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PubMed2000

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants.

BACKGROUND: Respiratory failure due to lung immaturity is a major cause of mortality in preterm infants. Although intermittent positive pressure ventilation (IPPV) saves lives, lung distortion during its use is associated with lung injury and chronic lung disease (CLD). Conventional IPPV is provided at 30-80 breaths per minute while a newer form of ventilation called high frequency oscillatory ventilation (HFOV) provides 'breaths' at 10-15 seconds. This has been shown to result in less lung injury in experimental studies. OBJECTIVES: The objective of this review is to determine whether the elective use of high frequency oscillatory ventilation (HFOV) as compared to conventional ventilation in preterm infants who are mechanically ventilated for the respiratory distress syndrome decreases the incidence of chronic lung disease (CLD) without adverse effects. SEARCH STRATEGY: Searches were made of the Oxford Database of Perinatal Trials, MEDLINE, EMBASE, previous reviews including cross references, abstracts, conferences and symposia proceedings, expert informants, journal handsearching by the Cochrane Collaboration, mainly in the English language. Expert informant's search in the Japanese language was made by Prof. Y. Ogawa. SELECTION CRITERIA: Randomized controlled trials comparing HFOV and CV in preterm or low birth weight infants with pulmonary dysfunction, mainly due to RDS, who are to be given IPPV. Randomization and commencement of treatment should have been as soon as possible after the start of IPPV and usually in the first 12 hours of life. DATA COLLECTION AND ANALYSIS: The methodological quality of each trial was independently reviewed by the various authors. Each author extracted data separately; they were compared and differences were resolved. The standard method of the Cochrane Neonatal Review Group was used to synthesize the data using relative risk (RR) and risk difference (RD). From 1/RD the number needed to treat (NNT) for benefits, and number needed to harm (NNH) for adverse effects, were calculated. MAIN RESULTS: Meta-analysis of the six eligible studies comparing HFOV with CV revealed that there is no difference in mortality. There are trends toward decreases in CLD in survivors at 28-30 days, 'death or CLD at 28-30 days' and CLD in survivors at 36-37 weeks postmenstrual age or discharge in the HFOV group. However, there are trends towards increases in severe (grades 3 & 4) intraventricular hemorrhage (IVH) and in periventricular leukomalacia (PVL) in the HFOV group. HFOV results in a small increase in any air leak syndrome (ALS), [summary RR 1.20 (1.03, 1.39)]. Only 2 trials have included neurodevelopmental follow up and more survivors in the HFOV group are abnormal [summary RR 1.26 (1.01, 1.58)]. In the subgroup of four trials where a high volume strategy (HVS) was used, HFOV results in more favourable pulmonary outcomes. There are significantly lower rates of CLD in survivors at 28-30 days [summary RR 0.53 (0.36, 0.76)] and of 'death or CLD at 28-30 days' [summary RR 0.56 (0.40, 0.77) with a non-significant trend towards a reduction in oxygen use at 36-37 weeks postmenstrual age or discharge [summary RR 0.74 (0.55, 1.01)]. There were no differences in the rates of IVH or PVL. Of the four trials in the subgroup using surfactant routinely, three also used the HVS. The trends in results were similar with surfactant to those for the HVS subgroup analysis. One trial suggests that HFOV may reduce the cost of in-hospital care. In the subgroup of two trials (HIFI 1989, Rettwitz-Volk 1998) not using a HVS there is no effect of HFOV on the rate of CLD; however, there is an increase in the rate of PVL [summary RR 1.64 (1.02, 2.64). REVIEWER'S CONCLUSIONS: The overall meta-analyses is dominated by the large HIFI study which did not use the HVS recommended on the basis of animal studies, and in which surfactant was not available. Studies which used HVS have shown some benefits in short term measures of CLD without an in

High-Frequency Ventilation↗

PubMed1999

Surfactant protein B (SP-B) -/- mice are rescued by restoration of SP-B expression in alveolar type II cells but not Clara cells.

