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Results for “surfactant dysfunction”

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PubMed2005

[The pulmonary expression of granulocyte-macrophage colony-stimulating factor and surfactant protein in adult idiopathic pulmonary alveolar proteinosis].

OBJECTIVE: To investigate the expression of granulocyte-macrophage colony-stimulating factor (GM-CSF), GM-CSF/IL-3/IL-5 receptor common beta chain (GM-CSFbetacR), surfactant protein (SP)-A and SP-D in adult patients with idiopathic pulmonary alveolar proteinosis (PAP), so as to demonstrate the possible association of GM-CSF, GM-CSFbetacR, SP-A and SP-D with human PAP. METHODS: The protein expression of GM-CSF, GM-CSFbetacR, SP-A and SP-D in the alveolar macrophages and alveolar type II epithelial cells was detected by immunohistochemical staining. RESULTS: The age was 51.8 +/- 9.5 years old for patients with idiopathic PAP (6; males 4, females 2) and 48.8 +/- 12.6 years old for the control adult individuals (6; males 4, females 2). There was no difference in the expression of GM-CSF (P = 0.818) and SP-D (P = 0.24) in alveolar macrophages between patients with idiopathic PAP and the controls. The expression of GM-CSFbetacR (P = 0.002) and SP-A (P = 0.004) in alveolar macrophages of patients with idiopathic PAP was less than that in the controls. There was no expression of GM-CSF in alveolar type II epithelial cells of patients with idiopathic PAP and the controls. There was a little expression of GM-CSFbetacR in alveolar type II epithelial cells of the controls. There was no expression of GM-CSFbetacR in alveolar type II epithelial cells of patients with idiopathic PAP. There was no difference in the expression of SP-A (P = 0.818) and SP-D (P = 0.485) in alveolar type II epithelial cells between patients with idiopathic PAP and the controls. CONCLUSION: The decreased protein expression of GM-CSFbetacR in alveolar macrophages may be one of the mechanisms causing dysfunction of the macrophages in adult patients with idiopathic PAP.

Adult↗

PubMedDate not supplied

Determinants of serum levels of surfactant proteins A and B and Clara cell protein CC16.

Increased leakage of surfactant proteins A and B (SP-A and SP-B) and Clara cell secretory protein (CC16) from the air spaces into the circulation occurs in a range of respiratory conditions. However, circulating levels depend not only on the rate of entry into the circulation, but also on the rate of clearance. In order to clarify the role of the kidney in the clearance of these proteins, serum levels were related to markers of glomerular filtration in 54 non-smoking patients with varying degrees of renal dysfunction, none of whom had respiratory disease or were receiving dialysis at the time of sampling. Serum SP-A was related to SP-B (r = 0.53, p < 0.001) and to CC16 (r = 0.33, p < 0.02). Similarly, SP-B was related to CC16 (r = 0.39, p < 0.004). Stepwise multiple linear regression analysis suggested that serum SP-A and SP-B are influenced by age (approximately 20 and approximately 25% of variance, respectively), whereas CC16 is determined by renal function and, to a lesser extent, by body weight (approximately 63% of variance in total). We conclude that CC16 is cleared from blood by the renal route, whereas SP-A and SP-B are not. Serum SP-A and SP-B are influenced by age, which we speculate reflects increased damage to the alveolocapillary barrier.

Adolescent↗

PubMed1999

Oxidative cell membrane alteration. Evidence for surfactant-mediated sealing.

Exposure to very intense ionizing irradiation produces acute tissue sequelae including inflammation, pain, and swelling that often results in tissue fibrosis and/or necrosis. Acute tissue necrosis occurs in hours when sufficiently rapid damage to membrane lipids and proteins leads to altered membrane structure, disrupting the vital electrochemical diffusion barrier necessary for cell survival. This damage mechanism is thought to underlie the interphase death of lethally irradiated postmitotic cells such as neurons, but it has also been implicated in the rapid cell death of lymphocytes and acute vascular changes due to capillary epithelium dysfunction. It is not known whether sealing of radiation-permeabilized cell membranes will prolong survival of lethally irradiated cells or perhaps lead to repair of damaged nucleic acids. The purpose of this study is to begin to address the first question.

