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J J Coalson

Publications and source records attributed to J J Coalson.

At least 37 records · Page 2Linked to original sources
PubMed1995

SP-A deficiency in primate model of bronchopulmonary dysplasia with infection. In situ mRNA and immunostains.

The surfactant protein secretory cells in airway and alveolar epithelium were studied in premature baboons with bronchopulmonary dysplasia and superimposed infection. PRN animals were delivered by hysterotomy at 140 d gestational age and ventilated on clinically appropriate oxygen for a 16-d experimental period. To assess 0 time and sacrifice time gestational parameters, 140 and 156 d were studied. BPD animals were delivered at 140 d and ventilated with positive-pressure ventilation and an FIO2 of 1.0 for 11 d followed by 5 d of oxygen sufficient to maintain PAO2 at 40 to 50 mm Hg. BPD-infected animals were comparably ventilated and treated like the BPD group except that 10(8) E. coli organisms were endotracheally instilled on Day 11. In situ hybridization studies for mRNA expression of SP-A, SP-B, and SP-C revealed that an SP-A mRNA deficiency, present at 140 d, persisted in the BPD and BPD-infected groups, whereas SP-A mRNA was abundant in PRN and 156 d gestation control groups. SP-B and SP-C mRNA expression in the two hyperoxically injured groups was particularly extensive in cells around peribronchiolar and perivasicular sites. Immunostaining with SP-A, SP-B, and SP-C antibodies showed variable staining patterns. The study clearly demonstrates that a deficiency of SP-A mRNA expression persists in chronic lung injury and that variable protein staining patterns are manifested depending upon the underlying pathology.

Animals↗
PubMed1995

Cell type-specific and inflammatory-induced expression of haptoglobin gene in lung.

BACKGROUND: Haptoglobin (HP) is a hemoglobin-binding protein and a major acute phase reactant. Recently, HP has been shown to possess antioxidant and angiogenic properties. HP is known to be produced mainly in the liver. Expression of HP in specific cells of nonhepatic origin including lung cells has not been studied before. The presence of extracellular plasma proteins in lung epithelial fluid has been assumed to be of blood serum origin. EXPERIMENTAL DESIGN: To investigate the expression of the HP gene in lung, the presence of HP mRNA and the production of HP protein in the lung were examined by Northern blot analysis and immunoprecipitation, respectively. Cellular expression of HP during development and inflammation were studied by in situ hybridization with lung tissues derived from different gestational stages from baboons and mice and from mice treated with lipopolysaccharide. RESULTS: Northern blot and in situ hybridization analyses established a high level of expression of HP in fetal and adult lung tissues, which were confined to the epithelial lining of the airways in mouse and baboon. After inflammation had been induced in vivo, expression of the HP gene rose fourfold in lung, an increase compatible with that observed in normal mouse liver. However, HP mRNA level was not significantly altered in airway epithelium. Instead, HP expression in alveolar epithelial cells, most likely type 2 cells, was strongly increased. CONCLUSIONS: Our data suggest that locally synthesized HP provides a major source of antioxidant and/or antimicrobial activity in the mucus blanket as well as in the alveolar fluid in the lung. The regulation and cell type-specific expression of HP during development and inflammation indicate a protective role for HP in lung and confirm recent reports that HP plays important roles in protecting against infection and in repairing injured tissues.

Animals↗
PubMed1995

The pathology of nosocomial pneumonia.

Of patients who die in the intensive care unit (ICU), the mortality rate is significantly higher in those who develop nosocomial bacterial pneumonias. Pneumonia is difficult to diagnose clinically in patients with acute lung injury, so the "gold standard" for a pneumonia diagnosis has been its histopathologic presence in autopsy lung specimens. The potential pitfalls in the proper sampling of the lung at autopsy and how the histopathological appearance may be altered in a diffusely injured lung are discussed. Pathologists are encouraged to carefully analyze and evaluate bronchoalveolar lavage (BAL) and protected specimen brush (PSB) specimens obtained from patients before death to help determine if pneumonia is present.