Surfactant protein B (SP-B) mRNA and protein are restricted to alveolar Type II and Clara cells in the respiratory epithelium. In order to investigate the function of SP-B in these distinct cell types, transgenic mice were generated in which SP-B expression was selectively restored in Type II cells or Clara cells of SP-B -/- mice. The 4.8-kilobase murine SP-C promoter was used to generate 3 transgenic lines which expressed human SP-B in Type II cells (mSP-C/hSP-B). Likewise, the 2.3-kilobase murine CCSP promoter was used to generate two transgenic lines which expressed human SP-B in Clara cells (mCCSP/hSP-B). mSP-C/hSP-B and mCCSP/hSP-B transgenic mice were subsequently bred to SP-B +/- mice in order to selectively express SP-B in Type II cells or Clara cells of SP-B -/- mice. Selective restoration of SP-B expression in Type II cells completely rescued the neonatal lethal phenotype in SP-B -/- mice. Expression of SP-B in some, but not all Type II cells of SP-B -/- mice, allowed postnatal survival, but resulted in significantly altered lung architecture and function. Selective restoration of SP-B expression in Clara cells of SP-B -/- mice resulted in respiratory dysfunction and invariable neonatal death, related to the complete absence of mature SP-B peptide in these mice. These results indicate that expression and processing of the SP-B proprotein to the mature peptide in Type II cells is absolutely required for lung function in vivo and that SP-B expression in Clara cells cannot substitute for this function.

Animals↗

PubMed1990

Molecular, pharmacologic, and clinical aspects of oxygen-induced lung injury.

The pathogenesis of O2 toxicity involves intracellular production of partially reduced O2 metabolites, which increases with O2 partial pressure. Cytotoxic O2 metabolites impair enzyme function and inhibit DNA, protein, and surfactant lipid biosynthesis. Compounds used clinically that increase O2 metabolism or that are metabolized through free radical intermediates may increase pulmonary O2 toxicity. Recent development of liposome-encapsulated and polyethylene glycol-conjugated antioxidant enzyme preparations may provide a clinically useful means of minimizing O2 toxicity and other oxidant injuries. Human pulmonary O2 toxicity is characterized initially by acute edematous lung injury followed by fibrosis and pulmonary hypertension. Functional changes due to O2 toxicity include diffusion impairment, worsening of ventilation/perfusion relationships, decreased lung compliance, and small airways dysfunction. It is likely that new data derived from molecular and cellular studies of O2 toxicity will continue to enrich the clinical atmosphere and allow more directed approaches to therapy of acute lung injuries, including ARDS.

Animals↗

PubMed2003

Aberrant Wnt/beta-catenin pathway activation in idiopathic pulmonary fibrosis.

To investigate the molecular events that may underpin dysfunctional repair processes that characterize idiopathic pulmonary fibrosis/usual interstitial pneumonia (IPF/UIP), we analyzed the expression patterns of beta-catenin on 20 IPF/UIP lung samples, together with two downstream target genes of Wnt signaling, cyclin-D1, and matrilysin. In 18 of 20 cases of IPF/UIP investigated on serial sections, nuclear beta-catenin immunoreactivity and abnormal levels of cyclin-D1 and matrilysin were demonstrated in proliferative bronchiolar lesions (basal-cell hyperplasia, squamous metaplasia, bronchiolization, honeycombing). The nature of these lesions was precisely defined using specific markers (DeltaN-p63, surfactant-protein-A, cytokeratin-5). Interestingly, nuclear beta-catenin accumulation was also demonstrated in fibroblast foci in most (16 of 20) IPF/UIP samples, often associated with bronchiolar lesions. Similar features were not observed in normal lung and other fibrosing pulmonary diseases (diffuse alveolar damage, organizing pneumonia, nonspecific interstitial pneumonia, desquamative interstitial pneumonia). Sequence analysis performed on DNA extracted from three samples of IPF/UIP did not reveal abnormalities affecting the beta-catenin gene. On the basis of these findings new models for IPF/UIP pathogenesis can be hypothesized, centered on the aberrant activation of Wnt/beta-catenin signaling, with eventual triggering of divergent epithelial regeneration at bronchiolo-alveolar junctions and epithelial-mesenchymal-transitions, leading to severe and irreversible remodeling of the pulmonary tissue.

