Fatal outcomes in family transmission of Mycoplasma pneumoniae.

BACKGROUND: Mycoplasma pneumoniae continues to be a significant cause of community-acquired pneumonia and, on rare occasions, manifests as fulminant disease that leads to mortality, even in healthy individuals. METHODS: We conducted a retrospective study on members of a family who were quarantined by the Centers for Disease Control and Prevention in 2002 for respiratory failure and death of a 15-year-old brother (sibling 1) and a 13-year-old sister (sibling 2). Collected airway, cerebrospinal fluid (CSF), and serum samples from both deceased siblings and serum samples from both parents and the remaining 3 ill siblings (sibling 3-5) were tested using a range of diagnostic assays. Autopsy lung tissue samples from sibling 2 were also assessed using immunohistochemical and immunoelectron microscopic methods. RESULTS: Autopsy evaluation of sibling 1 revealed cerebral edema consistent with hypoxic ischemic encepatholopathy and pulmonary findings of bronchiolitis obliterans with organizing pneumonia (BOOP). Postmortem lung examination of sibling 2 revealed lymphoplasmacytic bronchiolitis with intraluminal purulent exudate, BOOP, and pulmonary edema. Results of diagnostic assays implicated the household transmission of M. pneumoniae among all 5 siblings and both parents. Further analysis of lung tissue from sibling 2 demonstrated the presence of M. pneumoniae organisms and community-acquired respiratory distress syndrome toxin. M. pneumoniae was cultured directly from sibling 2 autopsy lung tissue. CONCLUSION: Evidence is provided that M. pneumoniae was readily transmitted to all members of the household and that the resulting infections led to a spectrum of individual responses with variation in disease progression, including lymphoplasmacytic bronchiolitis, BOOP, and death.

Efficacy of increasing dosages of clarithromycin for treatment of experimental Mycoplasma pneumoniae pneumonia.

OBJECTIVES: Mycoplasma pneumoniae respiratory infection is a common cause of acute respiratory infection in children and adults. We evaluated the efficacy of increasing dosages of clarithromycin for the optimized therapy of M. pneumoniae respiratory infection in a mouse model. METHODS: BALB/c mice were intranasally inoculated once with M. pneumoniae or SP4 broth (control). Groups of mice were treated with increasing dosages of clarithromycin (10, 25 or 75 mg/kg/day) or placebo subcutaneously daily. Groups of mice were evaluated after 1, 2, 3, 6 and 12 days of therapy. Outcome variables included quantitative M. pneumoniae culture, histopathological score of the lungs, bronchoalveolar lavage (BAL) cytokine/chemokine/growth factor concentrations and plethysmography after aerosolized methacholine to assess airway hyperresponsiveness. RESULTS: Elevated dosages of clarithromycin resulted in greater antimicrobial efficacy with significantly reduced M. pneumoniae quantitative cultures (P < 0.05), as well as greater improvement in markers of disease severity with significantly reduced lung histopathology scores, BAL cytokine concentrations and airway hyperresponsiveness (P < 0.05). CONCLUSIONS: Escalated dosing of clarithromycin resulted in significantly greater therapeutic efficacy in the treatment of experimental M. pneumoniae respiratory infection.

Aged mice display an altered pulmonary host response to Francisella tularensis live vaccine strain (LVS) infections.

Aging is a complex phenomenon that has been shown to affect many organ systems including the innate and adaptive immune systems. The current study was designed to examine the potential effect of immunosenescence on the pulmonary immune response using a Francisella tularensis live vaccine strain (LVS) inhalation infection model. F. tularensis is a Gram-negative intracellular pathogen that can cause a severe pneumonia. In this study both young (8-12 week old) and aged (20-24 month old) mice were infected intranasally with LVS. Lung tissues from young and aged mice were used to assess pathology, recruitment of immune cell types and cytokine expression levels at various times post infection. Bacterial burdens were also assessed. Interestingly, the lungs of aged animals harbored fewer organisms at early time points of infection (day 1, day 3) compared with their younger counterparts. In addition, only aged animals displayed small perivascular aggregates at these early time points that appeared mostly mononuclear in nature. However, the kinetics of infiltrating polymorphonuclear neutrophils (PMNs) and increased cytokine levels measured in the bronchial alveolar lavage fluid (BALF) were delayed in infected aged animals relative to young infected animals with neutrophils appearing at day 5 post infection (PI) in the aged animals as opposed to day 3 PI in the young infected animals. Also evident were alterations in the ratios of mononuclear to PMNs at distinct post infection times. The above evidence indicates that aged mice elicit an altered immune response in the lung to respiratory F. tularensis LVS infections compared to their younger counterparts.

