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The key role of the respiratory neural center is respiratory rhythm generation to maintain homeostasis through the control of arterial blood pCO2/pH and pO2 levels. The neuronal network responsible for respiratory rhythm generation in neonatal rat resides in the ventral side of the medulla and is composed of two groups; the parafacial respiratory group (pFRG) and the pre-Bötzinger complex group (preBötC). The pFRG partially overlaps in the retrotrapezoid nucleus (RTN), which was originally identified in adult cats and rats. Part of the pre-inspiratory (Pre-I) neurons in the RTN/pFRG serves as central chemoreceptor neurons and the CO2 sensitive Pre-I neurons express homeobox gene Phox2b. Phox2b encodes a transcription factor and is essential for the development of the sensory-motor visceral circuits. Mutations in human PHOX2B cause congenital hypoventilation syndrome, which is characterized by blunted ventilatory response to hypercapnia. Here we describe the generation of a novel transgenic (Tg) rat harboring fluorescently labeled Pre-I neurons in the RTN/pFRG. In addition, the Tg rat showed fluorescent signals in autonomic enteric neurons and carotid bodies. Because the Tg rat expresses inducible Cre recombinase in PHOX2B-positive cells during development, it is a potentially powerful tool for dissecting the entire picture of the respiratory neural network during development and for identifying the CO2/O2 sensor molecules in the adult central and peripheral nervous systems.
The goal of this study is to develop a controlled approach to quantifying the amount of lung damage after blunt chest trauma. The presented method is used to analyze computed tomography scans and to assess patients' risk for developing acute respiratory distress syndrome (ARDS). When used to predict which patients were at risk for ARDS, the method presented in this study had a sensitivity of 57% and a specificity of 100%.
Continuous air embolization (CAE) into the pulmonary arterial circulation of sheep results in functional and structural changes of chronic pulmonary hypertension. Release of elastin peptides into lung lymph during CAE and attenuation of CAE-induced pulmonary hypertension by neutrophil depletion suggest that neutrophil elastase may contribute to these changes. To investigate this notion, we treated awake sheep with a potent neutrophil elastase inhibitor, recombinant secretory leukoprotease inhibitor (SLPI) (100 mg/day by aerosol), during 12 days of CAE (CAE+SLPI; n = 7). Controls included sheep receiving CAE + vehicle (VEH) (n = 6), VEH alone (n = 3), and SLPI alone (n = 3). SLPI significantly attenuated the CAE-induced increases in lung lymph flow (day 8; 2.3 +/- 0.5 vs. 5.6 +/- 1.7 ml/15 min), protein clearance (day 8; 1.36 +/- 0.32 vs. 3.08 +/- 0.84 ml/15 min), and elastin peptide concentration (day 8; 243 +/- 41 vs. 398 +/- 44 ng/ml). SLPI delayed the onset of sustained pulmonary hypertension from day 8 to day 12. Both CAE groups showed similar structural changes in the pulmonary arteries. SLPI was well tolerated in control sheep and did not affect hemodynamics or structure. We conclude that serine proteases may contribute to the early initiation of chronic pulmonary hypertension but do not play a striking role in its eventual development.
The acute respiratory distress syndrome (ARDS) is a disorder of diffuse lung injury secondary to a wide variety of clinical insults (eg, sepsis) and is manifested by impaired oxygenation, pulmonary edema, and decreased static and dynamic compliance. More recently, airflow resistance has been shown to be increased in humans with ARDS. We designed a prospective, randomized, placebo-controlled, crossover trial to determine the presence and reversibility of increased airflow resistance in ARDS. We studied eight mechanically ventilated patients with ARDS (criteria: PaO2 < or = 70 mm Hg with FIO2 < or = 0.4; diffuse bilateral infiltrates; and pulmonary artery wedge pressure < or = 18 mm Hg). Each was intubated with a No. 8.0 orotracheal tube. We measured dynamic compliance (Cdyn), static compliance (Cstat), airflow resistance across the lungs (RL), shunt fraction (Qs/Qt on FIO2 = 1.0), minute ventilation (VE), PaO2/PAO2, and dead space to tidal volume ratio (VD/VT). Patients were blindly assigned to receive either metaproterenol (1 mL 0.5% in 3 mL saline solution) or saline solution (4 mL) aerosolized over 15 min 6 h apart and in random order so that patients served as their own controls. Metaproterenol significantly reduced RL, peak and plateau airway pressure, and increased Cdyn. Metaproterenol tended to increase PaO2/PAO2, but had no effect on pulmonary shunt or dead space ventilation. We conclude that the increase in airflow resistance of ARDS is substantially reversed by aerosolized metaproterenol without affecting dead space. These data suggest that abnormalities of RL are at lest partially due to bronchospasm.
