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PubMed1997

Pulmonary dysfunction in neonatal SP-B-deficient mice.

Pulmonary function was assessed in newborn wild-type and homozygous and heterozygous surfactant protein B (SP-B)-deficient mice after birth. SP-B +/+ and SP-B+/- mice became well oxygenated and survived postnatally. Although lung compliance was decreased slightly in the SP-B+/- mice, lung volumes and compliances were decreased markedly in homozygous SP-B-/- mice. They died rapidly after birth, failing to inflate their lungs or oxygenate. SP-B proprotein was absent in the SP-B-/- mice and was reduced in the SP-B+/- mice, as assessed by Western analysis. Surfactant protein A, surfactant proprotein C, surfactant protein D, and surfactant phospholipid content in lungs from SP-B+/- and SP-B-/- mice were not altered. Lung saturated phosphatidylcholine and precursor incorporation into saturated phosphatidylcholine were not influenced by SP-B genotype. Intratracheal administration of perfluorocarbon resulted in lung expansion, oxygenation, and prolonged survival of SP-B-/- mice and in reduced lung compliance in SP-B+/+ and SP-B+/- mice. Lack of SP-B caused respiratory failure at birth, and decreased SP-B protein was associated with reduced lung compliance. These findings demonstrate the critical role of SP-B in perinatal adaptation to air breathing.

Animals↗

PubMed2004

Congenital alveolar proteinosis.

Pulmonary alveolar proteinosis is recently described as a rare cause of lung dysfunction and respiratory distress in term neonates. In several cases, a deficiency or insufficiency of surfactant protein B SP-B has been caused by a frame shift mutation in the gene encoding SP-B. Three siblings with congenital pulmonary alveolar proteinosis showed clinical and radiological evidence. Histopathological and immunohistochemical studies in the last sibling revealed deficiency of SP-B, one of the group of 3 specific lipoproteins that reduce the surface tension between air and liquid interface within pulmonary alveoli, suggesting a gene associated illness.

Biopsy, Needle↗

PubMed1992

Triiodothyronine treatment maintains surfactant synthesis during sepsis.

BACKGROUND: Pulmonary compromise with altered surfactant metabolism is frequently noted during sepsis; triiodothyronine is necessary for normal surfactant synthesis. We evaluated the role of physiologic replacement of triiodothyronine during sepsis-induced hypothyroidism on surfactant synthesis and lung structural integrity. METHODS: Male Sprague Dawley rats (average weight, 330 gm) underwent sham laparotomy or cecal ligation and puncture; treatment was administered to rats that underwent cecal ligation and puncture by Alzet osmotic pump consisting of triiodothyronine (3 ng/hr) or saline control. The rats were killed 24 hours after serum triiodothyronine determination by radioimmunoassay (normal, 60 to 160 ng/dl). Surfactant was obtained by saline lavage. Lipid content was determined by Folch extraction; phospholipid content was verified by chromatography. Blinded histologic analysis of lung confluence and alveolar sparing was done in separate subgroups. Results are +/- SE. RESULTS: Control rats with sepsis were hypothyroid at 24 hours; rats given triiodothyronine were euthyroid (rats that underwent sham laparotomy, 67.7 +/- 4.9 ng/dl; control rats, 37.6 +/- 5.7 ng/dl; and triiodothyronine, 85.7 +/- 19 ng/dl; p less than 0.05 compared with triiodothyronine by analysis of variance). Surfactant production was significantly improved by triiodothyronine compared with control (60.7 +/- 22.6 mg vs 23.2 +/- 11.3 mg; p less than 0.05 by analysis of variance). Lung histologic integrity was maintained by triiodothyronine treatment during sepsis. CONCLUSIONS: Triiodothyronine supplementation may be beneficial in septic-induced pulmonary dysfunction.

Animals↗

PubMed1992

Long-term pulmonary consequences in survivors with bronchopulmonary dysplasia.