Cell Membrane↗

PubMed1993

New frontiers in critical care medicine.

Critical care medicine integrates various treatment modalities to provide care of patients with multiple system dysfunction or failure and to determine the diagnosis of the particular condition. The pulmonary artery catheter advanced from a simple tool to measure intracardiac pressures and output to methodology enabling clinicians to understand the balance between oxygen delivery and utilization. Critical care developed new concepts in the treatment of respiratory failure including not only forms of mechanical ventilation such as pressure control but also methods such as ECMO and surfactant therapy which may preclude the need for mechanical ventilation or minimize its needs. Sepsis represents the greatest problem in caring for the critically ill. Continued development of genetically engineered drugs may ultimately improve survival and reduce complications. Critical care has become a subspecialty, synthesizing the basic knowledge from anesthesiology, internal medicine, pediatrics and surgery. Its multidisciplinary delivery represents the way of the future.

Bacterial Infections↗

PubMed1995

Prevention and therapy of the adult respiratory distress syndrome.

The complex pathophysiology of adult respiratory distress syndrome (ARDS) makes preventive and therapeutic concepts difficult. Ample experimental evidence indicates that ARDS can be prevented by blocking systemic inflammatory agents. Clinically, only heparin, for inhibition of coagulation phenomena, is presently used among this array of approaches. Corticosteroids have not proven to be beneficial in ARDS. Alternative antiinflammatory agents are being proposed and are under current clinical investigation (e.g. indomethacin, acetylcysteine, alpha 1-proteinase inhibitor, antitumor necrosis factor, interleukin 1 receptor antagonist, platelet-activating factor antagonists). Symptomatic therapeutic strategies in early ARDS include selective pulmonary vasodilation (preferably by inhaled vasorelaxant agents) and optimal fluid balance. Transbronchial surfactant application, presently tested in pilot studies, may be available for ARDS patients in the near future and may have acute beneficial effects on gas exchange, pulmonary mechanics, and lung hemodynamics; its impact on survival cannot be predicted at the present time. Strong efforts should be taken to reduce secondary nosocomial pneumonia in ARDS patients and thus avoid the vicious circle of pneumonia, sepsis from lung infection, and perpetuation of multiple organ dysfunction syndrome. Optimal respirator therapy should be directed to ameliorate gas-exchange conditions acutely but at the same time should aim at minimizing potentially aggravating side effects of artificial ventilation (barotrauma, O2 toxicity). Several new techniques of mechanical ventilation and the concept of permissive hypercapnia address these aspects. Approaches with extracorporeal CO2 removal and oxygenation are being used in specialized centers.

Humans↗

PubMed2006

ABC A-subfamily transporters: structure, function and disease.

ABC transporters constitute a family of evolutionarily highly conserved multispan proteins that mediate the translocation of defined substrates across membrane barriers. Evidence has accumulated during the past years to suggest that a subgroup of 12 structurally related "full-size" transporters, referred to as ABC A-subfamily transporters, mediates the transport of a variety of physiologic lipid compounds. The emerging importance of ABC A-transporters in human disease is reflected by the fact that as yet four members of this protein family (ABCA1, ABCA3, ABCR/ABCA4, ABCA12) have been causatively linked to completely unrelated groups of monogenetic disorders including familial high-density lipoprotein (HDL) deficiency, neonatal surfactant deficiency, degenerative retinopathies and congenital keratinization disorders. Although the biological function of the remaining 8 ABC A-transporters currently awaits clarification, they represent promising candidate genes for a presumably equally heterogenous group of Mendelian diseases associated with perturbed cellular lipid transport. This review summarizes our current knowledge on the role of ABC A-subfamily transporters in physiology and disease and explores clinical entities which may be potentially associated with dysfunctional members of this gene subfamily.

ATP-Binding Cassette Transporters↗

PubMed2006

Primary pulmonary choriocarcinoma combined with adenocarcinoma.