Adult↗

PubMed2024

Inflammatory and tissue injury marker dynamics in pediatric acute respiratory distress syndrome.

BACKGROUNDThe molecular signature of pediatric acute respiratory distress syndrome (ARDS) is poorly described, and the degree to which hyperinflammation or specific tissue injury contributes to outcomes is unknown. Therefore, we profiled inflammation and tissue injury dynamics over the first 7 days of ARDS, and associated specific biomarkers with mortality, persistent ARDS, and persistent multiple organ dysfunction syndrome (MODS).METHODSIn a single-center prospective cohort of intubated pediatric patients with ARDS, we collected plasma on days 0, 3, and 7. Nineteen biomarkers reflecting inflammation, tissue injury, and damage-associated molecular patterns (DAMPs) were measured. We assessed the relationship between biomarkers and trajectories with mortality, persistent ARDS, or persistent MODS using multivariable mixed effect models.RESULTSIn 279 patients (64 [23%] nonsurvivors), hyperinflammatory cytokines, tissue injury markers, and DAMPs were higher in nonsurvivors. Survivors and nonsurvivors showed different biomarker trajectories. IL-1α, soluble tumor necrosis factor receptor 1, angiopoietin 2 (ANG2), and surfactant protein D increased in nonsurvivors, while DAMPs remained persistently elevated. ANG2 and procollagen type III N-terminal peptide were associated with persistent ARDS, whereas multiple cytokines, tissue injury markers, and DAMPs were associated with persistent MODS. Corticosteroid use did not impact the association of biomarker levels or trajectory with mortality.CONCLUSIONSPediatric ARDS survivors and nonsurvivors had distinct biomarker trajectories, with cytokines, endothelial and alveolar epithelial injury, and DAMPs elevated in nonsurvivors. Mortality markers overlapped with markers associated with persistent MODS, rather than persistent ARDS.FUNDINGNIH (K23HL-136688, R01-HL148054).

Humans↗

PubMed2006

Engineering three-dimensional pulmonary tissue constructs.

In this paper, we report on engineering 3-D pulmonary tissue constructs in vitro. Primary isolates of murine embryonic day 18 fetal pulmonary cells (FPC) were comprised of a mixed population of epithelial, mesenchymal, and endothelial cells as assessed by immunohistochemistry and RT-PCR of 2-D cultures. The alveolar type II (AE2) cell phenotype in 2-D and 3-D cultures was confirmed by detection of SpC gene expression and presence of the gene product prosurfactant protein C. Three-dimensional constructs of FPC were generated utilizing Matrigel hydrogel and synthetic polymer scaffolds of poly-lactic-co-glycolic acid (PLGA) and poly-L-lactic-acid (PLLA) fabricated into porous foams and nanofibrous matrices, respectively. Three-dimensional Matrigel constructs contained alveolar forming units (AFU) comprised of cells displaying AE2 cellular ultrastructure while expressing the SpC gene and gene product. The addition of tissue-specific growth factors induced formation of branching, sacculated epithelial structures reminiscent of the distal lung architecture. Importantly, 3-D culture was necessary for inducing expression of the morphogenesis-associated distal epithelial gene fibroblast growth factor receptor 2 (FGFr2). PLGA foams and PLLA nanofiber scaffolds facilitated ingrowth of FPC, as evidenced by histology. However, these matrices did not support the survival of distal lung epithelial cells, despite the presence of tissue-specific growth factors. Our results may provide the first step on the long road toward engineering distal pulmonary tissue for augmenting and/or replacing dysfunctional native lung in diseases, such as neonatal pulmonary hypoplasia.

Animals↗

PubMed1998

Clearance of Clara cell secretory protein 16 (CC16) and surfactant proteins A and B from blood in acute respiratory failure.

