The use of exogenous surfactant to treat patients with acute high-permeability lung edema.
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Bronchi↗
Biomedical subjects
B Robertson
Publications and source records attributed to B Robertson.
The adult respiratory distress syndrome: first trials with surfactant replacement.
Following diverse insults, patients may develop a high permeability lung oedema which results in tachypnoea, cyanosis, hypoxaemia, and pan-lobar infiltrates on the chest radiograph. Although a variety of interventional therapies have been evaluated, none has been found effective, and current treatments are entirely supportive. Recently, cellular and biochemical analyses of bronchoalveolar lavage fluid have disclosed abnormalities which suggest that acute inflammatory events and surfactant abnormalities are present in the lungs of patients with adult respiratory distress syndrome (ARDS). The similarities to abnormalities seen in neonates with respiratory distress syndrome are striking. Treatment of those infants with surfactant replacement has been of both short-term and long-term benefit. Therefore, it is rational to investigate the benefits which surfactant administration may have for patients with ARDS. We present an overview of ARDS, and our initial experience with surfactant replacement in three patients.
Adult↗
The evolution of neonatal respiratory distress syndrome into chronic lung disease.
Bronchopulmonary dysplasia (BPD) is a distortion of postnatal lung development induced by ventilator treatment for respiratory distress syndrome or other forms of respiratory failure in the newborn. This paper reviews established and proposed mechanisms involved in the pathogenesis of BPD including severe surfactant deficiency, ventilation with high insufflation pressure and high oxygen concentrations, protein leakage and low levels of antioxidants in the immature lung, and a protease-antiprotease imbalance interfering with the layout of elastin and leading to growth without proper alveolarisation. Since the primary insult occurs during the first few days after birth, prophylaxis is highly important. Promising attempts have been made to prevent, or curb, the evolution of BPD by administration of antioxidants, corticosteroids, or exogenous surfactant.
Animals↗
Composition and surface properties of the bronchial lipids in adult patients with cystic fibrosis.
Bronchial secretions from seven patients with cystic fibrosis (CF) were aspirated by fibreoptic bronchoscopy and analysed for lipid composition. The total lipid fraction was also used to measure dynamic surface tension. Pooled samples from 'normal' patients, healthy volunteers, patients with chronic bronchitis, and individual samples from two patients with bronchiectasis were used as controls. Increased bronchial inflammation and infection correlated with a decrease of the phospholipid fraction, and an increase of the cholesterol, diglyceride and triglyceride fractions. When individual phospholipids were analysed, patients with clinically severe CF showed a markedly decreased phosphatidylcholine fraction, whereas the phosphatidylinositol fraction was significantly higher in CF patients than in controls (p less than 0.05). Minimum surface tension was higher in CF patients compared to patients with chronic bronchitis (p less than 0.05). This might be related to earlier reported specific changes in the pattern of fatty acids of the CF bronchial phospholipids.
Adult↗
Neuropeptide regulation of inflammatory and immunologic responses. The capacity of alpha-melanocyte-stimulating hormone to inhibit tumor necrosis factor and IL-1-inducible biologic responses.
Administration of the pituitary hormone alpha-melanocyte-stimulating hormone (alpha-MSH) to mice was found to inhibit a number of IL-1 and TNF-inducible biologic responses in situ. The ability of either IL-1 or TNF to cause fever, enhance plasma levels of acute phase proteins, and increase the numbers of peripheral blood neutrophils was inhibited by the simultaneous peripheral administration of this neuropeptide. In addition, alpha-MSH reversed the depressive influences of IL-1 or TNF on the effector phase of contact hypersensitivity (CH) responses in animals given an adoptive transfer of primed lymphocytes from hapten-sensitized donors. Intracerebral injection of nanogram quantities of alpha-MSH inhibited the ability of peripherally administered IL-1 or TNF to induce both fever and neutrophilia without affecting the increase in plasma levels of serum amyloid P and fibrinogen. Also, nanogram quantities of alpha-MSH given intracerebrally to normal mice did not reverse the depressed CH responses observed after peripheral IL-1 or TNF administration. These findings suggest that both fever and neutrophilia are linked to the direct action of IL-1 or TNF on the brain. This was supported by the observation that an intracerebral injection of IL-1 or TNF in low doses increased core body temperature and circulating neutrophil numbers without affecting plasma levels of acute phase proteins or CH responsiveness. Our results provide additional support for the hypothesis that bidirectional control exists between elements of the neuroendocrine and immune systems.
Animals↗
Neocortical and hippocampal electrical activity following decapitation in the rat.