Animals↗
PubMed1994

Acute inflammatory injury in the lung precipitated by oxidant stress induces fibroblasts to synthesize and release transforming growth factor-alpha.

Although transforming growth factor-alpha (TGF-alpha) is widely distributed in transformed cells and in some normal cells and much is known about its structure and metabolism, there is little information about its physiological actions. TGF-alpha is not thought to be synthesized by nontransformed fibroblasts, but it is thought to be a mitogen for these and epithelial cells (Derynck, R. (1986) J. Cell. Biochem. 32, 293-304). We report here that fibroblasts obtained from hamsters with oxidant-induced lung injury release TGF-alpha at levels comparable with those reported for transformed cells. In conditioned media, one isoform of 18 kDa was recognized by a monoclonal antibody to mature TGF-alpha; five isoforms ranging from 18 to 42 kDa were recognized in cell lysates. Conditioned media from these fibroblasts stimulated tyrosine phosphorylation of the epidermal growth factor (EGF)/TGF-alpha receptor, competed with radioactive EGF for binding sites on A431 cells, and were mitogenic for mesenchymal and epithelial cells. This mitogenic activity could be almost completely blocked by anti-TGF-alpha. Conditioned media from normal lung fibroblasts exhibited none of these activities. Using normal lung fibroblasts, we found that TGF-alpha synthesis could be induced in vitro with 25 nmol/ml EGF, suggesting that the induction in vivo may have been due, in part, to a stimulation by EGF (or TGF-alpha) released by other cell types such as alveolar macrophages recruited to the injury site. TGF-alpha is, in general, a mitogen for epithelial cells (Derynck, 1986); more specific to acute injury in the lung, it may affect the proliferation (Ryan, R. M., Mineo-Kuhn, M. M., Kromer, C. M., and Finkelstein, J. N. (1994) Am. J. Physiol. 266, L17-L23) and metabolic activities (Whitsett, J. A., Weaver, T. E., Lieberman, M. A., Clark, J. G., and Daugherty, C. (1987) J. Biol. Chem. 262, 7908-7913) of alveolar epithelial type II cells. This is, we believe, the first report of a fibroblast-derived TGF-alpha induced with oxidant injury. If this response was ubiquitously manifested in other tissues, then fibroblast-derived TGF-alpha might be an important determinant of the epithelial and mesenchymal hyperplasia commonly observed in tissue repair.

Acute Disease↗
PubMed1994

Failure of acute perinatal asphyxia or meconium aspiration to produce persistent pulmonary hypertension in a neonatal baboon model.

OBJECTIVE: Our purpose was to determine whether perinatal asphyxia or meconium aspiration, or both, can produce the physiologic and histologic pulmonary vascular changes associated with the meconium aspiration syndrome. STUDY DESIGN: Twenty neonatal baboons were studied in four groups: 1, control; 2, meconium aspiration; 3, asphyxia (intermittent cord compression); and 4, asphyxia with meconium aspiration. Animals were ventilated for 24 hours under ketamine, diazepam, and pancuronium. Data were analyzed by means of mixed model analysis of measures. RESULTS: Meconium significantly impaired oxygenation (p < 0.001), whereas concurrent asphyxia moderated this effect (p < 0.034). Meconium also increased the need for ventilatory support (p < 0.002). No animal had persistent pulmonary hypertension; neither systemic nor pulmonary systolic pressures differed statistically between the groups. No animal showed evidence of abnormal pulmonary arteriolar muscularization. CONCLUSION: Sublethal perinatal asphyxia or meconium aspiration were insufficient to produce either the physiologic or histologic changes of severe meconium aspiration syndrome. It is unlikely that intrapartum fetal distress alone can produce this syndrome in human neonates.

Acute Disease↗
PubMed1994

Pathways of fibrin turnover in lavage of premature baboons with hyperoxic lung injury.