Complications of umbilical artery catheterization in a model of extreme prematurity.

OBJECTIVE: Umbilical artery catheter (UAC) use is common in the management of critically ill neonates; however, little information exists regarding the anatomic and vascular effects of UAC placement in premature newborns. STUDY DESIGN: Baboons were delivered at 125 days of gestation (term=185 days), treated with surfactant, had UACs placed and were ventilated for either 6 or 14 days. Animals were assigned to short-term (6 days, n=6) and long-term (14 days, n=30) UAC placement. At necropsy, aortas were removed with UACs still in place. Histological examination of upper, middle and lower aorta specimens stained with hematoxylin and eosin and immunolabeled to detect smooth muscle (alpha-actin) was carried out in a blinded manner. Controls were delivered at 125, 140 and 185 days and the aortas acquired immediately after birth. None of the non-catheterized control animals (125 days, n=4; 140 days, n=5; and 185 days, n=5) had aortic vessel thrombi or vascular wall abnormalities. RESULT: All 6 animals with short-term (6/6, 100%) and 18 animals with long-term (18/30, 60%) UAC placement displayed aortic thrombi and neointimal proliferation of the vascular wall. The majority (60%) of analyzed animals with UAC placement displaying neointimal hyperplasia were immunopositive for alpha-actin, indicating the presence of smooth muscle in these lesions. CONCLUSION: Our findings suggest that both short- and long-term UAC use is associated with aortic wall pathological abnormalities compared with control animals. This study emphasizes the judicious use and early removal of UACs if possible in order to potentially prevent significant hemostatic and aortic wall vascular complications.

Impact of macrolide therapy on mortality for patients with severe sepsis due to pneumonia.

Recent studies suggest that macrolides may have beneficial effects for patients at risk for certain infections. The current authors examined the effect of macrolide therapy on 30- and 90-day mortality for patients with severe sepsis caused by pneumonia. A retrospective cohort study was conducted at two tertiary teaching hospitals. Eligible subjects were admitted with a diagnosis of, had chest radiography consistent with, and had a discharge diagnosis of pneumonia and clinical criteria of severe sepsis. Subjects were considered to be on macrolides if they received at least one dose within 48 h of admission. Severe sepsis was present in 237 (30.1%) subjects, out of whom 104 (43.9%) received macrolides. Mortality was 20.3% at 30 days and 24.5% at 90 days. In the multivariable analysis, the use of macrolide was associated with decreased mortality at 30 days (hazard ratio (HR) 0.3, 95% confidence interval (CI) 0.2-0.7) and at 90 days (HR 0.3, 95% CI 0.2-0.6) in patients with severe sepsis and in patients with macrolide-resistant pathogens (HR 0.1, 95% CI 0.02-0.5). Macrolide use was associated with decreased mortality in patients with severe sepsis due to pneumonia and macrolide-resistant pathogens. Confirmatory studies are needed to determine whether macrolide therapy may be protective for patients with sepsis.

Deficiencies in lung surfactant proteins A and D are associated with lung infection in very premature neonatal baboons.

Surfactant proteins A (SP-A) and D (SP-D) are important in the innate host defense against pathogenic microorganisms. A deficit in these proteins in premature infants, either because of immaturity or as a consequence of superimposed chronic lung disease (CLD), could increase their susceptibility to infection. The study reported here examined infection in CLD in the premature newborn baboon, and correlated it with the amounts of SP-A and SP-D in lung tissue and lavage fluid. Two groups of baboons were delivered prematurely, at 125 d gestational age (g.a.), and differed principally in whether they developed naturally acquired pulmonary infections and sepsis. Group I animals were ventilated with clinically appropriate oxygen for 6 d and 14 d without clinical incident. Group II animals were ventilated for 5 to 71 d, but differed from those in Group I in that most developed pulmonary infection and/or sepsis. In Group I animals, tissue pools of both SP-A and SP-D were equal to or exceeded those in adults, and lavage pools of SP-A increased progressively with the time of ventilation to about 35% of adult levels after 14 d. In contrast, most Group II animals had concentrations of lavage SP-A that were less than 20% of that in adult animals. A low concentration of lavage SP-A correlated with the release of interleukin-8, and with a high "infection index" based on histopathology, microbiologic cultures, and clinical indications of sepsis. Our data suggest that the amounts of SP-A and SP-D in lavage fluid are indicators of the risk of infection in the evolution of neonatal CLD. Deficits in the amount of lavage SP-A, even after 60 d of ventilation, may have inhibited the resolution of infection and thereby contributed to the developing injury among our Group II animals.

