Tracheal Injection Research Articles

Keratinocyte growth factor increases surfactant pool sizes in premature rabbits.

Keratinocyte growth factor (KGF) is a recently described 19-kD glycoprotein that is a mitogen for epithelial-derived tissue and is expressed during embryonic tissue differentiation. We investigated whether human recombinant KGF (rKGF) could increase alveolar and lung-tissue saturated phosphatidyl-choline (Sat PC) in preterm rabbits delivered at 28.5 d gestation. Preterm rabbits were given 1, 5, or 10 mg/kg rKGF by tracheal injection at 30 min of age. Lung tissue and total lung (alveolar plus lung tissue) Sat PC increased by 48 h (5 and 10 mg/kg) (p < 0.01) and 72 h (1 and 10 mg/kg) (p < 0.05). A single intravascular or intramuscular dose of 10 mg/kg rKGF also increased long tissue and total-lung Sat PC by 48 h (p < 0.01). A single dose of rKGF given shortly after birth to preterm rabbits increased lung Sat PC in the preterm rabbits.

Substance P-induced histamine release in tracheally perfused guinea pig lungs.

The capacity of substance P (SP) and endogenously released tachykinins to liberate histamine was examined in isolated tracheally perfused guinea pig lungs. Increasing doses of tracheally injected SP were associated with the recovery of increasing amounts of histamine from lung effluent. The mechanism of SP-induced histamine liberation was explored in studies with neurokinin-(NK) receptor agonists and antagonists. Tracheal injection of either the NK1 agonist [Sar9,Met(O2)11]SP or the NK2 agonist [beta-Ala8]-neurokinin A-(4-10) was associated with a significant increase in histamine recovery from lung effluent. In addition, both the NK1 antagonist CP-99994 and the NK2 antagonist SR-48968 significantly inhibited SP-induced histamine release. These findings support the hypothesis that SP can liberate histamine from guinea pigs lungs by a mechanism that depends predominantly on NK1- and NK2-receptor activation. The liberation of endogenous tachykinins by acute tracheal injection of capsaicin was also associated with augmented histamine recovery, which was inhibited by combined NK1- and NK2-receptor blockade. Tracheal injection of SP was associated with an increase in the percentage of airway mast cells exhibiting histological evidence of degranulation. This study demonstrates that exogenous SP, as well as endogenous tachykinins released from capsaicin-sensitive neurons, can liberate histamine, most likely from airway mast cells, by a mechanism that depends predominantly on the activation of NK1 and NK2 receptors.

Tracheal mucociliary transport rate in awake dogs

Summary To measure tracheal mucociliary transport rate (tmtr) in awake dogs, restrained in dorsal recumbency 99mtechnetium-labeled macroaggregated albumin was administered by tracheal injection, and the cephalic movement of boluses containing the radiopharmaceutical was detected by a gamma camera positioned lateral to the dog's head and neck. The distance traveled by each bolus was measured, relative to external markers placed a known distance apart. Tracheal mucociliary transport rates were calculated by dividing the measured distance of radiopharmaceutical movement by elapsed time. The technique was efficient and well tolerated. Mean (± sd) tmtr was 35.3 ± 15.9 mm/min. Significant (P = 0.029) difference in tmtr was found between males and females, but significant difference attributable to age of the dog was not detected. This method of measuring tmtr in awake dogs has potential for evaluation of clinical animal patients with suspected tracheal mucociliary abnormalities.