The clinical and pulmonary function test evidence of abnormal airway function in infants with BPD is now well established. Studies have shown persistence of airway obstruction into childhood and evidence of residual dysfunction into adulthood. Furthermore, preterm neonates who have been mechanically ventilated but do not meet any of the BPD definitions also have residual pulmonary dysfunction during infancy. As an increasing number of very low birth weight infants survive in the surfactant era, care must be taken to note that their airways are likely to be extremely compliant and thereby exceedingly susceptible to airway barotrauma in the neonatal period. The long-term consequences of airway injury could lead to residual abnormal airway function during infancy. It is hoped that barotrauma can be minimized substantially with a reduction in both the magnitude and duration of ventilatory support following surfactant therapy. With the advent of user-friendly commercial pulmonary function testing equipment, most neonatal follow-up services should include a comprehensive pulmonary follow-up ancillary to the existing neurodevelopmental follow-up services and may thereby reduce the severity of respiratory morbidities and the need for hospital readmissions.

Adrenal Cortex Hormones↗

PubMed2000

Surfactant function affected by airway inflammation and cooling: possible impact on exercise-induced asthma.

Pulmonary surfactant maintains patency of narrow conducting airways. An inflammation, with a leakage of plasma proteins into the airway lumen, causes surfactant to lose some of this ability. Will a lowering of temperature aggravate the deteriorating effect of an inflammation? Calf lung surfactant extract (CLSE) with proteins added was studied with a capillary surfactometer (CS) at temperatures of 25-42 degrees C. BALB/c mice were infected with respiratory syncytial virus (RSV). Six days later the lungs were lavaged and the surfactant in the lavage fluid was studied with the CS at temperatures of 25-42 degrees C. Lavage fluid from allergen challenged asthmatics was examined for its content of surfactant inhibitors at reduced temperatures. It was shown that CLSE with proteins gradually lost its ability to maintain patency as the temperature was lowered. Lavage fluid from the RSV infected mice showed a similar dysfunction at low temperatures. Lavage fluid from the airways of human asthmatics, when challenged with antigen but not with saline, contained agents inhibiting surface activity, particularly at reduced temperatures. Airway inflammation causes surfactant to lose its ability to maintain patency, particularly as the temperature is reduced. That might be a reason for the increased airway resistance observed in asthma patients hyperventilating in cold weather.

Albumins↗

PubMed1997

Ventilation strategies affect surfactant aggregate conversion in acute lung injury.

This study evaluated the effects of varying tidal volumes (VT) and positive end-expiratory pressure (PEEP) levels on surfactant aggregate conversion and lung function in an animal model of lung injury induced by N-nitroso-N-methylurethane. Lung-injured adult rabbits were initially ventilated using a VT of 10 ml/kg (VT10), a respiratory rate of 30 breaths/min (RR30), and a PEEP of 3.5 cm H2O. A trace dose of radiolabeled rabbit large surfactant aggregates was instilled after the onset of ventilation, and animals were then ventilated at different ventilator settings for 1 h. Ventilation strategies involving a lower VT (VT5, RR60) resulted in significantly superior oxygenation and lower surfactant aggregate conversion rates than strategies involving a higher VT ([VT10, RR30], [VT15, RR20], p < 0.05). Increasing the PEEP level to 8.0 cm H2O improved oxygenation, but it was sustained only with a low VT (VT5, RR60), and deteriorated with a high VT (VT10, RR30). Varying VT but not PEEP levels resulted in significant changes in surfactant aggregate conversion. We conclude that increased surfactant aggregate conversion resulting from suboptimal ventilation of injured lungs may play an important role in the pathophysiology of ventilation-induced lung dysfunction in acute lung injury.

Animals↗

PubMed1991

Procoagulant activity in bronchoalveolar lavage of severely traumatized patients--relation to the development of acute respiratory distress.