Surfactant proteins A and B (SP-A and SP-B) enter the circulation in a manner that acutely reflects changes in pulmonary function in patients with acute respiratory failure (ARF). There is a small but significant gradient in SP-A and SP-B from arterial to mixed venous (A-V) blood, and since we have detected both proteins in urine, the kidney may be a major site of their systemic clearance. Clara cell secretory protein 16 (CC16), which leaks from the respiratory tract, is known to be freely eliminated by the kidney. Lung plasma protein levels will depend on the rates of both protein entry into and clearance from plasma. In order to study the limiting variable determining these levels, we compared plasma CC16, SP-A, and SP-B in matching A-V blood samples from 37 ARF patients with indices of lung dysfunction and glomerular filtration rate (GFR) (of plasma cystatin C and creatinine). Cystatin C, CC16, SP-A, and SP-B were reduced in mixed venous plasma (all p < 0.001) and their A-V gradients were directly related to their arterial levels (all p < 0.03). Whereas CC16, SP-A, and SP-B reflected blood oxygenation (all p < 0.05), only SP-A and SP-B were related to lung injury score (LIS) (both p < 0.05). In contrast, whereas the clearances of both CC16 and cystatin C were related to that of creatinine (p < 0.02 for both), the clearances of SP-A and SP-B were not. Our study confirms that all three lung proteins are acutely cleared from the circulation of patients with ARF (half-lives < 18 min), and we conclude that whereas the plasma concentration of CC16 depends on GFR, plasma concentrations of SP-A and SP-B reflect lung function independently of this variable.

Acute Disease↗

PubMed2000

Inhalation toxicity of 1,6-hexamethylene diisocyanate homopolymer (HDI-IC) aerosol: results of single inhalation exposure studies.

The early acute pulmonary response of female Wistar rats exposed nose-only to a mixture of 1,6-hexamethylene diisocyanate homopolymer (HDI-IC) aerosol was examined. This study was designed to investigate the time course of the relationship between acute pulmonary irritation and ensuing disturbances of the air/blood barrier in rats exposed to concentrations of 3.9, 15.9, 54.3, or 118. 1 mg HDI-IC/m(3). The duration of exposure was 6 h, followed by serial sacrifices 0 h, 3 h, 1 day, 3 days, and 7 days postexposure. Concentrations were selected based on the results of a 4-h acute inhalation study in rats (LC(50) = 462 mg/m(3)). Bronchoalveolar lavage (BAL) fluid was analyzed for markers indicative of injury of the bronchoalveolar region, including phospholipids as proxy of altered surfactant homeostasis. Glutathione (GSH) was determined in BAL fluid and lung tissue. BAL cells with increased intracellular phospholipids were observed on day 1 and especially day 3, with some residual increase on day 7. Increased intracellular phospholipids and activity of acid phosphatases appear to suggest that phagocytized phospholipids may transiently affect lysosomal function. Following exposure to 15.9 mg/m(3), changes returned almost entirely to the level of the air-exposed control on day 7. Especially at higher exposure concentrations, lung weights and total number of cells in BAL were still statistically significantly elevated at this time point. Experimental evidence suggests that markers indicative of a dysfunction of the air/blood barrier, such as angiotensin-converting enzyme, total protein, and phospholipids engulfed by alveolar macrophages, were most sensitive to probe this type of changes. Although GSH in BALF was increased following exposure, there was an apparent depletion of tissue GSH immediately after cessation of exposure. In summary, this study suggests that respirable HDI-IC aerosol appears to cause a transient dysfunction of the air/blood barrier indicated by an increased extravasation of plasma constituents. Despite the remarkable extent of effects observed, most changes were reversible within a postexposure period as short as 7 days. First evidence of increased leakage of pulmonary epithelial barrier was observed at 3.9 mg/m(3). With respect to changes of early markers of pulmonary epithelial barrier dysfunction, approximately 3 mg HDI-IC/m(3) was considered to be the threshold concentration for acute pulmonary irritation.

Acid Phosphatase↗

PubMed2000

Small-bowel perforation in very low birth weight neonates treated with high-dose dexamethasone.