Haptoglobin in lung defence.

Haptoglobin (Hp) has been known to be associated with the host defence response to infection and inflammation. The biological functions of Hp can be related to its ability to bind haemoglobin or to modulate immune response. Hp is expressed at a high level in lung cells, yet its protective role(s) in the lung is not known. Using transgenic mice overexpressing Hp, we demonstrated that Hp can reduce blood-induced lung injury. Hp-mediated haemoglobin catabolism in lung cells appears to be linked to iron mobilization, and may be an efficient mechanism to reduce oxidative damage associated with haemolysis.

High-frequency oscillatory ventilation: effects on lung function, mechanics, and airway cytokines in the immature baboon model for neonatal chronic lung disease.

Acute lung injury models demonstrate that high-frequency oscillatory ventilation (HFOV) improves lung function, mechanics, and histopathology with reduced inflammatory mediators. Neither human HFOV trials nor premature animal studies have adequately evaluated these factors during prolonged HFOV. The objective of this study was to compare the effect of prolonged HFOV with low tidal volume (VT) positive pressure ventilation (LV-PPV) in an immature baboon model for neonatal chronic lung disease (CLD). After administration of prenatal steroids, 18 baboons were delivered by cesarean section at 125 d (term = 185 d), treated with exogenous surfactant, then randomized to either HFOV or LV-PPV by 5 min age. Animals were maintained on oxygen on an "as needed" basis and on nutritional support for 1 to 2 mo. Serial pulmonary function testing (PFT) was performed. Tracheal aspirates were analyzed for interleukin-6 (IL-6), IL-8, tumor necrosis factor-alpha (TNF-alpha), IL-1beta, and IL-10. Lungs were inflation fixed for morphometric analyses. From 12 h through 10 d age, HFOV animals had consistently lower fraction of inspired oxygen (FI(O(2))) and higher a/ A ratio. Pulmonary mechanics were significantly improved in HFOV animals at nearly every time point analyzed from 12 h to 28 d. There were no consistent differences in tracheal IL-6, TNF-alpha, IL-1beta, or IL-10 after 24 h age. Higher tracheal IL-8 values and macrophage/monocyte numbers were found in LV-PPV animals after 1 wk and 3 to 4 wk ventilation. Both groups exhibited pulmonary pathologic lesions found in extremely immature humans, including alveolar hypoplasia, variable saccular wall fibrosis, and minimal airway disease. HFOV animals had significantly better lung inflation patterns by panel of standards analysis. Early, prolonged HFOV significantly improved early lung function with sustained improvement in pulmonary mechanics out to 28 d. Immature baboons managed with HFOV had less pulmonary inflammation in the hyaline membrane disease (HMD) recovery phase. Though enhanced alveolization was not observed, HFOV for 1 to 2 mo resulted in consistently more uniform lung inflation than LV-PPV.

Pulmonary expression of the human haptoglobin gene.

Haptoglobin (Hp), a member of the acute-phase reactants, has long been known as a major hemoglobin-binding protein associated with hemoglobin catabolism. Recent studies indicate that another important biologic function of Hp is the modulation of the immune response. We found that Hp is expressed at high levels in specific cells, including alveolar macrophages and eosinophils in diseased or inflamed human lung tissues, but not in the normal lung. Expression of the human Hp gene was studied in two transgenic mouse lines carrying a 9-kb human Hp 2 gene. In both lines, the human Hp transgene was expressed constitutively in alveolar macrophages at a high level, whereas the endogenous mouse Hp was synthesized in airway epithelial cells. Expression of the human Hp transgene in lung cells was upregulated when the transgenic mice were treated with endotoxin. In humans and in Hp transgenic mice, human Hp messenger RNA was also detected in circulating eosinophils, but not in other blood cells. Our findings suggest that Hp is involved in a variety of lung inflammatory diseases, including respiratory allergy and asthma. The transgenic mouse line that overexpresses the human Hp gene in alveolar macrophages and eosinophils is a promising system for investigating the function of Hp in vivo during lung inflammation.