PRESSURE SUPPORT VENTILATION USING A NEW TRACHEAL GAS INJECTION TUBE

In order to explore new types of jet ventilation, we tested a tracheal gas injection tube (TGIT) which included six thin capillaries and provided high pressure injection. The driving pressure was chosen to yield a plateau of inspiratory tracheal pressure of 10 cm H2O. An original controller was built to monitor spirometry and trigger injection in order to deliver both pressure controlled ventilation (PCVTGIT) and a new mode of inspiratory pressure support jet ventilation (IPSTGIT). The PVCTGIT mode maintained the same end-tidal carbon dioxide concentration as conventional ventilation with the same tidal and minute ventilation. We studied 10 patients after abdominal surgery. During spontaneous breathing, the patients were allowed to breathe through the tube, successively with and without IPSTGIT. IPSTGIT, compared with spontaneous breathing increased minute ventilation (from 5.7 (SD 1.6) to 7.1 (1.7) litre min-1) (P less than 0.001). It reduced the total work of breathing (from 0.625 (0.223) to 0.263 (0.151) J litre-1, respectively) (P less than 0.01) and the occlusion pressure (from 2.62 (1.28) to 1.36 (0.74) cm H2O, respectively) (P less than 0.01). It is concluded that this TGIT used with a specific system for sensing and triggering ventilation allows inspiratory pressure support during low frequency jet ventilation.

Capsaicin-induced release of tachykinins: effects of enzyme inhibitors

We studied the effects of neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE) inhibition on the airway responses and the recovery of endogenously released substance P- and neurokinin A-like immunoreactivities (SP-LI and NKA-LI) after tracheal injection of capsaicin in isolated guinea pig lungs superfused through the trachea. Capsaicin in doses from 10(-10) to 10(-7) mol induced a dose-dependent increase in airway opening pressure and release of SP-LI and NKA-LI. Airway opening pressure changes and the recovery of SP-LI and NKA-LI were significantly greater in lungs superfused with the NEP inhibitor SCH 32615 than in control lungs. ACE inhibition with captopril did not increase the mechanical response or the recovery of SP-LI compared with lungs not receiving captopril. In lungs from guinea pigs pretreated with high doses of capsaicin 7-10 days before study, a regimen designed to deplete endogenous tachykinins, there was a significant decrease in the content and release of NKA-LI and SP-LI. There were no detectable airway effects of acute capsaicin infusion even after doses of 10(-5) mol. Because NEP is important in modulating the airway effects of endogenously released tachykinins after tracheal infusion of capsaicin, but ACE is not, it seems likely that tracheal administration of capsaicin releases tachykinins from epithelial rather than endothelial loci.

Release of ANP and its physiological role in pulmonary injury due to HCl

The effect of pulmonary injury induced by aspiration of HCl on plasma atrial natriuretic polypeptide (ANP) level was examined in rats given a constant infusion of water and electrolytes. In addition, using specific antiserum against ANP, we investigated the physiological role of ANP in rats after HCl aspiration. Rats were housed individually in metabolic cages and were given a constant infusion of sodium solution via catheters chronically inserted into the jugular vein. Plasma ANP levels were elevated at 3 and 24 h after tracheal injection of 0.2 ml of 0.1 N HCl via the cricothyroid membrane. Urine volume and urinary sodium excretion increased during the first 24 h after acid aspiration. However, this increase was reduced by the injection of anti-ANP serum. Furthermore, the injection of anti-ANP serum resulted in a significant (P less than 0.05) increase in wet lung weight from a value of 0.74 +/- 0.06 (HCl aspiration with normal rabbit serum injection) to 0.83 +/- 0.07% of body weight. These results indicate that ANP plays a physiological role in the regulation of urinary water and sodium excretion after pulmonary acid injury and suggest that ANP elevated in plasma after pulmonary injury may prevent pulmonary edema with its diuretic action and/or some direct action on water movement in the lung.