INTRODUCTION: Early postnatal treatment with high doses of corticosteroids may be effective in reducing the duration of mechanical ventilation in very low birth weight infants at risk for bronchopulmonary dysplasia. However, serious side effects may occur. MATERIAL AND METHODS: A retrospective study on 5 very low birth weight neonates, mean (+/- SEM): gestational age range 27.5 +/- 2 weeks, mean birth weight (+/- SEM): 836 g +/- 169 referred between April 1997 and October 1998 from a single academic neonatal intensive care unit to our tertiary pediatric surgical center with the diagnosis of intestinal perforation. During the same period, 60 very low birth weight infants have been treated in that unit following a standardized protocol including surfactant for respiratory distress syndrome and high-dose dexamethasone to prevent bronchopulmonary dysplasia. RESULTS: Pneumoperitoneum was diagnosed between 6 to 9 days after birth. Clinically, all babies remained surprisingly stable. An isolated ileal perforation, without sign of necrotizing enterocolitis, was found at laparotomy in each patient. A limited intestinal resection was performed, with primary end-toend anastomosis (3 cases) or with transient ileostomies (2 cases). Surgical outcome was favorable in all patients. CONCLUSION: isolated intestinal perforation may be a complication of the preventive treatment of chronic lung disease with high-dose corticosteroids in very low birth weight infants. Conversely, corticosteroids may reduce the clinical signs and the multiple organ dysfunction associated with an abdominal drama, explaining the very good surgical prognosis of these newborns. Attention must be paid to an insidious pneumoperitoneum.

Bronchopulmonary Dysplasia↗

PubMed2000

Novel pathways in the pathogenesis of respiratory syncytial virus disease.

Respiratory syncytial virus (RSV) is a leading cause of severe respiratory infections in infants and children. Extensive research in past decades has expanded our knowledge regarding the specific mechanisms involved in the pathogenesis of RSV bronchiolitis and subsequent chronic obstructive airway disease. Studies of RSV infection are performed in humans, cell culture models, and animal models, each with their own specific limitations. A recently developed murine model in which pulmonary dysfunction can be monitored and quantified appears to add a powerful tool for the study of specific pathogenic mechanisms of experimental RSV infections. Both immunologic and nonimmunologic factors have been implicated in the pathogenesis of RSV-induced diseases. Recently, a hypothesis that RSV bronchiolitis may be the result of production of Th2-type cytokines has become popular. There are, however, studies in human infants with RSV as well as in RSV-infected mice that suggest this theory is incorrect, or at least an oversimplification. There is compelling evidence that cells producing interferon gamma may contribute to RSV-induced wheezing, possibly through induction of leukotriene release. Among the nonimmunologic factors, pulmonary surfactant has recently attracted attention, especially because of the therapeutic implications for infants with severe bronchiolitis. A better understanding of the pathogenesis of RSV-induced diseases will be of considerable help in developing specific therapeutic strategies and in vaccine development.

Animals↗

PubMed2004

Bronchopulmonary dysplasia in preterm infants: pathophysiology and management strategies.

Bronchopulmonary dysplasia (BPD) has classically been described as including inflammation, architectural disruption, fibrosis, and disordered/delayed development of the infant lung. As infants born at progressively earlier gestations have begun to survive the neonatal period, a 'new' BPD, consisting primarily of disordered/delayed development, has emerged. BPD causes not only significant complications in the newborn period, but is associated with continuing mortality, cardiopulmonary dysfunction, re-hospitalization, growth failure, and poor neurodevelopmental outcome after hospital discharge. Four major risk factors for BPD include premature birth, respiratory failure, oxygen supplementation, and mechanical ventilation, although it is unclear whether any of these factors is absolutely necessary for development of the condition. Genetic susceptibility, infection, and patent ductus arteriosus have also been implicated in the pathogenesis of the disease. The strategies with the strongest evidence for effectiveness in preventing or lessening the severity of BPD include prevention of prematurity and closure of a clinically significant patent ductus arteriosus. Some evidence of effectiveness also exists for single-course therapy with antenatal glucocorticoids in women at risk for delivering premature infants, surfactant replacement therapy in intubated infants with respiratory distress syndrome, retinol (vitamin A) therapy, and modes of respiratory support designed to minimize 'volutrauma' and oxygen toxicity. The most effective treatments for ameliorating symptoms or preventing exacerbation in established BPD include oxygen therapy, inhaled glucocorticoid therapy, and vaccination against respiratory pathogens.Many other strategies for the prevention or treatment of BPD have been proposed, but have weaker or conflicting evidence of effectiveness. In addition, many therapies have significant side effects, including the possibility of worsening the disease despite symptom improvement. For instance, supraphysiologic systemic doses of glucocorticoids lessen the incidence of BPD in infants at risk for the disease, and promote weaning of oxygen and mechanical ventilation in infants with established BPD. However, the side effects of systemic glucocorticoid therapy, most notably the recently recognized adverse effects on neurodevelopment, preclude their routine use for the prevention or treatment of BPD. Future research in BPD will most probably focus on continued incremental improvements in outcome, which are likely to be achieved through the combined effects of many therapeutic modalities.