Lung injury induced by 100% O2 over 6 days is characterized by markedly less alveolar fibrin and rare hyaline membranes in premature versus adult baboons. To determine the mechanism(s) underlying alveolar fibrin deposition in the evolution of hyaline membrane disease (HMD) through diffuse alveolar damage (DAD) and bronchopulmonary dysplasia (BPD), we measured procoagulant and fibrinolytic activities in lung lavage of premature baboons with HMD, those treated with 100% O2 for 6 days (DAD) or for 7 days followed by 14 days 80% O2 (BPD). Lavage procoagulant activity, mainly due to tissue factor associated with Factor VII, was increased by hyperoxia. Plasminogen-dependent fibrinolytic activity, due to both tissue plasminogen activator and urokinase, was stable or increased after hyperoxia. Plasminogen activator inhibitor 1 (PAI-1) was detectable in lavage of animals with HMD but not those with evolving DAD or BPD. Antiplasmin activity was stable or decreased. Although plasminogen was undetectable in lavage, D-dimer was increased in lavage of the groups exposed to hyperoxia versus HMD. The defect in plasminogen activator activity in lavage fluids of adult baboons with DAD induced by O2 does not occur in premature baboons with HMD, evolving DAD, or BPD. Expression of fibrinolytic activity in the lower respiratory tract of premature baboons is dependent on local access to plasminogen, which is present in relatively low concentrations in plasma of these animals.

Age Factors↗
PubMed1994

Long-term partial liquid ventilation (PLV) with perflubron in the near-term baboon neonate.

PURPOSE: The feasibility and safety of continuous long-term (4-5 day) partial liquid ventilation (PLV) using perflubron was demonstrated in newborn baboons. PLV, a potential therapy for adult and neonatal respiratory distress syndrome (RDS), is conventional mechanical ventilation (CMV) with the lung filled to about functional residual capacity with perfluorochemical liquid. PROTOCOL: As a pilot trial for a larger preclinical study focused on the safety of extended duration PLV, three near term baboons were studied. The animals were delivered by cesarean section, anesthetized, intubated and placed on CMV. The animals were given intratracheal perflubron (30 ml/kg) and maintained on PLV for 96 hours. The transition back to gas ventilation occurred, after draining, over the fifth day (hrs 96-120). RESULTS: Two of the animals were born with normal pulmonary function, while the third developed respiratory distress prior to PLV. All the animals were adequately supported with PLV using moderate ventilator settings and low concentrations of oxygen. Perflubron distribution was enhanced by periodic rotation of the animals. Preliminary histology show vacuolated alveolar macrophages and no evidence of edema or other significant changes in the lungs. Pulmonary function in the RDS animal, after PLV treatment, showed normal gas exchange and lung mechanics. CONCLUSIONS: Three near term baboons, one with clinical RDS, tolerated 4 days of PLV followed by 1 day of CMV without complications using practical clinical management methods.

Animals↗
PubMed1993

Surfactant replacement therapy in utero for prevention of hyaline membrane disease in the preterm baboon.

OBJECTIVE: A previous study of intraamniotic administration of surfactant in preterm rabbit fetuses demonstrated that exogenous surfactant can be taken up into the lungs from amniotic fluid in quantities sufficient to alter pulmonary mechanical properties. On the basis of these findings we chose to test the hypothesis that intraamniotic administration of surfactant to the preterm baboon 24 hours before delivery will prevent the development of clinical and pathological aspects of hyaline membrane disease. STUDY DESIGN: Characteristics of hyaline membrane disease in the preterm baboon model include atelectasis, the formation of hyaline membranes in the airways and distal air saccules, overexpansion of distal airways, and disruption of airways by barotrauma associated with neonatal intensive care practices. Nine preterm baboons were treated with either saline solution (n = 4) or surfactant (n = 5) by intraamniotic injection on 136 to 137 days' gestation. One day later fetuses were delivered by cesarean section and maintained for 24 hours with standard neonatal intensive care techniques. RESULTS: All neonates completed the protocol, and surfactant-treated animals had better clinical courses as documented by Pao2/PAO2 (p < 0.05), FIO2 (p < 0.005), and Paco2 (p < 0.05). Significant radiographic differences (p < 0.02) were noted to be the result of surfactant treatment. No differences in ventilator pressures or neonatal cardiovascular parameters were found. Significant differences in pulmonary pathologic conditions (p < 0.01) were also found, but all animals had some degree of pathologic pulmonary changes associated with hyaline membrane disease. CONCLUSION: Therefore a single treatment with surfactant in utero significantly improved the clinical course but did not completely prevent hyaline membrane disease in an established animal model.