Resistance of hypotransferrinemic mice to hyperoxia-induced lung injury.

Oxidative stress plays a central role in the pathogenesis of acute and chronic pulmonary diseases. Safe sequestration of iron, which participates in the formation of the hydroxyl radical, is crucial in the lung's defense. We used a mouse line defective in the major iron transport protein transferrin to investigate the effect of aberrant iron metabolism on the lung's defense against oxidative injury. The tolerance to hyperoxic lung injury was greater in the hypotransferrinemic than in wild-type mice as documented by histopathology and biochemical indexes for lung damage. There was no increase in the levels of intracellular antioxidants, inflammatory cytokines, and heme oxygenase-1 in the hypotransferrinemic mouse lung compared with those in wild-type mice. However, there were elevated expressions of ferritin and lactoferrin in the lung of hypotransferrinemic mice, especially in the alveolar macrophages. Our results suggest that pulmonary lactoferrin and ferritin protect animals against oxidative stress, most likely via their capacity to sequester iron, and that alveolar macrophages are the key participants in iron detoxification in the lower respiratory tract.

Neonatal chronic lung disease in extremely immature baboons.

A borderline viability model of bronchopulmonary dysplasia (BPD)/chronic lung disease of infancy (CLD) with pathophysiologic parameters consistent with those in extremely immature humans with BPD/CLD is described. After prenatal steroid treatment of pregnant dams, 12 premature baboons were delivered by cesarean-section at 125 d (term gestation, 185 d), treated with exogenous surfactant, and maintained on appropriate oxygen and positive pressure ventilation for at least 1 to 2 mo. In spite of appropriate oxygenation (median FI(O(2)) at 28 d = 0.32; range, 0.21 to 0.50) and ventilatory strategies to prevent volutrauma, the baboons exhibited pulmonary pathologic lesions known to occur in extremely immature humans of less than 1,000 g: alveolar hypoplasia, variable saccular wall fibrosis, and minimal, if any, airway disease. The CLD baboon lungs showed significantly decreased alveolization and internal surface area measurements when compared with term and term + 2-mo air-breathing controls. A decrease in capillary vasculature was evident by PECAM staining, accompanied by dysmorphic changes. Significant elevations of TNF-alpha, IL-6, IL-8 levels, but not of IL-1beta and IL-10, in tracheal aspirate fluids were present at various times during the period of ventilatory support, supporting a role for mediator-induced autoinflammation. IL-8 levels were elevated in necropsy lavages of animals with significant lung infection. This model demonstrates that impaired alveolization and capillary development occur in immature lungs, even in the absence of marked hyperoxia and high ventilation settings.

Surfactant proteins A and D in premature baboons with chronic lung injury (Bronchopulmonary dysplasia). Evidence for an inhibition of secretion.

Surfactant proteins A and D (SP-A and SP-D) are believed to participate in the pulmonary host defense and the response to lung injury. In order to understand the effects of prematurity and lung injury on these proteins, we measured the amounts of SP-A and SP-D and their mRNAs in three groups of animals: (1) nonventilated premature baboon fetuses; (2) neonatal baboons delivered prematurely at 140 d gestation age (ga) and ventilated with PRN O(2); (3) animals of the same age ventilated with 100% O(2) to induce chronic lung injury. In nonventilated fetuses, tissue and lavage SP-A were barely detectable in baboons of 125 and 140 d ga, but they equaled or exceeded adult SP-A concentrations (g/g lung dry wt) at 175 d (term gestation, 185 d). In contrast, SP-D was readily detectable in tissue and lavage at 125 and 140 d ga. When the baboons of 140 d ga were ventilated for 10 d with 100% oxygen to produce chronic lung injury, the tissue concentration of SP-A was five times greater than that of normal adults; SP-D 16-times greater. Despite the sizable tissue pools of SP-A and SP-D, however, lavage SP-A was only 7% of that of normal adults and lavage SP-D just equaled the amount in normal adults. Nevertheless, because SP-D is normally in much lower concentration than is SP-A, their total comprised less than 12% of the SP-A and SP-D found in the lavage of a healthy adult. The results indicate that in chronic lung injury, SP-A is significantly reduced in the alveolar space. SP-D concentration in lavage is about equal to that in normal adults, possibly because of the 16-fold excess in tissue, but the total collectin pool in lavage is still significantly reduced. Because these collectins may bind and opsonize bacteria and viruses, decrements in their amounts may present additional risk to those premature infants who require prolonged periods of ventilatory support.