Animals↗

PubMed2003

Multiorgan engraftment and multilineage differentiation by human fetal bone marrow Flk1+/CD31-/CD34- Progenitors.

We previously reported that Flk1(+)/CD31(-)/CD34(-) cells isolated from human fetal bone marrow can differentiate at the single cell level into endothelial and hematopoietic cells in vitro. Here we report that within this cell population reside cells that can differentiate into the epithelium of liver, lung, gut, as well as the cells of both hematopoietic and endothelial system after primary or secondary transplantation into irradiated nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. Hence, Flk1(+)/CD31(-)/CD34(-) cells possess remarkable differentiation potential and may thereby provide an alternative to hematopoietic stem cells for transplantation. In addition, our results show this stem cell population effectively accelerated wound healing in NOD/SCID mice and thus holds therapeutic promise for treatment of genetic disorders, organ dysfunction, and tissue repair in humans.

Animals↗

PubMed2000

[The role of cell adhesion molecules and proinflammatory mediators in the pathogenesis of endotoxin adult respiratory distress syndrome].

The Gram-negative bacterial sepsis that is resistant to therapy results in the development of septic shock and the multiple organ dysfunction syndrome (MODS). It is established that the adult respiratory distress syndrom (ARDS) as a component of MODS is the reason for high mortality in these patients. The basic pathogenetic link between ARDS and the septic shock are the lesions of the alveolo-capillary membrane. They result from the sequestrated neutrophil cells in the lungs. Neutrophil extravasation is manifested by the following steps (stages): 1) weak initial adhesion; 2) rolling; 3) stable adhesion; and 4) extravasation. These processes are mediated by cell adhesion molecules that belong to four classes: selectins, selectin ligands, integrins and immunoglobulin superfamily. Thus cell adhesion molecules mediate the sequestration of neutrophil cells in the lungs and the damage of the pulmonary surfactant system.

Adult↗

PubMed2004

Pharmacologic treatments for acute respiratory distress syndrome and acute lung injury: systematic review and meta-analysis.