It has been debated whether or not decapitation of conscious animals is a humane procedure. This problem may be clarified on the basis of recent research that has indicated that neocortical low voltage fast activity (LVFA) and hippocampal rhythmical slow activity (RSA) can result from activity in either the cholinergic corticipetal projections from the basal forebrain or the serotonergic corticipetal projections from the brainstem. These inputs appear to produce, respectively, atropine-sensitive LVFA and RSA and atropine-resistant LVFA and RSA. In waking animals, atropine-resistant LVFA and RSA occur only in close correlation with motor activities such as spontaneous changes in posture, walking or struggling (Type 1 behavior). Painful stimuli readily elicit both Type 1 behavior and LVFA and RSA in atropine-treated rats. Atropine-sensitive LVFA and RSA may occur in anesthetized as well as in conscious animals, but atropine-resistant LVFA and RSA are generally absent during anesthesia. In the experiments reported here, rats were decapitated: (1) in the normal waking state; (2) after pretreatment with atropine or scopolamine; or (3) following induction of anesthesia with ethyl ether. Clear hippocampal RSA and neocortical LVFA were observed in conditions 1 and 3 but not in condition 2. It is concluded: (A) that atropine-sensitive LVFA and RSA are not good indices of conscious perception of pain since these waveforms occur during anesthesia as well as in the waking state; and (B) that the cerebral reaction to decapitation does not resemble the usual cerebral reaction to painful stimuli. This is consistent with the view that decapitation is not inhumane.
Animals↗
Size and structure of the hydrophobic low molecular weight surfactant-associated polypeptide.
The most abundant low molecular weight protein of pulmonary surfactant has unusual properties. Its primary structure has now been determined by analysis at the protein level. The highly hydrophobic polypeptide is resistant to cleavage with proteolytic enzymes, but it was possible to generate fragments by limited cleavage with concentrated HCl or with sodium in liquid ammonia. Acid hydrolysis of the peptide required exceptional conditions for release of all residues. The N-terminus is heterogeneous, and in its longest form the primary structure consists of 35 residues. This analysis establishes that the size of the major native hydrophobic surfactant polypeptide is considerably smaller than previously proposed. Biological effects of the polypeptide recombined with phospholipids are confirmed in vitro by using a pulsating bubble system and in vivo by using premature newborn rabbits. The molecule has branched-chain amino acid residues at about two-thirds of all positions and lacks nine types of residue. The middle third is composed entirely of hydrophobic residues, and fragments from this part are sparingly soluble even in organic solvents. The hydrophobic region is preceded by a more hydrophilic, N-terminal segment. Thus, the molecule has two contrasting parts, like a detergent, which may explain its essential role in the pulmonary surfactant system.
Amino Acid Sequence↗
Hydrophobic 3.7 kDa surfactant polypeptide: structural characterization of the human and bovine forms.
The human and bovine forms of the hydrophobic 3.7 kDa surfactant polypeptide have been structurally analyzed. The polypeptide is essentially inert to enzymatic proteolysis, and methods for analysis include peptide handling in organic solvents and fragment generation by limited acid hydrolysis. The molecule exhibits N-terminal trimming, and the relative abundance of the different starting positions varies both among species and between adult and fetal forms of the surfactant polypeptide. The bovine major form is one residue shorter than the mature 35-residue human molecule. Comparison of the porcine, human and bovine polypeptides reveals a conserved hydrophobic middle/C-terminal segment and a variable hydrophilic N-terminal part.
Amino Acid Sequence↗
Low-molecular-mass surfactant protein type 1. The primary structure of a hydrophobic 8-kDa polypeptide with eight half-cystine residues.
The low-molecular-mass surfactant protein fraction, soluble in chloroform/methanol, contains at least two separate polypeptide chains. The 8-kDa form (type I) was isolated, [14C]carboxymethylated after reduction, and submitted to structural analysis. Its highly hydrophobic nature complicated purification, proteolytic cleavages, and sequence analysis. Acid hydrolysis in 6 M HCl for 7 days was necessary for release of branched-chain residues in full yield. Pepsin was the only enzyme found to cleave the surfactant protein and was used to complement peptide generation by chemical cleavage with CNBr. The primary structure deduced consists of 79 residues with 8 half-cystine residues, and a total of 39% branched-chain hydrophobic residues. However, 11 residues are charged at physiological pH, and all properties of the primary structure are not entirely outstanding in relation to those of other proteins. Hydrophobic segments, coupled with a presumably tight folding from the presence of disulfide bridges, probably explain the unusual properties and the solubility in organic solvents.
Amino Acid Sequence↗
Rabbit lung after inhalation of lithium chloride.
