difference resistance (from 0.086 to 0.101 cmH2O.ml-1.s) significantly augmented RT,rs (from 0.157 to 0.167 cmH2O.ml-1.s). The former was entirely secondary to a significant increase in chest wall difference resistance (0.019 to 0.034 cmH2O.ml-1.s), which naturally raised chest wall total resistance (from 0.030 to 0.047 cmH2O.ml-1.s). Est,rs and Est,w also increased (14.7 and 13.1%, respectively) after abdominal incision. It can be concluded that the midline xiphipubic laparotomy accompanied by the bilateral ventrodorsal infracostal incision increases RT,rs as a consequence of augmented chest wall difference resistance and Est,rs as a result of higher Est,w.     

Respiratory system responsiveness in rabbits in vivo is reduced by prolonged continuous positive airway pressure.

Active, nonanesthetized, tracheotomized rabbits were subjected to continuous positive airway pressure (CPAP) for 4 days to determine the effects of chronic mechanical strain on lung and airway function. Rabbits were maintained for 4 days at a CPAP of 6 cmH(2)O (high CPAP), at a CPAP of 0 cmH(2)O (low CPAP), or without tracheostomy (no CPAP). After treatment with CPAP, changes in respiratory resistance in response to increasing concentrations of inhaled ACh were measured during mechanical ventilation to evaluate respiratory system responsiveness in vivo. Intraparenchymal bronchial segments were isolated from the lungs of all animals to evaluate airway smooth muscle responsiveness and bronchial compliance in vitro. Rabbits maintained for 4 days at high CPAP demonstrated significantly lower responsiveness to ACh compared with rabbits that were maintained at low CPAP or with no CPAP. Airways isolated from the lungs of animals subjected to the chronic application of high CPAP were also less responsive to ACh in vitro than the airways isolated from animals subjected to low CPAP or no CPAP. The persistence of the decreased responsiveness in the excised airway tissues suggests that the decreased respiratory system responsiveness observed in vivo results primarily from direct effects on the airways. The results demonstrate that the application of prolonged mechanical strain in vivo can reduce airway reactivity.     

Heliox Allows for Lower Minute Volume Ventilation in an Animal Model of Ventilator-Induced Lung Injury

Background

Helium is a noble gas with a low density, allowing for lower driving pressures and increased carbon dioxide (CO₂) diffusion. Since application of protective ventilation can be limited by the development of hypoxemia or acidosis, we hypothesized that therefore heliox facilitates ventilation in an animal model of ventilator–induced lung injury.

Methods

Sprague-Dawley rats (N=8 per group) were mechanically ventilated with heliox (50% oxygen; 50% helium). Controls received a standard gas mixture (50% oxygen; 50% air). VILI was induced by application of tidal volumes of 15 mL kg^-1; lung protective ventilated animals were ventilated with 6 mL kg^-1. Respiratory parameters were monitored with a pneumotach system. Respiratory rate was adjusted to maintain arterial pCO₂ within 4.5-5.5 kPa, according to hourly drawn arterial blood gases. After 4 hours, bronchoalveolar lavage fluid (BALF) was obtained. Data are mean (SD).

Results

VILI resulted in an increase in BALF protein compared to low tidal ventilation (629 (324) vs. 290 (181) μg mL^-1; p<0.05) and IL-6 levels (640 (8.7) vs. 206 (8.7) pg mL^-1; p<0.05), whereas cell counts did not differ between groups after this short course of mechanical ventilation. Ventilation with heliox resulted in a decrease in mean respiratory minute volume ventilation compared to control (123±0.6 vs. 146±8.9 mL min^-1, P<0.001), due to a decrease in respiratory rate (22 (0.4) vs. 25 (2.1) breaths per minute; p<0.05), while pCO₂ levels and tidal volumes remained unchanged, according to protocol. There was no effect of heliox on inspiratory pressure, while compliance was reduced. In this mild lung injury model, heliox did not exert anti-inflammatory effects.

Conclusions

Heliox allowed for a reduction in respiratory rate and respiratory minute volume during VILI, while maintaining normal acid-base balance. Use of heliox may be a useful approach when protective tidal volume ventilation is limited by the development of severe acidosis.     

Role of anti-L-selectin antibody in burn and smoke inhalation injury in sheep

We hypothesized that the antibody neutralization of L-selectin would decrease the pulmonary abnormalities characteristic of burn and smoke inhalation injury. Three groups of sheep (n = 18) were prepared and randomized: the LAM-(1-3) group (n = 6) was injected intravenously with 1 mg/kg of leukocyte adhesion molecule (LAM)-(1-3) (mouse monoclonal antibody against L-selectin) 1 h after the injury, the control group (n = 6) was not injured or treated, and the nontreatment group (n = 6) was injured but not treated. All animals were mechanically ventilated during the 48-h experimental period. The ratio of arterial PO2 to inspired O2 fraction decreased in the LAM-(1-3) and nontreatment groups. Lung lymph flow and pulmonary microvascular permeability were elevated after injury. This elevation was significantly reduced when LAM-(1-3) was administered 1 h after injury. Nitrate/nitrite (NO(x)) amounts in plasma and lung lymph increased significantly after the combined injury. These changes were attenuated by posttreatment with LAM-(1-3). These results suggest that the changes in pulmonary transvascular fluid flux result from injury of lung endothelium by polymorphonuclear leukocytes. In conclusion, posttreatment with the antibody for L-selectin improved lung lymph flow and permeability index. L-selectin appears to be principally involved in the increased pulmonary transvascular fluid flux observed with burn/smoke insult. L-selectin may be a useful target in the treatment of acute lung injury after burn and smoke inhalation.     