BACKGROUND: Multiple pharmacologic treatments have been studied for patients with acute respiratory distress syndrome (ARDS) and acute lung injury (ALI). Our objective was to systematically evaluate this literature to determine the effects of these interventions on important clinical outcomes. METHODS: We searched OVID versions of CENTRAL (The Cochrane Library Issue 3, 2003), MEDLINE (1966-week 2, January 2004), EMBASE (1980-week 4, 2004), CINAHL (1982-week 2, January 2004), and HEALTHSTAR (1995-December 2003); proceedings from four conferences (1994-2003); and bibliographies of review articles and included studies. We included randomized controlled trials (RCTs) of pharmacologic treatments compared with no therapy or placebo for established ARDS and ALI in adults admitted to an intensive care unit, with measurement of early mortality, late mortality, duration of ventilation, ventilator-free days, non-pulmonary organ dysfunction, or adverse events. We excluded trials in other populations incorporating subgroup analyses of patients with ARDS and ALI and studies of nitric oxide, partial liquid ventilation, and fluid and nutritional interventions. Two reviewers independently screened studies and abstracted data from studies included in the analysis. Data were pooled using random effects models where appropriate. RESULTS: We retrieved 75 potentially relevant articles and abstracts, of which 33 trials randomizing 3272 patients met our selection criteria. Meta-analysis showed no effect on early mortality for alprostadil ([prostaglandin E(1)] seven studies; 693 patients; relative risk [RR] 0.95; 95% confidence interval [CI], 0.77, 1.17), acetylcysteine (five studies; 235 patients; RR 0.89; 95% CI, 0.65, 1.21), early high-dose corticosteroids (two studies; 180 patients; RR 1.12; 95% CI, 0.72, 1.74), or surfactant therapy (nine studies; 1418 patients; RR 0.93; 95% CI, 0.77, 1.12). Most trials of alprostadil, early high-dose corticosteroids, and surfactant therapy showed more adverse events in the active therapy arm. Single small RCTs demonstrated lower hospital mortality (24 patients, RR 0.20; 95% CI, 0.05, 0.81) with corticosteroids for late phase ARDS and lower 1-month mortality (30 patients, RR 0.67; 95% CI, 0.47, 0.95) with pentoxifylline for patients with metastatic cancer and ARDS. Individual trials of nine additional interventions failed to show beneficial effects on prespecified outcomes. CONCLUSIONS: Effective pharmacotherapy for ARDS is extremely limited. Corticosteroids for late phase ARDS and pentoxifylline for patients with metastatic cancer and ARDS reduced mortality in single small studies. However, further research is required to investigate their potential benefit in the treatment of ALI/ARDS.

Acetylcysteine↗

PubMed2002

Structural determinants of fluorochemical-induced mitochondrial dysfunction.

Perfluorooctanoate (PFOA) and perfluorooctanesulfonate (PFOS) are thought to induce peroxisome proliferation and interfere with mitochondrial metabolic pathways. Direct measurements revealed that PFOA and the unsubstituted sulfonamide of perfluorooctane (FOSA) uncouple mitochondrial respiration by increasing proton conductance. The purpose of this investigation was to characterize structural determinants responsible for the mitochondrial uncoupling effect of several structurally related fluorochemicals. Included in the study were PFOA, PFOS, FOSA, the N-acetate of FOSA (perfluorooctanesulfonamidoacetate, FOSAA), N-ethylperfluorooctanesulfonamide (N-EtFOSA), and the N-ethyl alcohol [2-(N-ethylperfluorooctanesulfonamido)ethyl alcohol, N-EtFOSE] and N-acetic acid (N-ethylperfluorooctanesulfonamidoacetate, N-EtFOSAA) of N-EtFOSA. Each test compound was dissolved in ethanol and added directly to an incubation medium containing substrate-energized rat liver mitochondria. Mitochondrial respiration and membrane potential were measured concurrently using an oxygen electrode and a TPP+ -selective electrode, respectively. All of the compounds tested, at sufficiently high concentrations, had the capacity to interfere with mitochondrial respiration, albeit via different mechanisms and with varying potencies. At sufficiently high concentrations, the free acids PFOA and PFOS caused a slight increase in the intrinsic proton leak of the mitochondrial inner membrane, which resembled a surfactant-like change in membrane fluidity. Similar effects were observed with the sulfonamide N-EtFOSE. Another fully substituted sulfonamide, N-EtFOSAA, at high concentrations caused inhibition of respiration, the release of cytochrome c, and high-amplitude swelling of mitochondria. The swelling was prevented by cyclosporin A or by EGTA, indicating that this compound induced the mitochondrial permeability transition. The unsubstituted and mono-substituted amides FOSA, N-EtFOSA, and FOSAA all exerted a strong uncoupling effect on mitochondria resembling that of protonophoric uncouplers. Among these compounds, FOSA was a very potent uncoupler of oxidative phosphorylation, with an IC50 of approximately 1 microM. These data suggest that the protonated nitrogen atom with a favorable pKa is essential for the uncoupling action of perfluorooctane sulfonamides in mitochondria, which may be critical to the mechanism by which these compounds interfere with mitochondrial metabolism to induce peroxisome proliferation in vivo.

Alkanesulfonic Acids↗

PubMed2005

Comparative genetics and innate immune functions of collagenous lectins in animals.