An extremely rare autopsy case of primary pulmonary choriocarcinoma combined with adenocarcinomatous components in a 77-year-old Japanese man is described. The patient died of rapidly progressive respiratory dysfunction without ante-mortem diagnosis. Autopsy revealed necro-hemorrhagic areas of the primary lung tumor with a typical biphasic pattern of choriocarcinoma. Topographical analysis suggested that moderately to poorly differentiated adenocarcinoma components partially surrounded the choriocarcinomatous components. Moreover, dedifferentiated carcinomatous components were scattered next to both adenocarcinomatous and choriocarcinomatous areas, and a few cells of the dedifferentiated carcinomatous components had a similar immunoreaction to conventional adenocarcinomatous or choriocarcinomatous components, such as surfactant apoprotein A, placental alkaline phosphatase or beta-human chorionic gonadotropin. Additionally, epithelial membrane antigen-positive cytotrophoblastic cells were rarely found in choriocarcinomatous areas. The present case suggests that primary lung choriocarcinoma can occur closely related to conventional pulmonary adenocarcinoma, although collision tumor was not completely ruled out.

Adenocarcinoma↗

PubMed2006

Transgenic expression of group V, but not group X, secreted phospholipase A2 in mice leads to neonatal lethality because of lung dysfunction.

In an effort to elucidate the functions of secreted phospholipase A2 (sPLA2) enzymes in vivo, we generated transgenic (Tg) mice for group V sPLA2 (sPLA2-V) and group X sPLA2 (sPLA2-X), which act potently on phosphatidylcholine in vitro. We found that sPLA2-V Tg mice died in the neonatal period because of respiratory failure. The lungs of sPLA2-V Tg mice exhibited atelectasis with thickened alveolar walls and narrow air spaces, accompanied by infiltration of macrophages and only modest changes in eicosanoid levels. This severe pulmonary defect in sPLA2-V Tg mice was attributable to marked reduction of the lung surfactant phospholipids, phosphatidylcholine and phosphatidylglycerol. Given that the expression of sPLA2-V is greatly elevated in human lungs with severe inflammation, our present results raise the intriguing possibility that this isozyme may contribute to ongoing surfactant hydrolysis often observed in the lungs of patients with respiratory distress syndrome. In contrast, sPLA2-X Tg neonates displayed minimal abnormality of the respiratory tract with normal alveolar architecture and surfactant composition. This unexpected result was likely because sPLA2-X protein existed as an inactive zymogen in most tissues. The active form of sPLA2-X was detected in tissues with inflammatory granulation in sPLA2-X Tg mice. These results suggest that sPLA2-X mostly remains inactive under physiological conditions and that its proteolytic activation occurs during inflammation or other as yet unidentified circumstances in vivo.

Animals↗

PubMed2006

What's new in pediatric intensive care.

PURPOSE: To provide an update on new developments in the field of pediatric intensive care. RESULTS: Pediatric intensive care and acute medicine continues to grow internationally with improving intensive care unit mortality rates (2.4% in the United States) and a positive effect on child survival from the leading causes of death in the developing and developed world (sepsis and trauma, respectively). New approaches have developed for the practicing clinician in the use of hypothermia, helium, surfactant, glucose, insulin, hydrocortisone, fluid resuscitation and fluid removal, superior vena cava oxygen saturation, goal-directed, coagulation, immune modulation, and multiple-organ extracorporeal support (MOSES) therapies. Some old drugs have fallen out of favor (propofol and etomidate) while new drugs are being evaluated with favorable (calfactant) and yet to be described effects (activated protein C). New diagnostic tests (troponin and brain natriuretic peptide levels) are being used to aid in diagnosis of heart dysfunction, and a new drug class of Ca+ + sensitizers holds promise for recalcitrant heart dysfunction (levosimendan). CONCLUSION: The field is alive, successful, and progressing across the globe.

Child↗

PubMed2001

Heat stress attenuates ventilator-induced lung dysfunction in an ex vivo rat lung model.