Abnormal surfactant metabolism and function in preterm ventilated baboons.

We evaluated surfactant metabolism and function and the effects of antenatal glucocorticoids in very preterm baboons. Pregnant baboons were randomized to receive saline (controls) or 6 mg betamethasone (beta) 48 and 24 h before delivery at 125 +/- 2 d gestation (term is 184 d). The newborn baboons were treated with [14C]dipalmitoylphosphatidylcholine-labeled surfactant and ventilated for 6 d. Lung function for six control and six betamethasone-treated animals was similar. Recoveries of 14C-saturated phosphatidylcholine (Sat PC) were similar: 4.8% (control) and 3.6% (beta) in alveolar wash and 15.4% (control) and 17.7% (beta) in total lungs. Alveolar and total lung pool sizes of Sat PC were about 23 and 190 micromol/kg, respectively. The preterm baboons secreted 8.7% (control) and 6.5% (beta) of de novo synthesized Sat PC labeled with 3H-palmitate from Day 5 to Day 6. These preterm baboons had high estimated Sat PC synthetic and net tissue accumulation rates but low secretion of Sat PC. The large aggregate surfactant fractions from the preterm baboons had high minimal surface tensions and were less effective when used to treat surfactant-deficient preterm rabbits than surfactant from newborn or adult baboons. Ventilation of the preterm baboon was associated with surfactant functional and metabolic abnormalities that were not altered by antenatal glucocorticoids.

Early high dose antioxidant vitamins do not prevent bronchopulmonary dysplasia in premature baboons exposed to prolonged hyperoxia: a pilot study.

The antioxidant vitamins ascorbic acid (AA) and alpha-tocopherol (alpha-TP) effectively inhibit oxygen free radical-induced lipid peroxidation. Using a premature baboon model of hyperoxia-induced bronchopulmonary dysplasia (BPD), we measured concentrations of AA, alpha-TP, and conjugated dienes (CD, marker of lipid peroxidation) in four animals (hyperoxic antioxidant group) receiving high dose antioxidant vitamin supplementation (AA, 100 mg x kg x(-1) x d(-1); alpha-TP; 20 mg x kg x(-1) x d(-1)) and one animal receiving standard dose antioxidant vitamin supplementation (AA, 10 mg x kg x(-1) x d(-1); alpha-TP, 1 mg x kg x(-1) x d(-1)). Respiratory and histopathologic data were compared with data from 10 historical animals exposed to hyperoxia (hyperoxic control group) and 11 historical animals treated as required with oxygen (normoxic control group) who had received standard dose antioxidant vitamin supplementation. Compared with standard dose antioxidant vitamin supplementation, high dose antioxidant vitamin supplementation effectively raised AA concentrations in plasma (37 +/- 22 micromol/L and 395 +/- 216 micromol/L, respectively) and tracheal aspirates (62 +/- 35 micromol/L and 286 +/- 205 micromol/L, respectively), and alpha-TP concentrations in plasma (10.1 +/- 2.5 micromol/L and 24.6 +/- 17.5 micromol/L, respectively). However, there was no apparent effect on tracheal aspirate CD concentrations (482 +/- 333 micromol/L and 1050 +/- 1111 micromol/L, respectively), and respiratory parameters in the hyperoxic antioxidant group were comparable to those of the hyperoxic control group but significantly worse than in the normoxic control group. Finally, no protective effect of high dose antioxidant vitamin supplementation was noted at the histopathologic level.

Site specificity of surfactant protein expression in airways of baboons during gestation.