Amniocentesis↗
PubMed1993

Decreased pulmonary damage in primates with inhalation injury treated with high-frequency ventilation.

OBJECTIVE: This study compared two forms of high-frequency ventilation (HFV) with conventional volume ventilation (CON) in a primate model of inhalation injury to determine whether ventilatory mode was a determinant of pulmonary damage. SUMMARY BACKGROUND DATA: The authors previously reported that the prophylactic use of high-frequency flow interruption in patients with bronchoscopically diagnosed inhalation injury requiring mechanical ventilatory support resulted in a significant decrement in mortality. They hypothesized that a reduction in ventilatory mode induced pulmonary damage was in part responsible for their clinical results. METHODS: Fifteen adult baboons were randomized to one of three ventilatory modes (CON, high-frequency flow interruption [HFFI], or high-frequency oscillatory ventilation [HFO]) after moderate smoke injury. Ventilatory support was tailored to the same physiologic endpoints. After 7 days, the animals were killed and pulmonary pathologic changes were scored and compared. Repetitive physiologic and biochemical data were compared using analysis of variance for repeated measures. RESULTS: Physiologic endpoints were achieved in CON and HFFI, but not in HFO. Hemodynamic variables did not differ between CON and HFFI. The barotrauma index was greater in CON compared to HFFI (p < 0.05), despite similar PO2, FIO2, AA gradient, and PCO2. Animals treated with HFFI had significantly less parenchymal damage than those treated with CON (p = 0.03) or HFO (p = 0.0008). CONCLUSIONS: The prophylactic use of HFFI led to a significant decrement in ventilatory mode induced pulmonary damage and offers an explanation for the decreased mortality in inhalation injury patients treated with HFFI.

Animals↗
PubMed1993

Tissue inhibitor of metalloproteinase-1 mRNA is specifically induced in lung tissue after birth.

Interactions between extracellular matrix, proteins, metalloproteinases, and their inhibitors play a major role in determining the structure of the lung during in utero development and after birth. To better understand the molecular mechanisms underlying lung development and morphogenesis, expression of the tissue inhibitor of metalloproteinase (TIMP-1) gene was examined 1) through the course of late fetal development, 2) when normal fetal development was interrupted by premature birth and extrauterine survival, and 3) during exposure of prematurely delivered neonates to hyperoxia. Total RNA isolated from lung tissue of fetal baboons (Papio sp) at 140, 150, and 180 d of gestation (term gestation = 180 d); baboons prematurely delivered at 140 d of gestation, 1, 2, 6, and 10 d old; and premature baboons ventilated for 6 and 10 d with 100% oxygen was examined by Northern blot analysis. The results demonstrated that TIMP-1 mRNA, which is expressed at low levels during fetal development, undergoes a marked increase in abundance shortly after both premature and term birth. This parturition-induced pattern of gene expression appears to be tissue specific to the lung and, contrary to results reported for adult and neonatal animals, is not affected by ventilation of the premature lungs with 100% inspired oxygen. Although the physiologic consequences of TIMP-1 mRNA induction by birth are not yet known, these data suggest a possible role for TIMP-1 in postnatal adaptation of lung tissue.

Animals↗
PubMed1992

Rescue ventilation with high frequency oscillation in premature baboons with hyaline membrane disease.