Cumulative Effects of Repeated Surfactant Treatments in the Rabbit

The responses of the adult rabbit lung to multiple doses of surfactant after intratracheal injections of either natural calf surfactant or Surfactant-TA were evaluated. For each surfactant, four groups of 1.4-kg rabbits were studied: group 1 received 100 mg of surfactant containing isotopically-labeled dipalmitoylphosphatidylcholine; group 2 received the same labeled surfactant and then three tracheal injections of vehicle; group 3 received labeled surfactant and then three doses (100 mg) of unlabeled surfactant; group 4 was treated in the same way as group 3 except that the final dose was of the labeled surfactant. All rabbits were killed, and alveolar washes were recovered 24 h after the labeled surfactant dose had been given. The amount of labeled palmitate-saturated phosphatidylcholine (Sat PC) in alveolar washes did not change after multiple doses of calf surfactant, indicating that subsequent doses did not alter the clearance of previous doses. The four doses of calf surfactant increased the alveolar Sat PC pool size by a factor of 2.5 only when measured 6 h after the last dose, but the total lung Sat PC pool size doubled, indicating a loss of most of the surfactant Sat PC to the lung tissue. In contrast, Surfactant-TA increased the alveolar pool size by a factor of 4 after the single dose and by a factor of 11 after the multiple doses, and the percentage clearance of labeled Sat PC from the lungs decreased with multiple doses, indicating an effect of subsequent doses on the initial dose. The quantity of Sat PC cleared from the lungs increased by about a factor of 2 after the multiple doses of Surfactant-TA. Although repetitive surfactant doses changed alveolar and lung Sat PC pool sizes the quantity of Sat PC cleared from the lungs increased, and the lungs accommodated the large amount of surfactant without short-term adverse effects.

INCREASE IN TRACHEAL PRESSURE DURING JET VENTILATION

Gas injection systems used in several techniques of ventilation cause increases in airway pressure and physiological changes which are frequently overlooked. The momentum flux theory describes such phenomena most appropriately. We have defined and measured the characteristics of such increases in airway pressure, using a lateral tracheal injection system which has been described previously. In such a system, wall friction is a major source of loss in jet momentum flux, in contrast with the changes in axis-symmetrical systems. This process results in a potentially beneficial increase in airway pressure and in greater mixing, which might be clinically useful.

Clearance of surfactant phosphatidylcholine via the upper airways in rabbits.

A possible route of clearance of surfactant phosphatidylcholine from the lungs is via the airways. To quantify surfactant loss via this pathway, latex bags were surgically placed into the abdomens of adult rabbits such that secretions cleared via the esophagus could be collected. The rabbits then were given treatment or trace doses of radiolabeled phosphatidylcholine-surfactant by tracheal injection and/or intravascular radiolabeled precursors of phosphatidylcholine. Labeled saturated phosphatidylcholine was measured in all fluids that were collected from the bags at 2-h intervals for 24 h and in alveolar washes and lung tissues at 24 h. No more than 7% of either treatment or trace doses of intratracheal surfactant-saturated phosphatidylcholine was lost via clearance up the airways over 24 h. Clearances of endogenously synthesized and secreted saturated phosphatidylcholine were estimated to be no more than 3% of the flux of labeled saturated phosphatidylcholine through the alveolar pool. These experiments demonstrate that surfactant phosphatidylcholine clearance via movement up the airways is not a major pathway leading to surfactant catabolism.

Lysophosphatidylcholine uptake and metabolism in the adult rabbit lung

Tracer quantities of 3H-labeled lysoPC and 32P-labeled natural rabbit surfactant were given intratracheally via a bronchoscope and [ 14C]palmitate was given intravenously to 25 rabbits with labeled PC and lysoPC measured in the alveolar wash, lung homogenate, lamellar bodies and microsomes at five times from 10 min to 6 h after tracheal injection. Surprisingly, only 31% of the administered lysoPC remained in its original form in the total lungs (alveolar wash + lung homogenate) by 10 min, of which 77% was in the alveolar wash. Meanwhile, by 10 min an additional 37% was already converted to PC, of which more than 98% was in the lung homogenate. LysoPC continued to be rapidly and efficiently converted to PC, with 62% conversion measured at 3 h. The converted lysoPC initially appeared with high specific activity in microsomes, then in lamellar bodies, and finally in the alveolar wash. The intravascular palmitate labeled lung PC had similar specific activity-time profiles in the subcellular fractions, while intratracheally administered natural rabbit surfactant had a constantly low specific activity in microsomes and much higher specific activities in lamellar bodies and alveolar wash. Another 25 rabbits received intratracheal lysoPC labeled in both the choline and palmitate moieties and then were studied from 1 to 24 h after tracheal injection. The ratio of the palmitate to choline labels indicated uptake and conversion to PC primarily by direct acylation rather than transacylation and by intact reuptake and conversion rather than breakdown and resynthesis. LysoPC is an attractive ‘metabolic probe’ of surfactant metabolism which undergoes very rapid and efficient intracellular conversion to PC via a subcellular pathway that parallels the remodeling and de novo synthetic pathways.