Our laboratory has previously shown decreased mortality rates and the attenuation of lung injury in rats exposed to heat stress (H) 18 h prior to induction of sepsis. In the present study, we examined the hypothesis that heat stress would protect lungs against ventilator-induced lung injury. Male Sprague-Dawley rats were anesthetized and randomly allocated to receive either sham treatment or exposure to heat (rectal temperature 41 degrees C, for 15 min). The lungs were harvested 18 h later, a pressure-volume (P- V) curve was constructed, and the lungs were either lavaged for cytokine and surfactant analyses (preventilation data) or were mechanically ventilated with VT 40 ml/kg in a warmed, humidified chamber. After 2 h of mechanical ventilation, another P-V curve was constructed and the lungs were lavaged for cytokine and surfactant analyses (postventilation data). Mechanical ventilation in control lungs produced a 47% decrease in chord compliance, an increase in lung lavage levels of tumor necrosis factor (TNF)-alpha (722 +/- 306 pg/ml), interleukin (IL)-1beta (902 +/- 322 pg/ml), and macrophage inflammatory protein-2 (MIP-2) (363 +/- 104 pg/ml) as compared with low levels of cytokines detected in preventilation data, and no change in percentage of surfactant large aggregates (LA). In contrast, in mechanically ventilated lungs from animals that were exposed to heat stress we observed a smaller decrease in chord compliance (17%), a significant attenuation in cytokine levels (TNF-alpha 233 +/- 119 pg/ml; IL-1beta 124 +/- 53 pg/ml; MIP-2 73 +/- 52 pg/ml; p < 0.05) and a significant increase in percentage LA compared with control animals. We conclude that exposing animals to heat stress confers protection against the effects of an injurious form of mechanical ventilation, by a mechanism that may involve attenuation of cytokines and preservation of some surfactant properties.

Animals↗

PubMed1994

Modulation of the ionic milieu of the airway in health and disease.

Airway surface liquid (ASL) is an integral part of lung defense mechanisms. Ion transport by airway epithelia regulates the volume and composition of this fluid. A better understanding of the mechanisms of ion transport will enable the development of new therapies for airway diseases associated with defects in these mechanisms. A useful model of a disease with abnormal airway epithelial ion transport is cystic fibrosis (CF), a distinct genetic syndrome of altered lung defense mechanisms characterized by chronic bacterial infection and a steady decline in lung function. Traditional therapies for CF include antibacterial drugs and augmentation of clearance of secretions, but investigators are now studying pharmacological approaches to target the more basic defect of the disease, i.e. abnormal sodium and chloride ion transport. Early treatment in childhood, prior to lung damage, might prevent or at least retard the decline in pulmonary function that remains the hallmark of CF. Ion transport dysfunction may also contribute to other airway diseases such as asthma and chronic bronchitis. Pharmacological intervention at this level may prove beneficial in these common lung diseases as well.

Animals↗

PubMed2026

Maternal transfer of nonylphenol drives oxidative, immune, and epigenetic dysregulation in zebrafish offspring.

Nonylphenol (NP), a widespread surfactant and endocrine-disrupting pollutant, poses significant ecological and public health risks globally; however, its transgenerational effects remain poorly understood. Using zebrafish (Danio rerio), we compared chronic maternal NP exposure (50 and 100 µg/L, 28 days) with acute embryonic exposure (0.22 µmol/L) during 0-3 days post-fertilization (dpf) to delineate mechanistic differences in toxicity. Maternal NP exposure produced severe developmental defects in offspring, including edema, axial curvature, impaired swim bladder inflation, reduced growth, cardiac dysfunction, and decreased viability. These phenotypes were accompanied by systemic molecular disruptions including oxidative stress, altered estrogen receptor (ER) expression, dysregulated mitogen-activated protein kinase (MAPK) signaling, and suppressed innate immune response characterized by attenuated neutrophil/macrophage density, reduced CD68 and complement protein C3 expression, diminished nitrite load, and downregulation of pro-inflammatory mediators at both transcript and protein levels. Maternal exposure further induced apoptosis and persistent epigenetic reprogramming (alterations in DNA methylation and histone-modifying enzymes), hallmarks of transgenerational toxicity. In contrast, direct embryonic NP exposure elicited morphological abnormalities without significant lethality, accompanied by induction of pro-inflammatory cytokines, nitric oxide (NO) synthesis, and MAPK activation, reflecting an augmented inflammatory response. These mechanistic contrasts reveal that maternal NP exposure is a potent driver of systemic, heritable molecular reprogramming, whereas embryonic exposure triggers acute inflammatory pathways. Together, our findings underscore the global relevance of NP as a transgenerational toxicant, advocating for its urgent inclusion in ecotoxicological risk assessments and regulatory frameworks.

Animals↗

PubMed2004

Role of mild cleansing in the management of patient skin.

