Surfactant Dysfunction in Lung Contusion With and Without Superimposed Gastric Aspiration in a Rat Model

Raghavendran, Krishnan; Davidson, Bruce A.; Knight, Paul R.; Wang, Zhengdong; Helinski, Jadwiga D.; Chess, Patricia R.; Notter, Robert H.

doi:10.1097/shk.0b013e3181673fc5

Cited by 38 publications

(43 citation statements)

References 44 publications

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“…Despite these changes, surfactant composition and activity were unaltered in adult mice exposed to 100% oxygen as neonates. The various surfactant-related assessments used here have been shown to be able to document surfactant dysfunction in multiple animal models of acute lung injury (14,25,27,44,45,54,57,69). Acute surfactant dysfunction directly following severe hyperoxic exposure in adult animals is well documented (27,36,44,45), but this was not true for the recovered adult animals here that were exposed to 100% oxygen as neonates.…”

Section: Discussionmentioning

confidence: 81%

Neonatal oxygen adversely affects lung function in adult mice without altering surfactant composition or activity

Yee

Chess

McGrath‐Morrow

et al. 2009

American Journal of Physiology-Lung Cellular and Molecular Phys

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116

123

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Despite its potentially adverse effects on lung development and function, supplemental oxygen is often used to treat premature infants in respiratory distress. To understand how neonatal hyperoxia can permanently disrupt lung development, we previously reported increased lung compliance, greater alveolar simplification, and disrupted epithelial development in adult mice exposed to 100% inspired oxygen fraction between postnatal days 1 and 4. Here, we investigate whether oxygen-induced changes in lung function are attributable to defects in surfactant composition and activity, structural changes in alveolar development, or both. Newborn mice were exposed to room air or 40%, 60%, 80%, or 100% oxygen between postnatal days 1 and 4 and allowed to recover in room air until 8 wk of age. Lung compliance and alveolar size increased, and airway resistance, airway elastance, tissue elastance, and tissue damping decreased, in mice exposed to 60 -80% oxygen; changes were even greater in mice exposed to 100% oxygen. These alterations in lung function were not associated with changes in total protein content or surfactant phospholipid composition in bronchoalveolar lavage. Moreover, surface activity and total and hydrophobic protein content were unchanged in large surfactant aggregates centrifuged from bronchoalveolar lavage compared with control. Instead, the number of type II cells progressively declined in 60 -100% oxygen, whereas levels of T1␣, a protein expressed by type I cells, were comparably increased in mice exposed to 40 -100% oxygen. Thickened bundles of elastin fibers were also detected in alveolar walls of mice exposed to Ն60% oxygen. These findings support the hypothesis that changes in lung development, rather than surfactant activity, are the primary causes of oxygen-altered lung function in children who were exposed to oxygen as neonates. Furthermore, the disruptive effects of oxygen on epithelial development and lung mechanics are not equivalently dose dependent. bronchopulmonary dysplasia; epithelium; hyperoxia; type II cells BRONCHOPULMONARY DYSPLASIA (BPD) is a chronic lung disease often seen in premature infants with very low birth weight (21). At autopsy, lungs of infants who die from BPD are less vascularized, with fewer and larger alveoli (7). Although the pathophysiology of BPD is complex and related in part to gestational age, neonatal hyperoxia is recognized as an important contributing factor to this disease in many infants (see Refs. 3,12,17, 37 for review). Premature infants with BPD have low plasma levels of glutathione (59), and hyperoxia in the context of an immature antioxidant defense increases the potential for oxidative stress injury. The use of exogenous surfactant, antenatal steroids, and milder ventilation strategies has markedly increased survival and other improved outcomes for premature infants over the past two decades. However, many patients continue to show decreased lung capacity, even as young adolescents (19,20,55). Moreover, these children are often rehospitalized following r...

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Section: Discussionmentioning

confidence: 81%

Neonatal oxygen adversely affects lung function in adult mice without altering surfactant composition or activity

Yee

Chess

McGrath‐Morrow

et al. 2009

American Journal of Physiology-Lung Cellular and Molecular Phys

Self Cite

116

123

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“…• Alterations in alveolar surfactant aggregates, whereby the most active large aggregate forms of surfactant are reduced in activity and/or percent content, while less active small aggregate forms of surfactant become more prevalent 72,80,[85][86][87][88][89][90][91][92][93] • Biophysical inhibition and/or chemical alteration of components in the alveolar surfactant film induced by cell membrane lipids, 75,79,83,[94][95][96] meconium, 97 or other substances present during the innate pulmonary inflammatory response, such as proteases, 98 phospholipases, 23,99,100 or reactive oxygen/nitrogen species 84,[101][102][103] • Altered synthesis, secretion, or composition of active surfactant due to injury-induced changes in alveolar type II pneumocytes, which are the primary cells of lung surfactant metabolism [104][105][106][107] All of the above mechanistic pathways of surfactant dysfunction are potentially present in the complex pathology of ALI/ARDS lung injury, and abnormalities in surfactant activity, large aggregate content, or composition have been well documented in bronchoalveolar lavage from patients with ALI/ARDS. 92,93,[108][109][110][111][112][113] Regardless of mechanism, the practical consequences of surfactant dysfunction in ALI/ARDS are not dissimilar to those in RDS.…”