BACKGROUND: There are disparate reports concerning the presence of surfactant proteins in the airways of lung. The recent finding of SP-A in tracheobronchial epithelium and submucosal glands in lungs from second trimester humans has renewed interest in potential new functions of surfactant in lung biology. METHODS: In situ hybridization studies were done to determine the distribution of SP-A, SP-B, and SP-C in baboon lung specimens from 60, 90, 120, 140, 160, and 180 (term) days of gestation and adults. Lungs from gestation controls were obtained at the time of hysterotomy and adult lungs at necropsy. Riboprobes used for in situ hybridization contained the entire coding regions for human SP-A, SP-B, and SP-C. RESULTS: At 60 days, SP-C mRNA expression was evident in focal portions of primitive tubular epithelium but not bronchi. This distal pattern of SP-C mRNA expression persisted and was present in some epithelial cells of respiratory bronchioles at term. At 90 days, SP-A mRNA expression was present in the epithelium of trachea and large bronchi. SP-B mRNA expression was found in small bronchi, bronchioles, and distal tubular epithelium at 120 days of gestation. SP-A mRNA bronchiolar localization became evident at 140 days of gestation and alveolar type 2 cellular expression at 160 days of gestation. Abrupt transitions of surfactant protein expression were identified (e.g., SP-A mRNA-positive cells in the epithelium of large bronchi with adjoining SP-B mRNA expression in small bronchi and bronchioles). CONCLUSIONS: Findings in the baboon indicate that there are well-delineated sites of surfactant protein mRNA expression in bronchial and bronchiolar epithelia. mRNA expressions of SP-A and SP-B are present in both bronchial and bronchiolar epithelium but at different sites, whereas SP-C expression is seen in loci of epithelial cells in respiratory bronchioles.

Effects of continuous bed rotation and prolonged mechanical ventilation on healthy, adult baboons.

OBJECTIVE: To study, in a model of prolonged mechanical ventilation, the role of continuous bed rotation on lung function and pathology. DESIGN: Prospective animal study. SETTING: Animal research laboratory. SUBJECTS: Healthy adult baboons (Papio cynocephalus), anesthetized with ketamine, sedated, paralyzed, mechanically ventilated for 11 days, and monitored with pulmonary and peripheral arterial catheters. INTERVENTIONS: Animals were divided into two experimental groups: a) mechanical ventilation alone (control, n = 7); and b) mechanical ventilation with continuous bed rotation therapy to 45 degrees (continuous rotation group, n = 5). Mechanical ventilation was provided for 11 days with an FIO2 of 0.21 and tidal volume of 12 mL/ kg. Bronchoalveolar lavage was performed through a fiberoptic bronchoscope. Nursing care procedures, antacids, enteral feeding, and prophylactic antibiotics were administered. MEASUREMENTS AND MAIN RESULTS: Measurements of hemodynamics, pulmonary functions, lung volumes, arterial blood gases, and chest radiographs were done daily. Bronchoalveolar lavage was performed at days 0, 7, and 11. There were no significant changes in hemodynamics, gas exchange, or pulmonary functions during the study period in either group. Microbiological surveillance cultures were negative in both experimental groups. In the control group after 7 days, six of seven animals developed patchy atelectasis; by day 11, two of seven animals demonstrated persistent radiologic abnormalities. Bronchoalveolar lavage neutrophils were significantly increased in control animals at days 7 and 11. Lung pathology in the control group showed areas of bronchiolitis, with surrounding bronchopneumonia in five of seven animals. None of the continuous rotation animals showed any radiologic or morphologic abnormalities. CONCLUSIONS: Prolonged mechanical ventilation in the control group resulted in atelectasis, increased concentrations of bronchoalveolar lavage neutrophils, and mild pneumonitis. These effects were not associated with changes in lung volumes, oxygenation, or hemodynamic parameters. Continuous bed rotation helped to prevent these abnormalities.

Regulation of transferrin gene expression during lung development and injury.