Routine everyday care of skin is an essential part of optimal patient management. Common problems such as xerosis, dermatitis, eczema, psoriasis, acne, rosacea, and photodamage leave the skin vulnerable to external insults, partly as a result of varying levels of barrier dysfunction. Cosmetic surgery procedures also typically damage the stratum corneum (SC) and leave skin with a very weak barrier during recovery phase. Cleansing is an important aspect of any skin care, since it not only removes unwanted dirt, soil, and bacteria from skin, but also removes dead surface cells, preparing skin to better absorb topically applied drugs/medication. Care must be taken to minimize any further weakening of the SC barrier during cleansing. Cleansers based on mild synthetic surfactants and/or emollients that cause minimal barrier perturbation are ideal for these patients. The present paper is a brief review of four clinical trials that evaluated the efficacy and compatibility of either mild syndet bars or cleansers in patients with atopic dermatitis, acne, rosacea, or patients who had received chemical peels or Retin-A(R) (tretinoin) treatment for sustained photodamage.

Acne Vulgaris↗

PubMed2001

[The lipid layer of the lacrimal tear film: physiology and pathology].

The preocular tear film (POTF) is composed of a deep aqueous-mucin phase that supports a thin superficial lipid phase. The tear lipid layer (TLL), although thin, stabilizes the POTF providing a 25% surface-tension decrease and a 90-95% aqueous evaporation reduction. TLL is formed from lipids secreted by tarsal meibomian glands and spread onto the ocular surface by blinking. The TLL itself is composed of two phases. A thin and deep polar phase, adjacent to the aqueous-mucin layer, has a surfactant role. A thicker and superficial nonpolar phase has antievaporative properties. At the same time, tear lipocalins help the TLL spread and stabilize the lipid-aqueous interface. For clinical examination, TLL is directly observed with the Tearscope. POTF stability and the evaporation rate depend on the lipid layer pattern. When chronic, POTF qualitative trouble (evaporative syndrome) due to a TLL anomaly, leads to secondary ocular surface impairment with increased tear instability and self-propagation of ocular dryness. Meibomian gland dysfunction (MGD) results from local pathology, dermatologic disease (ocular rosacea) or iatrogenic etiology. Cosmetic use is the other principal cause of TLL destabilization. Lid hygiene is the mainstay of MGD treatment. Systemic antibiotics (cyclins) can be associated in cases of severe symptoms. Topical treatment is useful if there is marginal lid inflammation or infection.

Humans↗

PubMed2005

Acute respiratory distress syndrome: update on the latest developments in basic and clinical research.

PURPOSE OF REVIEW: Acute lung injury/acute respiratory distress syndrome is a common, serious condition affecting a heterogeneous population of critically ill patients. Other than low tidal volume ventilation, no specific therapy has improved survival. Understanding the epidemiology, pathogenesis, and lessons to be learned from previous clinical trials is necessary for the development of new therapies and the rational design of studies assessing their efficacy. RECENT FINDINGS: Acute lung injury/acute respiratory distress syndrome occurs in 6-8% of the general intensive care unit population, with a mortality of 32-45%. A recent epidemiologic study found that multi-organ dysfunction, use of tidal volumes higher than 6 ml/kg, and high mean fluid balance were independent risks for mortality. Although high levels of inflammatory mediators are also markers for acute respiratory distress syndrome development and death, short courses of high-dose steroids are not effective in acute cases. The latest theory of biotrauma proposes cellular mechanisms by which mechanical ventilation incites a local and systemic inflammatory response; protective lung ventilation with low tidal volumes can attenuate this inflammation and injury to distal organs. Endogenous surfactant function is clearly impaired, but no commercially available surfactant preparation has been shown to reduce mortality. Results of trials to determine efficacy of steroids in late cases and optimal fluid management are pending. SUMMARY: The results of recent clinical trials have raised more questions. Further study of the inflammatory response, surfactant regulation, and the cellular impact of mechanical ventilation should help to develop new therapies, target patients most likely to benefit, and identify appropriate timing of intervention.

Journal Article↗

PubMedDate not supplied

Neonatal ECMO: Current controversies and trends.