In a prospective study in severely traumatized patients, procoagulant activity (PCA) was determined in bronchoalveolar lavage fluids (BAL). Bronchoscopy with lavage was serially performed during the first 15 days after injury (in total 148 samples of 25 patients). PCA was measured as recalcification times in the absence or presence of excess phosphatidylethanolamine and translated into procoagulant unit equivalents using standard thromboplastin. The data were correlated to the extent of respiratory failure in the injured patients and were compared to PCA in 29 lavage samples obtained from 10 healthy control subjects. A several-fold increase in BAL PCA was noted in all trauma victims, evident already within the first 24 h after injury. A progressive rise in PCA occurred from the 4th posttraumatic day and was highly significantly more pronounced in patients developing serious respiratory failure than in those with only mild pulmonary dysfunction. Significant correlations were noted between PCA increase and alveolar protein-leakage, granulocyte-influx and surfactant alterations, however with correlation coefficients not surpassing 0.55. We conclude that a marked increase in procoagulant activity occurs in severely injured patients, which may favour alveolar fibrin deposition and is related to the development of acute respiratory failure.

Blood Coagulation Factors↗

PubMed2006

Reactive nitrogen species in the respiratory tract.

Endogenous Nitric Oxide (NO) plays a key role in the physiological regulation of airway functions. In response to various stimuli activated inflammatory cells (e.g., eosinophils and neutrophils) generate oxidants ("oxidative stress") which in conjunction with exaggerated enzymatic release of NO and augmented NO metabolites produce the formation of strong oxidizing reactive nitrogen species, such as peroxynitrite, in various airway diseases including asthma, chronic obstructive pulmonary diseases (COPD), cystic fibrosis and acute respiratory distress syndrome (ARDS). Reactive nitrogen species provoke amplification of inflammatory processes in the airways and lung parenchyma causing DNA damage, inhibition of mitochondrial respiration, protein dysfunction and cell damage ("nitrosative stress"). These effects alter respiratory homeostasis (such as bronchomotor tone and pulmonary surfactant activity) and the long-term persistence of "nitrosative stress" may contribute to the progressive deterioration of pulmonary functions leading to respiratory failure. Recent studies showing that protein nitration can be dynamic and reversible ("denitration mechanisms") open new horizons in the treatment of chronic respiratory diseases affected by the deleterious actions of "nitrosative stress".

Animals↗

PubMed2002

Evaluation of alveolar surfactant aggregates in vitro and in vivo.

In acute lung injury, a decrease in surface-active large aggregates and an increase in the less surface-active small surfactant aggregates are observed. The objective of the current study was to determine if the increase in small aggregates interfered with the function of large aggregates, thereby independently contributing to lung dysfunction. Isolated large aggregates, small aggregates, and large aggregate+small aggregate combinations were analysed for in vitro surface activity utilizing a pulsating bubble surfactometer. Subsequently, large aggregates, small aggregates, and large aggregate+ small aggregate combinations were administered to surfactant-deficient, adult Sprague-Dawley rats. Physiological parameters were measured during 1 h of ventilation. After sacrifice, the whole lung lavage was analysed for protein concentration, and surface activity of the recovered large aggregates. The minimum surface tension of the large aggregate+small aggregate preparations (10 mN x m(-1)) was significantly higher than large aggregates alone (1 mN x m(-1)), but lower than small aggregates alone (21 mN x m(-1) ) after 100 pulsations. In vivo, rats receiving large aggregates+small aggregates showed immediate increases in oxygenation, similar to animals given large aggregates, whereas animals given small aggregates and control animals maintained low oxygenation values. In conclusion, small aggregates interfered with large aggregates function in vitro, but this was not observed in vivo in this experimental model.

Animals↗

PubMedDate not supplied

Treatment and prevention of acute respiratory failure: physiological basis.

Acute respiratory failure is caused by many factors and remains one of the most common reasons for admission to the intensive care unit (ICU). In all cases of acute respiratory failure, there is a shortage of surfactant at the alveolar level. This deficit of surfactant leads to an increase in alveolar surface tension that increases the retraction forces of the lung, leading to end-expiratory alveolar collapse, finally resulting in respiratory dysfunction, which includes hypoxemia, low lung compliance, increase of intrapulmonary shunts, low functional residual capacity, atelectasis, and pulmonary edema. The goal of the treatment and prevention of acute respiratory failure is therefore based on the following three main items: re-opening the collapsed alveolar units; preserving the active surfactant component in the remaining functional alveolar units, and preventing end-expiratory collapse. The following strategies can be used to prevent and/or treat acute respiratory failure: counterbalancing the retraction forces of the lung by applying sufficiently high external pressures; and/or decreasing the surface tension at the air-liquid interface by means of exogenous surfactant, and/or eliminating the air-liquid interface by filling the lung with perfluorocarbons. By applying these therapeutic strategies in routine clinical practice, we should achieve a reduction in the mortality rate of patients suffering from acute respiratory failure.