The medical criteria for inoperability have been difficult to define in patients with lung cancer. Sixty-six patients with non-small cell lung cancer and radiographically resectable lesions were evaluated prospectively in a clinical trial. The patients were considered by cardiac or pulmonary criteria to be high risk for pulmonary resection. If exercise testing revealed a peak oxygen uptake of 15 mL.kg-1.min-1 or greater, the patient was offered surgical treatment. Of the 20 procedures performed, nine were lobectomies, two were bilobectomies, and nine were wedge or segmental resections. All patients were extubated within 24 hours and discharged within 22 days after operation (median time to discharge, 8 days). There were no deaths, and complications occurred in 8 (40%) of the 20 patients. Five patients whose peak oxygen uptake was lower than 15 mL.kg-1.min-1 also underwent surgical intervention; there was one death. Thirty-four patients whose peak oxygen uptake was less than 15 mL.kg-1.min-1 and 7 who declined operation underwent radiation therapy alone (35 patients) or radiation therapy and chemotherapy (6 patients). There were no treatment-related deaths, and the morbidity rate was 12% (5/41). The median duration of survival was 48 +/- 4.3 months for the patients treated surgically and 17 +/- 2.7 months for those treated medically (p = 0.0014). We conclude that a subgroup of patients who would be considered to have inoperable disease by traditional medical criteria can be selected for operation on the basis of oxygen consumption exercise testing. There is a striking survival benefit to an aggressive surgical approach in these patients.
We designed a series of experiments to compare the pulmonary dysfunction observed in models of cardiogenic and noncardiogenic pulmonary edema in chronically instrumented awake sheep. Cardiogenic pulmonary edema was induced by inflating the balloon of a Foley catheter surgically positioned in the mitral valve orifice causing increased left atrial pressure (increases PLA). Noncardiogenic pulmonary edema was induced by intravenous infusion of Perilla ketone (PK). Calculated microvascular pressure remained constant during PK infusion but increased from 9.4 +/- 0.7 to 42.8 +/- 2.4 cm H2O during increases PLA. Comparable increases in lung lymph flow (QL) were observed in the two protocols (five to seven times baseline). Pulmonary edema as quantified by chest radiograph scores increased from 0 (normal) to 2.9 +/- 0.5 and 3.4 +/- 0.1 in the PK and increases PLA groups, respectively. Room air alveolar to arterial oxygen pressure difference (P[A-a]O2) increased from 24 +/- 3 to 46 +/- 7 mm Hg in the PK group and from 23 +/- 4 to 56 +/- 6 mm Hg in the increases PLA group. Dynamic compliance of the lungs (Cdyn) expressed as the percentage of the baseline value decreased to 53 +/- 7 and 50 +/- 7% in the PK and increases PLA groups, respectively. Resistance to airflow across the lungs (RL) increased from 2.5 +/- 0.6 to 3.3 +/- 0.8 cm H2O.L-1.sec-1 in the PK group and from 1.4 +/- 0.3 to 4.2 +/- 1.1 in the increases PLA group. Significant correlations were observed between changes in the severity of pulmonary edema observed on chest radiographs, Cdyn, delta P(A-a)O2, and QL in both the increases PLA groups. We conclude that similar degrees of pulmonary edema, regardless of the mechanism, are associated with similar changes in QL, Cdyn, and delta P(A-a)O2. Hydrostatic pulmonary edema appeared to cause greater changes in RL than that resulting from increased microvascular permeability.
A theoretical model of high-frequency ventilation (HFV) is presented based on the physical convective exchange process that occurs due to the irreversibility of gas velocity profiles in oscillatory flow through the bronchial airways. Mass transport during the convective exchange process can be characterized by a convective exchange length, LE, which depends only on the irreversibility of bronchial velocity profiles and can be measured by the experimental technique of photographic flow visualization in bronchial tree models. Using the exchange length and the molecular diffusivity, a simple model of overall bronchial mass transfer is developed. The model allows a prediction of the mean gas concentration profiles along the airways, the site of maximum mass transfer resistance, and overall flow rate of the gas of interest in or out of the lung as functions of the parameters of HFV. The results predicted by the model agree with the limited experimental data available for animals and humans. For normal unassisted ventilation, total bronchial cross-sectional area around the 15th Weibel bronchial generation is predicted to be the single most important parameter in controlling the total gas transport rate along the airways. For the breathing of room air, values of the respiratory quotient around 0.78 are predicted, which are insensitive to VT and f. The model represents a fruitful combination of fluid mechanical theory and experiment with physiologic data to yield new and deeper insight into the operation of the human respiratory system during HFV and normal breathing.