Rabbits were exposed to aerosols of lithium chloride in metal concentrations of 0.6 and 1.9 mg/m3 (mass median aerodynamic diameter of 1 micron) for 4-8 weeks, 5 days/week, 6 h/day. The lungs were studied by light and electron microscopy, with particular reference to inflammatory changes, structure of alveolar macrophages and alveolar epithelial cells. Macrophages recovered by lung lavage were studied by light and electron microscopy and their oxidative metabolic activity was measured. The content of phospholipids was analysed in lung tissue. Exposure to lithium produced no significant effects. It thus seems that Li+ is less toxic to the lung than the other metals investigated with the same test system, e.g. Ni2+, Cd2+, Co2+, Cr3+ and Cr6+.
Administration, Inhalation↗
Prolonged ventilation of the premature newborn rabbit after treatment with natural or apoprotein-based artificial surfactant.
Premature rabbit neonates (gestational age 27 days) were treated at birth with natural surfactant purified from chloroform extracts of porcine lung lipids either by acetone precipitation (Surfactant CK, n = 10) or liquid gel chromatography (Curosurf, n = 22). Another group of animals received artificial surfactant "reconstituted" from isolated low molecular weight (less than or equal to 15 K) apoproteins and synthetic dipalmitoylphosphatidylcholine (DPPC) and dipalmitoylphosphatidylglycerol (DPPG) (Aposurf, n = 10). The phospholipid concentrations of the preparations were adjusted to provide the same individual dose of DPPC for each group of treated animals (3 or 4 mg). In comparison with untreated controls from the same litters, there was a 4-7-fold enhancement of lung-thorax compliance in all groups of surfactant-treated animals during a 3-h period of artificial ventilation. The average initial (20 min) compliance value was lower in the Aposurf-treated group than in animals receiving natural surfactant preparations, but the difference between the groups gradually diminished and was no longer statistically significant during the 2nd and 3rd h of artificial ventilation. Judged from the fall in tidal volume during ventilation with a short expiration phase (0.17 instead of 0.75 s), the apoprotein-based artificial surfactant was also less effective in stabilizing the lungs. A similar conclusion could be drawn from data on alveolar expansion in histological sections, evaluated by automated image analysis.(ABSTRACT TRUNCATED AT 250 WORDS)
1,2-Dipalmitoylphosphatidylcholine↗
Development of a questionnaire measure of adjustment to cancer: the MAC scale.
This paper describes the development of a self-rating scale to measure adjustment to cancer. The Mental Adjustment to Cancer (MAC) Scale has been completed by 235 patients with various types and stages of cancer. It is easily understood by, and acceptable to, patients. Data relating to reliability and internal consistency indicate that the MAC scale is a valuable research tool for clinical studies of patients' psychological adjustment to cancer.
Adaptation, Psychological↗
Aetiological agent of enterically transmitted non-A, non-B hepatitis.
Virus-like particles (VLPs) with a mean diameter of 32 nm were recovered from the stools of three acute phase cases of enterically transmitted non-A, non-B hepatitis (ET-NANBH) occurring in the Soviet Union, North Africa and North America. VLPs from two of these cases were studied in detail and were shown to react specifically with antibody in acute phase sera obtained from other cases of ET-NANBH in Asia, the Soviet Union, North Africa and North America. Partially purified VLPs were found to sediment at 183S in sucrose gradients and to cross-react with antibody in acute phase sera from geographically isolated cases of ET-NANBH. The latter virus preparations were also used to document the seroconversion of experimentally ET-NANBH-infected cynomolgus macaques to 32 nm VLPs. Our findings indicate that one virus or class of viruses is responsible for the majority of ET-NANBH.
Animals↗
Parallel recovery of epidermal antigen-presenting cell activity and contact hypersensitivity responses in mice exposed to ultraviolet irradiation: the role of a prostaglandin-dependent mechanism.
Contact hypersensitivity (CH) responsiveness to 2-4-dinitro-1-fluorobenzene (DNFB) is depressed in mice that are sensitized through skin sites exposed to ultraviolet radiation (UVR). This is partially due to a reduction in antigen-presenting cell (APC) activity within UVR-exposed skin, a condition marked by a decrease in the density of ATPase/Ia-positive epidermal cells. The purpose of this study was to correlate the histological and functional recovery of APC activity in the skin of C3H mice exposed to low-dose (4 X 450 J/m2) or high-dose (1 X 15 kJ/m2) UVR with the normalization of CH responsiveness. Skin biopsy specimens taken at various intervals after UVR exposure revealed a rapid recovery in the density of ATPase/Ia positive cells: about 70% of normal by 3 days, and normal after 5 days. Functional analyses showed that lymph node cells obtained from donors that were sensitized with DNFB 3 days after UVR treatment transferred normal ear-swelling responsiveness to non-primed recipients, thus indicating that APC activity in UVR-exposed skin paralleled the recovery of ATPase/Ia-positive epidermal cells. This suggested that an alternative mechanism causes the persistent depression of CH in mice exposed to UVR. Mice pretreated with indomethacin prior to UVR exposure demonstrated a capacity to elicit CH responses to DNFB, which paralleled the histological and functional recovery of APC in the skin (i.e., normal CH responses were elicited 3 days after exposure to UVR). We conclude from this study that APC activity in the skin recovers rapidly after exposure to UVR, and that a PG-dependent mechanism is responsible for many of the persistent and systemic effects that cause a depression in the CH responsiveness of mice treated with UVR.