Extracorporeal membrane oxygenation (ECMO), a technique for providing life support to patients with cardiac and/or respiratory dysfunction, allows the heart and lungs to "rest." The neonatal respiratory population has been a major benefactor of ECMO since 1982. Its use for neonatal respiratory disease increased dramatically until the past few years, when the number of neonatal respiratory ECMO cases began a downward trend. Fewer patients with persistent pulmonary hypertension of the newborn (PPHN), meconium aspiration syndrome, respiratory distress syndrome, or sepsis are requiring ECMO support as frequently as in the past. Many attribute this decline to the newer respiratory therapies-mainly, surfactant, high-frequency oscillatory ventilation, and inhaled nitric oxide. Neonates who continue to require ECMO today are sicker than the historic norm and have more complicated and lengthy ECMO runs. Patients with congenital diaphragmatic hernia, PPHN, and sepsis remain the most consistent in their representation among ECMO recipients within this author's institution, suggesting that the newer respiratory therapies have not had the same impact on these patients' needs for ECMO support. Better guidelines for determining which patients would benefit from earlier inititation of ECMO are needed.

Administration, Inhalation↗

PubMed2000

Down-regulation of thyroid transcription factor-1 gene expression in fetal lung hypoplasia is restored by glucocorticoids.

The thyroid transcription factor (TTF)-1 has an essential role in lung morphogenesis and development. It is involved in the transcription of surfactant proteins (SP), which are critical in respiratory function. Neonates with congenital diaphragmatic hernia die of respiratory failure caused by pulmonary hypoplasia with associated biochemical immaturity. To gain new insights into the causes of this disorder and the effect of prenatal hormonal treatment on reducing mortality in these infants, we evaluated the expression of TTF-1 as marker of lung morphogenesis and SP-B as marker of lung maturity. Using a rat model of lung immaturity, we show that TTF-1 and SP-B messenger RNA (mRNA) levels are drastically reduced in congenital lung hypoplasia. Interestingly, prenatal dexamethasone (Dex) treatment increased both TTF-1 and SP-B mRNAs over control levels when administered to rats with lung hypoplasia, but it had no effect on TTF-1 or a moderate effect on SP-B mRNA when administered to control rats. TRH alone also increases TTF-1 and SP-B mRNA levels but to a lesser extent than Dex. When administered together with Dex, TRH counteracts the induction observed with the glucocorticoid. The decrease in TTF-1 mRNA levels in lung hypoplasia is paralleled by a down-regulation of TTF-1 protein levels, as well as by a decrease in the TTF-1/DNA complex when the TTF-1-binding site of the SP-B promoter was used as a probe. Both parameters were reestablished after glucocorticoid treatment. Moreover, the regulation of TTF-1 gene expression described in this report is accompanied by the same regulation in its promoter activity, as demonstrated in transfection experiments performed in H-441 human lung-derived adenocarcinoma cells. In conclusion, our data demonstrate, for the first time, that lung hypoplasia and the associated respiratory dysfunction caused by SP-B deficiency are caused, in part, by down-regulation of TTF-1 gene expression. The observations that prenatal glucocorticoid treatment induces the expression of TTF-1 supports routine in utero glucocorticoid treatment of patients expected to have lung hypoplasia.

Adenocarcinoma↗

PubMed2002

Delivery systems for pulmonary gene therapy.

Delivery of therapeutic genes to the lungs is an attractive strategy to correct a variety of pulmonary dysfunctions such as cystic fibrosis, alpha-1 antitrypsin deficiency, pulmonary hypertension, asthma, and lung cancer. Different delivery routes such as intratracheal instillation, aerosol and intravenous injection have been utilized with varying degrees of efficiency. Both viral and non-viral vectors, with their respective strengths and weaknesses, have achieved significant levels of transgene expression in the lungs. However, the application of gene therapy for the treatment of pulmonary disease has been handicapped by various barriers to the delivery vectors such as serum proteins during intravenous delivery, and surfactant proteins and mucus in the airway lumen during topical application of therapeutic genes. Immune and cytokine responses against the delivery vehicle are also major problems encountered in pulmonary gene therapy. Despite these shortcomings much progress has been made to enhance the efficiency, as well as lower the toxicity of gene therapy vehicles in the treatment of pulmonary disorders such as cystic fibrosis, lung cancer and asthma.

Genetic Therapy↗