Section: Pharmaceutical Surfactantsmentioning

confidence: 99%

The Future of Exogenous Surfactant Therapy

Willson

Notter

2011

Respir Care

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Since the identification of surfactant deficiency as the putative cause of the infant respiratory distress syndrome (RDS) by Avery and Mead in 1959, our understanding of the role of pulmonary surfactant in respiratory physiology and the pathophysiology of acute lung injury (ALI) has advanced substantially. Surfactant replacement has become routine for the prevention and treatment of infant RDS and other causes of neonatal lung injury. The role of surfactant in lung injury beyond the neonatal period, however, has proven more complex. Relative surfactant deficiency, dysfunction, and inhibition all contribute to the disturbed physiology seen in ALI and acute respiratory distress syndrome (ARDS). Consequently, exogenous surfactant, while a plausible therapy, has proven to be less effective in ALI/ ARDS than in RDS, where simple deficiency is causative. This failure may relate to a number of factors, among them inadequacy of pharmaceutical surfactants, insufficient dosing or drug delivery, poor drug distribution, or simply an inability of the drug to substantially impact the underlying pathophysiology of ALI/ARDS. Both animal and human studies suggest that direct types of ALI (eg, aspiration, pneumonia) may be more responsive to surfactant therapy than indirect lung injury (eg, sepsis, pancreatitis). Animal studies are needed, however, to further clarify aspects of drug composition, timing, delivery, and dosing before additional human trials are pursued, as the results of human trials to date have been inconsistent and largely disappointing. Further study and perhaps the development of more robust pharmaceutical surfactants offer promise that exogenous surfactant will find a place in our armamentarium of treatment of ALI/ARDS in the future. Key words: surfactant; infant respiratory distress syndrome; RDS; acute lung injury; ALI; acute respiratory distress syndrome; ARDS; neonatal. [Respir Care 2011;56(9):1369 -1386.

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“…After BAL, rat lungs were excised, and the whole-cell lysate was used to assess in vitro MPO activity, as previously described (14)(15)(16).…”

Section: Whole Lung Myeloperoxidase Activitymentioning

confidence: 99%

Role of Macrophage Chemoattractant Protein-1 in Acute Inflammation after Lung Contusion

Suresh

Machado-Aranda

et al. 2012

Am J Respir Cell Mol Biol

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Lung contusion (LC), commonly observed in patients with thoracic trauma is a leading risk factor for development of acute lung injury/ acute respiratory distress syndrome. Previously, we have shown that CC chemokine ligand (CCL)-2, a monotactic chemokine abundant in the lungs, is significantly elevated in LC. This study investigated the nature of protection afforded by CCL-2 in acute lung injury/acute respiratory distress syndrome during LC, using rats and CC chemokine receptor (CCR) 2 knockout (CCR2 2/2 ) mice. Rats injected with a polyclonal antibody to CCL-2 showed higher levels of albumin and IL-6 in the bronchoalveolar lavage and myeloperoxidase in the lung tissue after LC. Closed-chest bilateral LC demonstrated CCL-2 localization in alveolar macrophages (AMs) and epithelial cells. Subsequent experiments performed using a murine model of LC showed that the extent of injury, assessed by pulmonary compliance and albumin levels in the bronchoalveolar lavage, was higher in the CCR2 2/2 mice when compared with the wild-type (WT) mice. We also found increased release of IL-1b, IL-6, macrophage inflammatory protein-1, and keratinocyte chemoattractant, lower recruitment of AMs, and higher neutrophil infiltration and phagocytic activity in CCR2 2/2 mice at 24 hours. However, impaired phagocytic activity was observed at 48 hours compared with the WT. Production of CCL-2 and macrophage chemoattractant protein-5 was increased in the absence of CCR2, thus suggesting a negative feedback mechanism of regulation. Isolated AMs in the CCR2 2/2 mice showed a predominant M1 phenotype compared with the predominant M2 phenotype in WT mice. Taken together, the above results show that CCL-2 is functionally important in the down-modulation of injury and inflammation in LC.Keywords: lung contusion; macrophage chemoattractant protein-1; CC chemokine ligand-2; CC chemokine receptor 2; inflammation Thoracic injury is involved in nearly one-third of all acute trauma admissions (1-4), often including clinically significant lung contusion (LC) with subsequent respiratory deficits. LC is an important independent risk factor for the development of acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and ventilator-associated pneumonia in affected patients (1-4), all of which are associated with high mortality and morbidity (5).The clinical pathophysiology of LC includes hypoxemia, hypercarbia, increased work of breathing, and decreased lung volumes and compliance in association with ventilation-perfusion mismatching, intrapulmonary shunting, edema, and segmental lung damage (1, 6, 7). As 30% of patients with LC progress to ALI/ ARDS (1), it is important to delineate the factors responsible for the development of progressive respiratory failure. Several lines of evidence suggest that factors in addition to traumainduced tissue damage may contribute to respiratory failure in LC (1, 3).Macrophage chemoattractant protein (MCP)-1/CC chemokine ligand (CCL)-2 is produced by a number of cells in response to inflammatory stimuli, suc...

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Surfactant Dysfunction in Lung Contusion With and Without Superimposed Gastric Aspiration in a Rat Model

Cited by 38 publications

References 44 publications

Neonatal oxygen adversely affects lung function in adult mice without altering surfactant composition or activity

Neonatal oxygen adversely affects lung function in adult mice without altering surfactant composition or activity

The Future of Exogenous Surfactant Therapy

Role of Macrophage Chemoattractant Protein-1 in Acute Inflammation after Lung Contusion

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