Transferrin (TF), the major iron-transporting protein in vertebrates, is mainly synthesized in the liver. Although its source in lung is unknown, TF is a major inhibitor for lipid peroxidation and microbial propagation in lung fluid, and iron-free TF has been shown in rabbits to decrease the severity of respiratory failure and to improve surfactant activity. This study shows that TF is produced and secreted by the lung. In baboons and humans. TF gene expression displays distinct temporal patterns in different lung cells as revealed by in situ hybridization. Although expression of TF mRNA in submucosal glands remains active during development and throughout adulthood, its level in airway epithelial increases with advancing gestational age, reaches its peak before birth, declines 6-12 mo after birth, and diminishes in the older adult. In premature baboons maintained on ventilatory support, expression of TF mRNA is suppressed in both airway epithelium and glands. TF production by airway epithelia before birth most likely prevents oxidative damage in the newborn period, and its loss during injury may allow further lung damage.

Effects of prolonged controlled mechanical ventilation on diaphragmatic function in healthy adult baboons.

OBJECTIVE: To study diaphragmatic strength and endurance after a prolonged period of mechanical ventilation. DESIGN: Prospective animal study. SETTING: Animal research laboratory. SUBJECTS: Seven uninjured adult baboons (Papio cynocephalus) were anesthetized with ketamine, sedated, paralyzed, and mechanically ventilated. Animals were monitored with pulmonary arterial and peripheral arterial catheters. INTERVENTIONS: Mechanical ventilation was provided for 11 days with an FIO2 of 0.21 and tidal volume of 15 mL/kg. Pulmonary function tests, including lung volumes, arterial blood gases, and chest radiographs were also monitored. Nursing care procedures included frequent turning, chest physiotherapy, and endotracheal suction. Antacids and prophylactic antibiotics (intravenous penicillin, topical polymyxin B, and gentamicin sulfate) were administered. In three animals, fishhook electrodes were surgically placed around both phrenic nerves on both day 0 and after 11 days of mechanical ventilation for diaphragmatic stimulation. On day 0, the electrodes were removed after phrenic nerve stimulation studies were performed. After 11 days of mechanical ventilation, animals were electively killed and full autopsy performed. MEASUREMENTS AND MAIN RESULTS: Hemodynamic and pulmonary function parameters were measured at baseline and every day during the 11 days of mechanical ventilation. Diaphragmatic strength and endurance were measured on days 0 and 11. Diaphragmatic endurance was determined by an inspiratory resistive loading protocol. There were no significant changes in hemodynamics, lung volumes, or gas exchange during the period of mechanical ventilation. On day 7, the chest radiographs showed patchy lobar atelectasis in six animals, which cleared by day 11 in all but two of the animals. Lung pathology showed mild, focal pneumonitis. By day 11, maximum transdiaphragmatic pressure had decreased by 25% from day 0 and diaphragmatic endurance had decreased by 36%. CONCLUSIONS: Eleven days of mechanical ventilation and neuromuscular blockade in healthy baboons resulted in nonsignificant changes in hemodynamics, oxygenation, and/or lung function. However, significant impairment in diaphragmatic endurance and strength were seen. Based on these results, it is likely that prolonged mechanical ventilation by itself impairs diaphragmatic function independent of underlying lung disease.

Lung manganese superoxide dismutase protein expression increases in the baboon model of bronchopulmonary dysplasia and is regulated at a posttranscriptional level.

The expression of lung manganese superoxide dismutase (MnSOD) mRNA and protein were examined in a premature baboon model of hyperoxia-induced bronchopulmonary dysplasia (BPD) and BPD superimposed with bacterial infection. When 140-d gestation baboons were delivered by hysterotomy and treated for 16 d with appropriate ventilatory and oxygen support (pro re nada controls), there was an increase in both MnSOD mRNA and protein compared with 140-d or 156-d gestation, nonventilated controls. The concentration of MnSOD protein was also elevated when the prematurely delivered baboons were ventilated with a high fraction of inspired O2 to produce a primate homolog of BPD, but there was a significant decrease in the concentration of MnSOD mRNA in BPD animals compared with pro re nada controls. In the lungs of premature baboons in which Escherichia coli infection was superimposed on hyperoxia-induced BPD, MnSOD mRNA was diminished to approximately the same extent as in BPD alone, but MnSOD protein was significantly increased compared with all other groups. Taken together these data indicate that the premature baboon is capable of mounting an antioxidant response and that increased MnSOD protein expression in BPD and BPD-infected premature baboons is regulated, at least in part, at a posttranscriptional level.