We tested the hypothesis that high-frequency oscillatory ventilation can be efficacious in hyaline membrane disease (HMD) even after lung injury is established. We compared high frequency oscillatory ventilation (HFOV) rescue (n = 8; 15 Hz; I:E = 1:2) after 8 hours of positive pressure ventilation (PPV) with positive end-expiratory pressure, to continued PPV (control, n = 7) in premature baboons with HMD over a 24 hour period. Ventilator settings and physiologic parameters were recorded hourly. At necropsy (24 hours), lung status pressure-volume curves, alveolar phospholipids (PL), platelet activating factor-like activity (PAF), and lung water were determined. Roentgenographic and morphologic differences in lung inflation were quantified by standard techniques. No intergroup differences were found in heart rate, blood pressures, ventilator settings, FiO2, blood gases, or chest radiographs during the first 8 hours. Both groups had progressive physiologic disease. At 8 hours, HFOV-rescue animals, in contrast to controls, had immediate significant time-related improvements in Pa/AO2 (at the same Paw) and in oxygenation index (Pa/AO2/Paw) lasting for 16 hours. No significant intergroup differences in lung/body weight, lung water, lung mechanics, PL, PAF, or frequency of moderate to severe roentgenographic changes existed at 24 hours. Although all animals had morphologic evidence of HMD, saccular aeration was more uniform and airway dilatation less evident in HFOV rescue (P less than 0.0001). Based on the improved gas exchange, we conclude that HFOV rescue was efficacious in the "late' treatment of HMD, presumably because of the more uniform saccular aeration.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Fibrinolytic activity in bronchoalveolar lavage of baboons with diffuse alveolar damage: trends in two forms of lung injury.

BACKGROUND AND METHODS: Alveolar fibrin deposition is prominent in diffuse alveolar damage, the morphologic hallmark of the adult respiratory distress syndrome. To determine if a persistent abnormality of fibrin clearance occurs in the alveolar compartment during evolving diffuse alveolar damage, we characterized abnormalities of fibrin turnover in serial bronchoalveolar lavage specimens from two baboon models: a) diffuse alveolar damage induced by 80% oxygen and bronchoscopic seeding of Pseudomonas aeruginosa; and b) a more fulminant form of diffuse alveolar damage induced by bronchoscopic seeding of Pseudomonas and the infusion of oleic acid. RESULTS: Lavage procoagulant activity, due mainly to tissue factor associated with Factor VII, was increased and exceeded regulation by extrinsic pathway inhibitor in both models. Fibrinolytic activity was transiently diminished in baboons with evolving diffuse alveolar damage induced by oleic acid/Pseudomonas, but was preserved after 80% oxygen/Pseudomonas. Concentrations of plasminogen activator inhibitor-2 did not increase in lavage specimens obtained during evolving diffuse alveolar damage. Concentrations of alpha 2 antiplasmin and plasminogen activator inhibitor-1 tended to be higher in the lavage of oleic acid/Pseudomonas baboons with low fibrinolytic activity. Immunohistochemical analyses showed that tissue factor was distributed along the alveolar surface of controls and baboons with diffuse alveolar damage. Alveolar fibrin deposition was increased, by morphometric analyses, in both models. CONCLUSIONS: These data indicate that while increased procoagulant activity is characteristic of evolving diffuse alveolar damage and favors alveolar fibrin deposition, fibrinolytic activity may be transiently diminished or remain intact during evolving diffuse alveolar damage in baboons.

Animals↗
PubMed1992

Surfactant proteins and lipids are regulated independently during hyperoxia.