Clearance of surfactant phosphatidylcholine from adult rabbit lungs.

Rabbits were given various doses of rabbit surfactant and treatment doses of approximately 100 mg/kg body wt of calf surfactant and Surfactant TA by tracheal injection. The linear loss of radiolabeled phosphatidylcholine from the total lung (alveolar wash and lung tissue) was 3.1, 1.5, and 1.8%/h for rabbit surfactant, calf surfactant, and Surfactant TA, respectively. After 24 h only 6% rabbit, 19% calf, and 9.7% Surfactant TA phosphatidylcholine were recovered by alveolar wash, and alveolar macrophage fractions contained less than 1% of the injected labeled phosphatidylcholine. The loss of rabbit surfactant phosphatidylcholine 24 h after tracheal injection did not change for doses in the range of 0.5-70 mumol phosphatidylcholine per kilogram, indicating nonsaturable clearance pathways. Very little of the labeled rabbit surfactant phosphatidylcholine lost from the lungs could be recovered in other organs, and 90% of the recovered labeled phosphatidylcholine in the liver was unsaturated, implying de novo synthesis using precursors from degraded phosphatidylcholine. The surfactant did not change endogenous lung phosphatidylcholine synthesis or its secretion to the alveolus. There were no adverse effects of the surfactant treatments noted in healthy rabbits.

Maternal Treatments with Corticosteroids and/or T&lt;sub&gt;3&lt;/sub&gt; Change Lung Volumes and Rupture Pressures in Preterm Rabbits

Pregnant does were treated with betamethasone, T3, the combination of beta-methasone and T3 or vehicle control on days 24 and 25 of gestation. At 26 days gestational age, pressure-volume curves and lung rupture pressures and volumes were measured in the various groups of rabbits randomized to receive saline or surfactant by tracheal injection. Alveolar wash and lung tissue quantities of saturated phosphatidylcholine were comparable across the hormone-treated and control groups. Corticosteroids increased maximal lung volumes more than did T3. Corticosteroids augmented the lung volumes of surfactant-treated lungs more than did T3, and no additive effects on lungs treated with both hormones and surfactant were noted. Both corticosteroids and surfactant decreased lung rupture pressures from 51.7 +/- 4.1 to about 44 cm H2O. T3 decreased lung rupture pressure to 48.9 +/- 3.9 cm H2O and the combination of T3 and corticosteroids resulted in rupture pressures comparable to T3 alone. There were no additive effects of the combined use of T3 and corticosteroids and T3 antagonized the decreased lung rupture pressures caused by corticosteroids. While T3 did not alter the increase in lung volumes noted with corticosteroids, lung structure as assessed by lung rupture was differentially affected by the two hormones.

Characterization of tracheal mast cell reactions in vivo. Inhibition by a beta-adrenergic agonist.