Acute Disease↗

PubMed2000

YM-40461 improves airway clearance in guinea pigs with induced subacute bronchitis.

The effects of the surfactant secretagogue YM-40461 on the mucociliary transport (MCT) velocity were examined in guinea pigs with induced bronchitis. Guinea pigs were exposed to SO2 gas (900 ppm, 3 h/d) for 5 d. MCT velocity was measured by the movement of a 30% gelatin solution containing Evans blue dye placed on the tracheal mucosal surface. Repeated doses of YM-40461 improved the MCT guinea pigs with bronchitis within 5 d after the completion of SO2 exposure, with an ED50 value of 3.1 mg/kg p.o. At a dose of 10 mg/kg p.o., YM-40461 restored MCT to the control level (98.0% recovery). Ambroxol, bromhexine and salbutamol also improved MCT, but were far less effective than YM-40461. Airway fluid collected from bronchitic animals revealed increased disaturated phosphatidylcholine (DSPC, a major component of surfactants)-to-protein ratio and decreased surface tension produced by YM-40461 treatment (10 mg/kg). These results suggest that YM-40461 ameliorates MCT dysfunction in animals with SO2 gas-induced bronchitis by increasing the DSPC-to-protein ratio in the airway.

Animals↗

PubMed2002

Halothane potentiation of hydrogen peroxide-induced inhibition of surfactant synthesis: the role of type II cell energy status.

UNLABELLED: Small concentrations of inhaled anesthetics can affect Type II cell surfactant production and exacerbate oxidant-mediated lung injury. We hypothesized that inhaled anesthetics augment oxidant-induced Type II pneumocyte dysfunction related to their different effects on cellular adenosine triphosphate (ATP) status. Freshly isolated Type II cells were exposed to different concentrations of hydrogen peroxide (H2O2) in the presence or absence of an in vitro halothane exposure. Cells exposed to 100 microM H2O2 alone demonstrated a 23% decrease in ATP levels and a 32% decrease in phosphatidylcholine (PC) synthesis compared with controls. Halothane alone decreased PC synthesis by only 12% and reduced ATP levels by 20%. However, when exposed to both halothane and H2O2 together, ATP levels decreased by 40%, and PC synthesis rates decreased by 51%. Pretreatment of cells with nicotinamide, an inhibitor of poly adenosine diphosphate ribose polymerase, completely prevented the ATP loss and PC synthesis decline caused by H2O2 alone, but it had no effect on the halothane-augmented portion of the cell injury. These data suggest that the ability of halothane to enhance oxidative damage may be related to its own specific effects on cell energetics that may not be amenable to the same treatments used to mitigate other cellular mechanisms of oxidative stress. IMPLICATIONS: A mediator of inflammation (hydrogen peroxide) and an inhaled anesthetic (halothane) interact to decrease cell energy and secretion of a substance (surfactant) required for healthy lung function from cells that line gas-exchange compartments. This interaction represents a possible mechanism by which inflammatory lung disease may become more severe intraoperatively.

Adenosine Triphosphate↗

PubMed2001

Human surfactant protein a suppresses T cell-dependent inflammation and attenuates the manifestations of idiopathic pneumonia syndrome in mice.