We examined the effects of intravenous sodium nitroprusside (NP) infusion on pulmonary arterial pressure (Ppa), pulmonary vascular resistance (PVR), dynamic compliance (Cdyn), resistance to airflow across the lungs (RL), and alveolar-arterial O2 pressure gradient (PAO2-PaO2) (room air) after endotoxemia in awake sheep. NP infused 2.5 h after endotoxin administration immediately reduced mean Ppa from 30 +/- 3 to 17 +/- 3 (SE) cmH2O, PVR from 6.3 +/- 0.7 to 4.8 +/- 0.5 cmH2O.l-1.min, and RL from 340 +/- 48 of base line to 205 +/- 73% and increased Cdyn from 54 +/- 5 of base line to 80 +/- 14% without affecting PAO2--PaO2. Ppa and lung mechanics returned immediately to preinfusion levels when NP was stopped. In vitro experiments with NP showed a dose-dependent relaxation of preconstricted pulmonary artery and vein, carbachol-preconstricted sheep tracheal strips, and bronchial rings. We conclude that NP reverses pulmonary hypertension and lung mechanics abnormalities after endotoxin and that this is due to effects of NP on airway and vascular smooth muscle. The return of these abnormalities after NP cessation suggests the continued presence of vascular and airway-constricting factors late after endotoxin. The lack of effect of NP on blood oxygenation suggests that deleterious effects on hypoxic vasoconstriction are offset by improved lung mechanics.
The mechanism of sustained alterations in pulmonary hemodynamics and lung mechanics after endotoxin infusion in sheep remains unclear. We examined the effects of metaproterenol, propranolol, atropine, and ibuprofen on pulmonary artery pressure (Ppa), dynamic compliance (Cdyn), resistance to airflow across the lungs (RL), specific airway conductance (SGaw), and alveolar-arterial oxygen difference (delta AaPO2) (room air) given 2.5 h after endotoxemia (except for propranolol, which was given 1 h after metaproterenol) in awake sheep. Atropine infusion had no effect on any of the variables measured. Ibuprofen infusion immediately reduced mean Ppa from 31 +/- 2 (mean +/- SEM) to 24 +/- 2 cm H2O (p less than 0.05). Metaproterenol and ibuprofen immediately increased Cdyn and SGaw and decreased RL to near baseline (p less than 0.05). No intervention affected delta AaPO2 (p greater than 0.05). In sheep treated with metaproterenol, propranolol immediately returned lung mechanics (p less than 0.05) to premetaproterenol levels without affecting delta AaPO2 (p greater than 0.05). Ibuprofen reduced lung lymph thromboxane-B2 towards baseline levels (p less than 0.05). We conclude that endotoxemia causes prolonged bronchoconstriction and pulmonary hypertension in sheep, which is largely mediated by constrictor prostanoids rather than by cholinergic mechanisms and is reversible with ibuprofen given 2.5 h after endotoxin.
Although reduced lung compliance is a hallmark of the adult respiratory distress syndrome (ARDS), the role of increased airflow resistance in this disorder has not been well studied. Because animal models of ARDS show marked increases in airflow resistance and because mediators known to participate in lung parenchymal injury have also been implicated in models of increased airway reactivity, we hypothesized that increased airflow resistance is a major contributor to altered lung mechanics in human ARDS. We studied 10 mechanically ventilated patients with ARDS (criteria: PaO2 less than or equal to 70 mm Hg breathing FIO2 greater than or equal to 0.4; bilateral pulmonary roentgenographic infiltrates; Ppaw less than or equal to 18 mm Hg) measuring dynamic (Cdyn) and static (Cstat) compliance, airflow resistance across the lungs (RL), shunt fraction (QS/QT breathing FIO2 = 1.0), minute ventilation (VE), (a/A)PO2, dead space to tidal volume ratio (VD/VT), airflow (pneumotachograph), transpulmonary pressure (intratracheal pressure minus esophageal pressure) and volume (integrated from flow) at 50 L/min peak flow rate. Airflow resistance was uniformly elevated and averaged six times normal (5.32 +/- 0.92 cm H2O/L/s versus 0.88 +/- 0.08) (p less than 0.05). Cdyn correlated directly with (a/A)PO2. RL correlated with peak pressure, but did not correlate with VE, shunt, (a/A)PO2, or VD/VT. We conclude that increased pulmonary airflow resistance contributes significantly to the altered lung mechanics in ARDS. These data are consistent with studies of animal models of ARDS and long-term survivors of ARDS and may be secondary to tissue factors, airway hyperreactivity, or airway inflammation.