In 12 anesthetized dogs, we tested the effects of pharmacologic beta-adrenergic stimulation on the severity of tracheal mast cell reactions in vivo (Am Rev Respir Dis 1979; 119:62). In control dogs, tracheal arterial injections of compound 48/80 produced arteriovenous differences in histamine concentrations across the trachea (35 +/- 15 ng/ml), but not the lung; this finding suggested selective degranulation of tracheal mast cells. Tracheal arteriovenous histamine differences correlated (r = 0.70) with tracheal contractions (12 +/- 4 g/cm) induced by compound 48/80 in these animals. In other dogs, injections of isoproterenol (10 micrograms/kg) before compound 48/80 prevented the development of both tracheal arteriovenous differences and contractions. We concluded that pharmacologic beta-adrenergic stimulation inhibited degranulation of tracheal mast cells. The preparation appears suitable for examining the effects of endogenous stimuli on the severity of mast cell reactions in the central airways of anesthetized dogs.

Oral progestagens and experimental pulmonary emphysema

Oral and subcutaneous dimethisterone progesterone and megestrol acetate prevented the bronchoconstrictive effects of nicotine cigarette smoke and lobeline in anesthetized male rats made experimentally emphysemic by tracheal ligation and intratracheal injection of phytohemagglutinin. Physiologic endpoints were pulmonary resistance tidal volume and functional residual capacity. Compared with 10.66 for sham operated controls rats with tracheal ligation had significantly increased functional residual capacity of 18.56 ml/kg. Progesterone 10 mg/kg dimethisterone 10 mg/kg and megestrol acetate .2 mg/kg in .5% methocel vehicle sc 3 times weekly for 4 weeks prevented this increase in functional residual capacity. Dimethisterone 50 mg/kg and megestrol acetate 1 mg/kg orally on the same schedule similarly prevented emphysema. Dimethisterone sc significantly lowered the increase in pulmonary resistance due to 5-10 puffs of cigarette smoke .1 mg/kg nicotine iv or 2 mg/kg lobeline iv. Megestrol acetate sc decreased bronchoconstriction due to nicotine only.

The effect of viscose rayon ribers on lung function in rats.

Experiments have been performed to determine the effect of viscose rayon fibers upon the pulmonary mechanics of a group of rats. Daily intratracheal injection of synthetic fiber suspension for 20 days produced an increase in index of alveolar pressure and a decrease in tidal volume, respiratory rate, and minute volume. In control animals there was no significant change in pulmonary function after intratracheal injection of normal saline. Comparison of the values after the first exposure of rayon fibers with those after intra tracheal injection of histamine did not show significant difference except in higher respiratory rate after histamine. In both exposed and control groups, infection was present when the animals were killed at the end of the experiment. The significant changes in lung function in control animals with approximately the same histological findings indicated that the changes in dust-exposed animals were mostly related to the rayon fibers.

Preliminary identification of the lung surfactant system.

Preliminary identification of the lung surfactant system.

Silica and Collagen in the Lungs of Silicotic Rats Treated with Cortisone

The inhibiting effect of cortisone on proliferating connective tissue (Ragan, Howes, Plotz, Meyer, and Blunt, 1949 ; Spain, Molomut, and Haber, 1950a ; Cavallero, Sala, Amira, and Borasi, 1951) and phagocytosis (Spain and others, 1950b) led us to observe the effect of this hormone on the developing silicotic nodule. Short-term studies on the effect of cortisone on the reaction of the mouse peritoneum to quartz showed a delay in macrophage response (Curran, 1952) and an inhibition of fibrosis (Magarey and Gough, 1952 ; Schiller, 1953). Over a longer period the effect of cortisone has been observed on the development of fibrosis in rats injected intratracheally with 50 mg. of quartz (Harrison, King, Dale, and Sichel, 1952). Cortisone treatment decreased the mobility of dust-laden phagocytes, and the marked alteration in the distri bution of dust throughout the lung modified the normal pattern of fibrosis. The fibrosis in the cortisone-treated animals was irregular, diffuse, and generally less. In this paper we report the analyses of lungs for silica and collagen, and hilar lymph glands for silica, from the above experiment on rats. The amount of collagen gave an indication of the amount of fibrosis ; generally there was less in the cortisone group. The partition of silica between lung and lymph node gave a rough measure of macrophage activity. These analytical results con firmed previous histological findings. This confirmation was not so marked when the same methods were applied to material from a later experiment in which King, Harrison, and Attygalle (1954) observed the effect of cortisone upon estab lished silicosis. One hundred days after an intra tracheal injection of quartz cortisone was given to a group of rats and the hormone treatment then continued regularly for 260 days. On histological examination the lungs of the cortisone-treated animals appeared similar to those of the controls, which had received quartz alone. The maximum grade of fibrosis was present in both groups 150 days after injection of the quartz, i.e., 50 days after the start of cortisone treatment, and this picture p rsisted till the end of the experiment. Chemical examination, however, showed differences between the two groups.