We have previously shown an association between growth factor-induced upregulation of surfactant protein (SP)-A and suppression of alveolar inflammation in our murine model of donor T cell-dependent lung dysfunction after bone-marrow transplantation, referred to as idiopathic pneumonia syndrome (IPS). We hypothesized that SP-A protects the lung in vivo from IPS injury by downregulation of alveolar inflammation. Human SP-A (100 microg), purified by n-butanol extraction or preparative isoelectric focusing, was transtracheally instilled on Day 4 after BMT during a time of in vivo donor T-cell activation. At 48 h after treatment, immunohistochemical staining of lung sections showed that SP-A did not alter T cell- dependent cellular infiltration. However, macrophages from SP-A-instilled mice were less injured and spontaneously produced less tumor necrosis factor-alpha than did cells from buffer-instilled mice. Although exogenous SP-A did not significantly alter bronchoalveolar lavage fluid (BALF) high levels of total protein (TP), an inverse correlation between BALF SP-A and TP concentrations (r = -0.65; P = 0.02) was observed in SP-A-treated but not in buffer-instilled mice. The only difference between the effects of the two sources of SP-A was that butanol-extracted SP-A, but not isoelectric focusing-purified SP-A, suppressed the interferon-gamma/nitric oxide pathway. We conclude that SP-A downregulates T cell-dependent alveolar inflammation by multiple pathways leading to decreased IPS injury.

Animals↗

PubMed1998

Ultrastructural pathology of the alveolar type II pneumocytes of human donor lungs. Electron microscopy, stereology, and microanalysis.

Alveolar type II pneumocytes (PII) were studied in 12 human donor lungs perfused with modified Euro-Collins solution during single-lung transplantation (SLTx). While one lung was transplanted, the contralateral donor lung (cDL) was fixed at the time of SLTx for examination by electron microscopy, stereology, and microanalysis. Three groups were then formed: group A (n = 7), cDL without contusions, uneventful early postoperative course; group B (n = 3), cDL with conclusions, uneventful early postoperative course; group C (n = 2), cDL without contusions, early postoperative respiratory dysfunction. The major findings were that the presence of contusions had no effect on PII ultrastructure and that intracellular surfactant-storing lamellar bodies of cDL in group C were characterized by a higher volume-to-surface ratio (VsR) and larger area per cell profile than group A. Correlation analysis based on pooled data (groups A and C) showed that ischaemic time had little effect on PII ultrastructure and bore no relationship to postoperative clinical variables. The duration of preoperative donor intubation had a pronounced influence on ultrastructure and postoperative clinical variables. The stereologically estimated amount of intracellular surfactant and mitochondrial VsR were the only ultrastructural parameters that were significantly associated with early postoperative oxygenation. Lamellar bodies were the only ultrastructural components found to have a significant relationship to postoperative intubation time. The ultrastructural integrity of type II pneumocytes of human donor lungs is an important determinant of early respiratory function following clinical lung transplantation.

Adolescent↗

PubMed1988

Systemic complications of acute pancreatitis.

The multisystem involvement in acute pancreatitis (AP) is a reflection of the pancreatic gland's capacity to produce a number of potent vasoactive peptides, hormones, and enzymes. The various prognostic criteria are early evaluations of these metabolic derangements. The pathogenesis of hypocalcemia, long recognized as an indicator of severity of AP, is multifactorial. Imbalances of parathyroid hormone (PTH)-calcitonin, the interactions of glucagon, gastrin and other pancreatic hormones with PTH-calcitonin, the role of free fatty acids in binding serum calcium with albumin, and the translocation of calcium ion in muscles and liver, have been recently described but remain conflicting theories. Yet, the time-honored theory of calcium-soap formation enjoys wide acceptance. Hyperglycemia, hypoglycemia, and occasional ketoacidosis in acute pancreatitis have been studied thoroughly. The complex cause-and-effect relationship between hyperlipidemia with acute pancreatitis needs further study. The coagulation abnormalities seem to be initiated by activated trypsin, and their role in microvascular coagulation appears to form a unifying hypothesis for major organ dysfunction, but this requires further investigation. Adult respiratory distress syndrome may be the result of active enzymes that digest pulmonary surfactant and/or microvascular thrombosis. The depression of cardiac function and shock are suspected to be secondary to vasoactive peptides such as bradykinin, or myocardial depressant factor, whose structure has yet to be elucidated. The renin-angiotensin alterations and renal complications in acute pancreatitis have received scant attention in the literature. The onset of moderate visual disturbances, or even blindness, in a patient with acute pancreatitis as a result of retinal vessel thrombosis is fortunately uncommon. Rare but interesting are the manifestations such as subcutaneous fat necrosis, arthralgia, and pancreatic encephalopathy. Despite the extensive literature on the complexities of the pathogenesis of complications of acute pancreatitis, there have been very few advances in the prevention and management of specific complications. It is hoped that further work on modification of enzymatic disturbances induced in acute pancreatitis will result in its effective treatment and prevention of serious complications.