Mechanical ventilation and volutrauma: study in vivo of a healthy pig model

Mechanical ventilation is essential in intensive care units. However, it may itself induce lung injury. Current studies are based on rodents, using exceptionally large tidal volumes for very short periods, often after a "priming" pulmonary insult. Our study deepens a clinically relevant large animal model, closely resembling human physiology and the ventilator setting used in clinic settings. Our aim was to evaluate the pathophysiological mechanisms involved in alveolo/capillary barrier damage due to mechanical stress in healthy subjects. We randomly divided 18 pigs (sedated with medetomidine/tiletamine-zolazepam and anesthetised with thiopental sodium) into three groups (n=6): two were mechanically ventilated (tidal volume of 8 or 20 ml/kg), the third breathed spontaneously for 4 hours, then animals were sacrificed (thiopental overdose). We analyzed every 30' hemogasanalysis and the main circulatory and respiratory parameters. Matrix gelatinase expression was evaluated on bronchoalveolar lavage fluid after surgery and before euthanasia. On autoptic samples we performed zymographic analysis of lung, kidney and liver tissues and histological examination of lung. Results evidenced that high Vt evoked profound alterations of lung mechanics and structure, although low Vt strategy was not devoid of side effects, too. Unexpectedly, also animals that were spontaneously breathing showed a worsening of the respiratory functions.     

Source of ethane in expirate of rats ventilated with 100% oxygen

Ethane in alveolar expirate may have its source in organs other than the lung and be transported to the lung for elimination. We determined ethane production rates in rats (group I) ventilated with hydrocarbon-free air (HFA) before and after exsanguination. To determine whether the lung is the source of increased ethane production during exposure to 100% O2, we measured ethane in the expirate of nine exsanguinated, Sprague-Dawley rats (group II) mechanically ventilated with HFA and then with 100% O2. In all nine animals, ethane elimination rates on 100% O2 increased compared with HFA values. In five of the nine rats, HFA ventilation was reinstated after O2 (group III). In all five, ethane elimination fell with HFA ventilation compared with the value on 100%. Six rats with circulation intact were ventilated with HFA and then 100% O2 (group IV). Ethane production rate for group IV animals breathing HFA was not significantly different from the exsanguinated animals in group II while ventilated with HFA. The mean increase in ethane production for the group II animals was not significantly different from the group IV animals. Lung slices from four other rats (group V) were incubated in saline at 37 degrees C with FeCl2 (10 mg) added to enhance free radical formation. Paired lung samples from the same rat were incubated with either HFA or 100% O2. Headspace gas was analyzed chromatographically for ethane at 120 min. Mean ethane in the O2 samples was higher than for HFA. Rat lung tissue is the main source of increased ethane production during 100% O2 exposure.     

Tidal volume amplitude affects the degree of induced bronchoconstriction in dogs.

When isolated constricted airway smooth muscle is oscillated, muscle tone decreases. We investigated whether changing tidal volume (VT) would affect induced bronchoconstriction in an in vivo canine model. Open-chest dogs were intubated with a double-lumen endotracheal tube, which isolated each main bronchus, and mechanically ventilated with a dual-cylinder ventilator. Bronchial pressure (Pbr) and flow were measured separately in each lung. Resistance and elastance were calculated by fitting the changes in Pbr, flow, and volume to the equation of motion. After baseline measurements at the same VT (150 ml), the two lungs were ventilated with different VT (50 vs. 250 ml) at a constant positive end-expiratory pressure. A continuous infusion of methacholine was begun, and measurements were repeated. The two lungs were then ventilated with the same VT (250 ml), and measurements were again repeated. A similar protocol was performed in a second group of dogs in which mean Pbr was kept constant. Bronchoconstriction was more severe in the lung ventilated with lower VT in both protocols. When VT was reset to the same amplitude in the two lungs, the difference in bronchoconstriction was abrogated. These results demonstrate that large VT inhibits airway smooth muscle contraction, regardless of mean Pbr.     

Neurokinins and inflammatory cell iNOS expression in guinea pigs with chronic allergic airway inflammation

In the present study we evaluated the role of neurokinins in the modulation of inducible nitric oxide synthase (iNOS) inflammatory cell expression in guinea pigs with chronic allergic airway inflammation. In addition, we studied the acute effects of nitric oxide inhibition on this response. Animals were anesthetized and pretreated with capsaicin (50 mg/kg sc) or vehicle 10 days before receiving aerosolized ovalbumin or normal saline twice weekly for 4 wk. Animals were then anesthetized, mechanically ventilated, given normal saline or N(G)-nitro-l-arginine methyl ester (l-NAME, 50 mg/kg ic), and challenged with ovalbumin. Prechallenge exhaled NO increased in ovalbumin-exposed guinea pigs (P < 0.05 compared with controls), and capsaicin reduced this response (P < 0.001). Compared with animals inhaled with normal saline, ovalbumin-exposed animals presented increases in respiratory system resistance and elastance and numbers of total mononuclear cells and eosinophils, including those expressing iNOS (P < 0.001). Capsaicin reduced all these responses (P < 0.05) except for iNOS expression in eosinophils. Treatment with l-NAME increased postantigen challenge elastance and restored both resistance and elastance previously attenuated by capsaicin treatment. Isolated l-NAME administration also reduced total eosinophils and mononuclear cells, as well as those cells expressing iNOS (P < 0.05 compared with ovalbumin alone). Because l-NAME treatment restored lung mechanical alterations previously attenuated by capsaicin, NO and neurokinins may interact in controlling airway tone. In this experimental model, NO and neurokinins modulate eosinophil and lymphocyte infiltration in the airways.