Collagenous lectins such as mannan-binding lectins (MBLs), ficolins (FCNs), surfactant proteins A and D (SP-A, SP-D), conglutinin (CG), and related ruminant lectins are multimeric proteins with carbohydrate-binding domains aligned in a manner that facilitates binding to microbial surface polysaccharides. MBLs and FCNs are structurally related to C1q, but activate the lectin complement pathway via interaction with MBL-associated serine proteases (MASPs). MBLs, FCNs, and other collagenous lectins also bind to some host macromolecules and contribute to their removal. While there is evidence that some lectins and the lectin complement pathway are conserved in vertebrates, many differences in collagenous lectins have been observed among humans, rodents, and other vertebrates. For example, humans have only one MBL but three FCNs, whereas most other species express two FCNs and two MBLs. Bovidae express CG and other SP-D-related collectins that are not found in monogastric species. Some dysfunctions of human MBL are due to single nucleotide polymorphisms (SNPs) that affect its expression or structure and thereby increase susceptibility to some infections. Collagenous lectins have well-established roles in innate immunity to various microorganisms, so it is possible that some lectin genotypes or induced phenotypes influence resistance to some infectious or inflammatory diseases in animals.

Animals↗

PubMed2004

Airway injury in lung disease pathophysiology: selective depletion of airway stem and progenitor cell pools potentiates lung inflammation and alveolar dysfunction.

Identification of early events that contribute to the establishment of chronic lung disease has been complicated by the variable involvement of the airway and alveolar compartments in the complex physiology of end-stage disease. In particular, the impact of airway injury on alveolar integrity and function has not been addressed and would be facilitated by development of animal models of lung disease that specifically target a single cell type within the airway epithelium. We have previously demonstrated that ganciclovir treatment of CCtk transgenic mice, which express the herpes simplex thymidine kinase gene under regulation of the mouse Clara cell secretory protein (CCSP) promoter, results in elimination of the airway progenitor and stem cell pools and a consequent failure of airway regeneration that is associated with rapid morbidity and mortality. In this study, we used the CCtk model to test the hypothesis that selective airway injury initiates profound lung dysfunction through mechanisms that compromise alveolar integrity. Results demonstrate that elimination of the CCSP-expressing cell population results in secondary alveolar inflammation, edema, and depletion of the alveolar type II cell population. On the basis of these data we conclude that selective airway injury can serve as the inciting injury in diseases characterized by severely compromised alveolar function.

Animals↗

PubMedDate not supplied

Possible physiological role of myocardial fatty acid binding protein in phospholipid biosynthesis.

Accumulation of free fatty acids and their esters resulting from the degradation of membrane phospholipids is one of the major causes for the myocardial dysfunction during ischemia and reperfusion. In this communication, we have studied the possible physiological role played by fatty acid binding protein (FABP) in stimulating key enzymes involved in phospholipid biosynthesis. Purified rat heart FABP bound a maximum of either 2 mol of [1- 14C]palmitoyl coenzyme A (CoA), oleoyl CoA, or oleic acid per mol of FABP as observed by Scatchard analysis. FABP caused a threefold increase in the incorporation of [1- 14C]palmitoyl CoA into phosphatidic acid as compared to only a 1.5-fold increase by bovine serum albumin (BSA). Myocardial FABP also enhanced acyl CoA monoacylglycerophosphorylcholine acyl transferase minimally at a substrate concentration (greater than 200 microM), the activity of this enzyme was enhanced 4.5- and 2-fold by FABP and BSA, respectively. The maximum stimulation of the enzyme activity took place at the fatty acyl CoA concentration where inhibition of the enzyme activity is usually observed due to the surfactive property of acyl CoAs. These results thus indicate that under abnormal pathophysiological conditions such as ischemia, when acyl CoA concentration increases, FABP may protect acyl CoA monoacylglycerophosphorylcholine acyl transferase as well as stimulate glycerophosphate acyl transferase to limit the loss of membrane phospholipids, suggesting a possible role of FABP in phospholipid biosynthesis.

Acyl Coenzyme A↗