A STUDY OF THE EFFECT OF SENSITIZATION ON THE DEVELOPMENT OF THE LESIONS OF EXPERIMENTAL PNEUMONIA IN THE RABBIT

While preliminary treatment with culture filtrates or dead cells of the extremely virulent strain A gave rise to varying degrees of immunity, the exudative lung lesions developing after tracheal injection with live organisms of the same virulent strain were not strikingly increased in any group or series of these rabbits. Despite carefully graduated dosage in the preliminary treatment, none of the animals developed symptoms of a definitely anaphylactic nature. In similar experiments following sensitization with the attenuated avirulent culture AA, tracheal injection of virulent or avirulent organisms of the same strain failed to incite any definite increase in the exudative lung reaction. In none of the rabbits were symptoms resembling anaphylaxis noted. The immunity which was induced by the larger sensitizing doses of culture filtrates of the strain in the virulent state was lacking when similar doses of the culture filtrates of organisms in the non-virulent state were used. Extensive lesions developed in both sensitized and unsensitized rabbits when the strain used in the tracheal injection was one apparently combining moderate virulence with exceptional toxicity, indicating that the exudative lung reaction was one of adjustment rather than of acquired hypersusceptibility. When, in the experiments, small amounts of sera from normal rabbits, or from animals immunized to culture filtrates, were added to the culture before tracheal injection, an increased fibrinous lung reaction was frequently found. The present study would seem to give some ground for the view that while in pneumonia a hypersensitive condition probably takes some part in the inception of the infection, the subsequent development of the diffuse exudative reaction in the lung is not directly due to an acquired hypersusceptibility, but to intrinsic qualities possessed by the pneumococcus itself. This study was carried on in the Department of Bacteriology of the College of Physicians and Surgeons of Columbia University, New York, and later, through the courtesy of Dr. Charles Norris, in the Bellevue Hospital Laboratories. It was completed in the Laboratories of the New York State Department of Health at Albany. I am greatly indebted to Dr. Augustus Wadsworth for his advice and criticism.

The effect of sensitization on pneumococcus lesions of the lobar type in rabbits

For the purpose of ascertaining to what extent conditions of hypersusceptibility determine the character of pneumococcus lesions of the lung, series of experiments were made with a moderately virulent strain, and with an extremely virulent strain in its virulent state and after artificial attenuation. Rabbits were inoculated intravenously for purposes of sensitization with .1-15 c.c. pneumococcus filtrates or dead cells and then after two weeks injected tracheally with 1. c.c. live cultures. The animals surviving 48 hours were killed. Microscopic sections were made of all lungs.In these experiments with attempted active sensitization none of the animals developed symptoms resembling anaphylactic shock nor was the lung involvement definitely increased in any series of previously treated rabbits. Tracheal injection of the moderately virulent organisms, however, caused marked lesions in both sensitized and unsensitized control rabbits.In experiments with attempted passive sensitization, mixtures of 1 c.c. vi...

TRACHEAL INJECTIONS as a WAY of ADMINISTERING REMEDIES

TRACHEAL INJECTIONS as a WAY of ADMINISTERING REMEDIES