Acute Disease↗

PubMed1976

The centrineurogenic etiology of the respiratory distress syndrome: induction by isolated cerebral hypoxemia and prevention by unilateral pulmonary denervation.

Twenty-eight anemic control dogs were subjected to isolated cerebral hypoxemic (PO2,35+/-5 mm Hg) perfusion for 2 hours. All were found to have functional pulmonary impairment. Two hours later, twenty were sacrificed and found to have the bilateral anatomic complex of the respiratory distress syndrome (RDS). All those not sacrificed expired within 20 hours with progressive respiratory distress and at autopsy had the bilateral anatomic complex. Twenty-three beagles with chronic denervation (autotransplantation) of the left lung also were subjected to the 2 hour isolated cerebral arterial hypoxemic perfusion. Minimal pulmonary functional impairment was measurable in all. Ten of sixteen were long-term survivors. The six that succumbed did not appear to suffer respiratory deaths. These six, as well as seven sacrificed 2 hours after perfusion, had the anatomic complex of RDS in the normally innervated right lungs. However, the denervated left lungs were anatomically normal. These findings are offered as additional evidence that RDS has a centrineurogenic etiology. We postulate the following sequence: "shock" causes cerebral (probably hypothalamic) cellular oxygen deprivation and dysfunction; there is autonomically mediated, increased resistance of the pulmonary venules ("postcapillary sphincters"); this leads to capillary hypertension, congestion, hemorrhage, edema, surfactant inactivation, and atelectasis. Pulmonary denervation blocks this sequence and protects the lung.

Animals↗

PubMed2003

Open lung in ARDS.

Every year, millions of patients worldwide receive ventilator support during surgery. Mechanical ventilation has become an important therapy in the treatment of patients with impaired pulmonary function and particularly in patients suffering from adult respiratory distress syndrome (ARDS). ARDS is caused by multiple factors and is characterized by respiratory dysfunction including hypoxemia and decreased lung compliance. It is known that the decrease in lung distensibility is due to a disturbed surfactant system with an elevated surface tension. This increase in surface tension leads to an increase in forces acting at the air-liquid interface, resulting finally in end-expiratory collapse, atelectasis, an increase in right-to-left shunt and a decrease in paO2.

Animals↗

PubMed2000

Interstitial pneumonia in Hermansky-Pudlak syndrome: significance of florid foamy swelling/degeneration (giant lamellar body degeneration) of type-2 pneumocytes.

Although usual interstitial pneumonia (UIP)-like IP has been known as the most serious complication of Hermansky-Pudlak syndrome (HPS), its pathologic features and pathogenesis are poorly understood. We investigated biopsied and autopsied lung tissues from five patients who died of UIP-like IP associated with HPS (HPSIP). The salient histopathologic features of HPSIP observed were: (1) alveolar septa displaying florid proliferation of type-2 pneumocytes (2PCs) with characteristic foamy swelling/degeneration; (2) patchy fibrosis with lymphocytic and histiocytic infiltration centered around respiratory bronchioles, occasionally showing constrictive bronchiolitis; and (3) honeycomb change without predilection for the lower lobes or subpleural area. Those peculiar 2PCs were histochemically characterized by the over accumulation of phospholipid, immunohistochemically by a weak positivity for surfactant protein, and ultrastructurally by the presence of numerous giant lamellar bodies that compressed the nucleus with occasional cytoplasmic disruption, together suggesting a form of cellular degeneration with an over accumulation of surfactant (giant lamellar body degeneration). The present study strongly indicates that there is a basic defect in the formation/secretion process of surfactant by the 2PCs in HPS, which may well be the triggering factor for the HPSIP development. Other factors, such as macrophage dysfunction, may be working synergistically for further acceleration of the inflammatory process.

Adult↗