Adenosine Triphosphatases↗
Respiratory failure in mice caused by a hybridoma making antibodies to the 15 kDa surfactant apoprotein.
Hybridoma cells were obtained by fusing spleen cells from mice, immunized against the 15 kDa porcine surfactant apoprotein, with a myeloma cell line. Adult mice were inoculated intraperitoneally with this hybridoma; mice that were not inoculated or were inoculated with myeloma cells served as controls. Lung-thorax compliance was measured at various intervals after inoculation. The animals were then killed for histologic-morphometric evaluation of alveolar air expansion, inflammatory reaction in the pulmonary parenchyma, and intraalveolar edema. In the hybridoma group, the mice developed respiratory failure 9 days after inoculation, with markedly reduced lung-thorax compliance, lung congestion, alveolar collapse, hemorrhagic pulmonary edema, and hyaline membranes. Morphometric data from the same animals showed reduced volume density of alveolar air, and increased volume densities of intraalveolar "fluid" (edema) and tissue components. These lung lesions are similar to those in the adult respiratory distress syndrome.
Animals↗
Inactivation of exogenous surfactant in experimental respiratory failure induced by hyperoxia.
Adult guinea pigs were exposed to 100% oxygen until, after 54-85 h, they developed severe respiratory insufficiency. One subgroup of animals was ventilated artificially with 100% oxygen for an additional 60-960 min. When the PaO2 was less than 15 kPa or the PaCO2 greater than 20 kPa, 1 ml of porcine surfactant (phospholipid concentration 80 mg.ml-1) was instilled via the trachea. These animals were ventilated for one more hour and then sacrificed. Surfactant instillation did not improve the blood gases, nor the pulmonary pressure-volume characteristics. All hyperoxia-exposed guinea pigs showed prominent histologic lung lesions, including intraalveolar edema and desquamation of airway epithelium. Compared to normal guinea pigs the volume density of intraalveolar "gas" was decreased and that of intraalveolar fluid increased. The alveolar expansion pattern in histologic sections was not improved in the surfactant-treated animals, compared to hyperoxia-exposed guinea pigs studied immediately after death. In hyperoxia-exposed animals, about 1.5 ml of edema fluid was sampled from the airways. Evaluated with pulsating bubble, our surfactant preparation had a minimum surface tension (gamma min) close to zero. However, the gamma min values of edema fluid from surfactant-treated and nontreated guinea pigs were both about 20 mN.m-1. the edema fluid thus seemed to inhibit the essential physical properties of exogenous surfactant. This, together with the prominent lung lesions, may explain the failure of surfactant replacement therapy at a late stage of hyperoxia-induced respiratory failure.
Animals↗
Surfactant treatment and incidence of intraventricular haemorrhage in severe respiratory distress syndrome.
As part of a multicentre study of porcine surfactant administration in respiratory distress syndrome, 29 babies weighing 2000 g or less were studied in the neonatal intensive care unit of the Royal Maternity Hospital, Belfast. Fourteen babies of a mean gestational age of 28.1 weeks were randomly allocated to the treatment group (200 mg/kg phospholipid given intratracheally) and 15 babies of a mean gestational age of 28.7 weeks formed the control group. All babies had severe respiratory distress syndrome (oxygen requirement over 60%, mechanical ventilation, and age 15 hours or less). Almost immediate improvement in oxygenation was seen in the treated group so that oxygen concentrations could be reduced and remained significantly lower than those of control babies for the first seven days of life. Alveolar-arterial oxygen gradients were also significantly different for the first five days after treatment. More babies in the treatment group survived (79% v 40%) but the difference was not significant. The incidence of pneumothorax and of intraventricular haemorrhage, however, was significantly lower in treated babies compared with controls. For babies weighing less than 1200 g the risk of developing or extending intraventricular haemorrhage after entry to the study was also reduced in the treatment group (29% v 100%).
Cerebral Hemorrhage↗
The pulmonary surfactant system: biochemical aspects and functional significance.
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Animals↗