Adult hamsters were exposed to 100% oxygen for up to 8 days. At time of death lung tissue was analyzed for the expression of surfactant protein (SP) genes, and surfactant was isolated from alveolar lavage fluid. Surfactant was analyzed for the composition of proteins and phospholipids and for its surface properties. We found, over the 8 days of exposure, that an alveolitis composed of polymorphonuclear leukocytes (PMNs) and alveolar macrophages, accompanied by exudation of edema fluid, appeared in the alveolar spaces. The steady-state levels of SP mRNAs declined after 8 days of exposure to 100% oxygen, but the patterns indicated individual genetic control. SP-A was elevated early in the course of the hyperoxic exposure but decreased significantly by day 8; SP-B decreased continuously; SP-C was unchanged (or slightly elevated) through day 2 and then declined. The amounts of recoverable lavage surfactant increased by greater than threefold, and the phospholipid composition showed increasing percentages of disaturated phosphatidylcholine. All surfactants lowered surface tension to less than 10 dyn/cm, but the adsorption rates decreased as exposure progressed. The results indicate that lung injury induced by 100% oxygen is accompanied by altered patterns of surfactant metabolism, possibly because of a changing type II cell phenotype or alterations in Clara cell-derived surfactant. These changes may result in perturbed physiological function contributing to decreased lung compliance.

Animals↗
PubMed1992

Pathophysiologic, morphometric, and biochemical studies of the premature baboon with bronchopulmonary dysplasia.

Pathophysiologic, morphometric, and biochemical (surfactant and coagulation-fibrinolytic parameters) features were studied in premature baboons with and without bronchopulmonary dysplasia (BPD). A total of 22 baboons were delivered by hysterotomy at 75% of gestation and randomized into two groups. Group 1 (PRN) animals were ventilated with high-frequency oscillation for 48 to 72 h and then changed to positive-pressure ventilation (PPV) while maintained on clinically appropriate oxygen for the 21-day experimental period. Group 2 (BPD) animals were ventilated with PPV and 1.0 FlO2 for 7 days followed by 0.8 FlO2 for 14 days. Group 3 (control) animals were delivered and immediately killed at 140 days gestation. Group 1 animals showed no significant airway or saccular lesions, and alveolarization of the saccules was present. Group 2 animals showed metaplastic or hyperplastic epithelial lesions in airways and an alternating pattern of atelectatic but more normal appearing saccules and alveoli interposed between foci of thickened overexpanded saccular walls with no alveolarization. Differences within and between the three study groups were analyzed morphometrically. When numerical densities were examined by comparing control, PRN, BPD-atelectatic areas, and BPD-overexpanded areas. Type II cells were significantly increased in the BPD-overexpanded sites above those of control and PRN values. The interstitial cells were significantly more numerous in the BPD-atelectatic blocks compared with control and BPD-overexpanded blocks. Endothelial cell numerical densities were significantly decreased in the overexpanded sites of the BPD animals compared with the control, PRN, and BPD-atelectatic values. Volume density data showed that the interstitial compartment of the BPD group was significantly larger than those of the control and PRN groups. This was seen as significant increases in the cellular, noncellular, and connective tissue fiber components. Vascular endothelium or lumen volume densities were not different between the BPD and PRN animals, but did differ from those of the 140-day gestation controls. Comparable levels of lavage plasminogen-dependent fibrinolytic activity, were detectable at the 21-day study interval. The phospholipid composition of pulmonary surfactant, including disaturated PC and total PG, was similar between BPD and PRN groups at 21 days. The pathologic, morphometric, and biochemical patterns in this study probably represent those seen in human neonates with mild to moderate clinical BPD who survive. At this time, it is not known if the destructive endothelial lesion and the lack of alveolarization in the overexpanded and fibrotic lesions will resolve over time in long-term BPD survivors.

Animals↗
PubMed1992

The contribution of experimental models to our understanding of the pathogenesis and treatment of bronchopulmonary dysplasia.

The extensive data from animal models of BPD and specific aspects of lung injury have helped to expand and refine the concept of pathogenesis introduced by Northway et al. Given the complexity and heterogeneity of the human illness, it is unreasonable to presume that any single model or research group could elucidate all of the features and interactions of this complex disease. Therefore, we have combined data from animal homologues of BPD with that available on specific injury mechanisms to construct a more comprehensive model of pathogenesis (Fig. 5). Of particular interest is the recent data suggesting that the accelerated maturation of the prematurely born infant is associated with specific defects in gene expression that might increase vulnerability to lung injury. Additional animal research is needed both to further refine this model of pathogenesis and to develop the basis for a more rationale approach to the prevention and treatment of BPD. Based on the research progress to date, we feel the priorities for the future should at the least include continued definition of the biochemical and molecular mechanisms underlying various types of lung injuries; evaluation of those mechanisms (and the consequences of their interruption) in a developmentally relevant setting; and further elaboration of the currently available BPD models to include factors (such as ante- and postpartum infections) that have not previously been part of these animal model systems. This approach, we feel, will complement human studies and ultimately lead to the prevention and better clinical management of this major health care problem.

Animals↗
PubMed1991

Elastase activity in bronchoalveolar lavage fluid from oxygen-exposed, Pseudomonas-infected baboons.

The adult respiratory distress syndrome is a major cause of morbidity and mortality in critical care patients. Lung injury in this syndrome is frequently associated with lung infection. The combined insults result in an influx of neutrophils and damage to the pulmonary epithelium. We investigated whether active neutrophil elastolytic activity was present in the bronchoalveolar fluid in baboons with mild or moderate hyperoxic lung injury and infection. Group A (N = 7) was exposed for 6 days to FIO2 = 0.8 and then inoculated by intratracheal bolus with Pseudomonas aeruginosa strain DGI-R130 (PA); the FIO2 was reduced to 0.5. Group B (N = 6) was exposed to similar concentrations of inspired oxygen but inoculated with buffered saline. Antibiotics included parenteral penicillin and topical gentamicin and polymyxin B. All 3 were given continuously in group B but stopped 24 h prior to PA inoculation in group A. Bronchoalveolar lavage fluid was collected 1 week before oxygen administration, when the FIO2 was reduced (day 6 or 7) and prior to necropsy (day 11). Hemodynamic, pulmonary function, microbiological, and biochemical variables were studied. Injured, infected animals (group A) had significant elevations of mean pulmonary artery pressure and decreases in total lung capacity and PaO2 compared both to baseline and to group B at day 11. At autopsy, group A had significant increases of bronchoalveolar lavage fluid (BALF) neutrophils and bacterial pathogens. Elastase levels in BALF (equal to 0 at baseline) rose to 136 +/- 98 ng/ml in group A vs. 6 +/- 14 ng/ml in group B. The elastase was inhibited by inhibitors of serine proteases including ones specific for neutrophil elastase. On Sephacryl S-300 chromatography the elastase activity eluted near human alpha 2-macroglobulin and separated from other proteolytic activity. These studies demonstrate a significant level of elastase in BALF from injured, infected baboons compared to injured, uninfected animals.

Acute Disease↗
PubMed1991

Alterations in surfactant protein gene expression associated with premature birth and exposure to hyperoxia.

Steady-state levels of mRNAs for the three surfactant-associated proteins, SP-A, SP-B, and SP-C, were measured in a primate model of premature birth and survival. These values were determined by Northern and quantitative slot blot analyses of total lung RNA during both in utero and extrauterine development of the fetus as well as in response to hyperoxic exposure. The composition and surface properties of surfactant were also analyzed to determine the effect of differential expression of the surfactant proteins on the overall composition and function of surfactant. The data clearly demonstrate that the regulation of surfactant mRNA levels in the premature fetus is under complex physiological control. Interruption of in utero development by premature birth results in increased levels of all three surfactant mRNAs, presumably in response to precocious initiation of air breathing. Within the first 24 h after parturition both SP-B and SP-C mRNA levels are increased beyond the levels found in the full-term fetal controls. Expression of mRNA for these genes peaks on day 2 and thereafter drops to levels below that found on day 1. However, response of the SP-A gene to premature birth is slow and transcripts from this gene lag considerably behind values found in the full-term fetus. Furthermore, exposure of the premature fetus to hyperoxia results in an increase in the steady-state levels of SP-B and SP-C mRNA without significant changes in SP-A. Defects in the ability of the SP-A gene to respond to extrauterine exposure and hyperoxia may be contributing to development of bronchopulmonary dysplasia, a common clinical complication of premature birth in humans.

Animals↗