Despite advances in respiratory care and reduction in mortality of patients with respiratory failure, significant morbidity persists, often resulting from iatrogenic mechanisms. In particular, preterm infants <1500 gm experience significant acute and chronic respiratory complications. More importantly, during an era of increasing multiple births secondary to infertility management, a greater number of very low birth weight and very preterm infants are born. Those infants < 500 gm who survive the initial respiratory distress syndrome of prematurity, commonly (i.e. 85%) experience significant chronic lung disease with neurodevelopmental delay. In this regard, these fragile infants represent an underserved population with respect to existing respiratory therapies. The incidence of acute and chronic lung disease (i.e. bronchopulmonary dysplasia, BPD) in these preterm infants has not been substantially affected. BPD has been hypothesized to begin with acute inflammatory changes that occur secondary to toxic reactive oxygen species and mechanical stress shortly after initiating supplemental oxygen and mechanical ventilation in the management of respiratory distress syndrome (RDS). Inflammatory induced-alterations of the alveolar epithelium and elastic extracellular matrix (eECM) may render the lung refractile to remodeling, resulting in arrested lung development and impaired function. The preterm lung is particularly vulnerable to injury due to developmental deficiencies in eECM, surfactant, anti-oxidant and anti-inflammatory profiles. A logical strategy to prevent this progression is to augment anti-inflammatory capabilities in the lung. For this reason, innovative means to support pulmonary gas exchange while interrupting the inflammatory cascade and preserving lung structure/function are required. To address this issue, Dr. Wolfson’s research ranges from the development and laboratory/clinical testing of a non-invasive chest wall splint to offset respiratory muscle immaturity, to the use of an alternative respiratory media to support pulmonary gas exchange and drug delivery. In this regard, protocols under Dr. Wolfson’s direction at the bench and translated to the bedside, utilize perfluorochemical liquids as a core technology to protect the immature lung and treat the more mature, injured lung. Perfluorochemical liquids are colorless, odorless, chemically inert liquids. They have high respiratory gas solubility, relatively low surface tension, and are thus uniquely suited to inflate the lung at low pressure while supporting gas exchange. The combination of the physicochemical properties of the PFC liquid and biophysical effects of the liquid on lung mechanics support physiologic responses. Due to relatively low surface tension, high respiratory gas solubility and high spreading coefficients, PFC instillation replaces the gas-liquid interface with a liquid-liquid interface at the lung surface while supporting an adequate alveolar reservoir for pulmonary gas exchange. In turn, high surface tension at the gas-liquid interface is eliminated and interfacial tension is reduced, allowing the lung to be inflated at lower pressures and remain recruited thus affording mechanoprotection to break the cycle of iatrogenic chronic lung disease. To address the pulmonary mechanoprotective aspects of PFC liquids, we are currently:
Expanding our liquid ventilation designs and concepts to encompass transient, conditioning strategies through progression to gas breathing;
Evaluating impact of liquid as compared to gas ventilation on elastic extracellular matrix.
Our work also indicates that PFCs are cytoprotective. Proposed mechanisms include reducing biotrauma and pulmonary inflammation associated with ventilation by indirect mechanisms, such as providing a mechanical barrier against neutrophil and macrophage infiltration and activation, or by directly modifying cellular responses. Recent studies have demonstrated reduced pulmonary inflammation and improved lung morphology in models following ventilation with aerosolized or instilled PFC liquids. While the exact cytoprotective mechanisms have yet to be definitively elucidated, alterations in the diffusion and action of inflammatory mediators within PFCs, the actions of lipid-soluble PFCs within the cell membrane, intracellularly, and the distribution and sustained presence of PFCs within injured lung are all possibilities. We are currently exploring the impact of the physicochemical properties of the PFC liquids with respect to:
Time and PFC dose on the membrane packing in the polar headgroup regions and in the hydrocarbon core;
How PFC liquids affect membrane lateral organization, an important determinant of membrane function and properties;
Impact on oxidative stress pathways and oxidative gene regulation;
Impact on cytoskeleton.
The same properties that make PFC liquids attractive for liquid ventilation lend to their potential for intrapulmonary administration of various agents. Respiratory gas solubility supports gas exchange, while the low surface tension and ability to recruit lung volume also allow for drug distribution to under ventilated lung regions. Additionally, the inert nature precludes any drug-vehicle interactions. When agents are suspended in PFC liquid and delivered during liquid ventilation, it is possible to control the delivery rate, the time of injection, and the total amount of drug delivered to the target site, the lung. We are currently exploring the use of PFC liquids for intrapulmonary delivery of:
Anti-inflammatory proteins (i.e. rhCC10);
Anti-oxidant proteins (CuZnSOD, MnSOD) and genes (recombinant adenovirus expressing MnSOD or CuZnSOD;
Naked plasmid.
In addition to pulmonary mechanoprotective and cytoprotective applications of PFC liquids, Dr. Wolfson’s laboratory is also exploring the use of PFC liquids for therapeutic hypothermia. The physicochemical profile of high O2 solubility, low surface tension, high spreading coefficient, and evaporative characteristics of aerosolized perfluorochemical (PFC) support its use to increase heat carrying capacity of respired gas. Briefly, the effectiveness of hypothermic brain neuroprotection depends on how rapidly cooling is initiated and how quickly the therapeutic hypothermic zone is reached. Whole body surface or invasive intravascular methods are encumbered by equipment requirements and systemic instability. Due to proximity to the cerebral circulation, the nasopharyngneal pathway is uniquely suited for selective brain hypothermia; however, nasopharyngneaNP cooling with gases or liquids is limited by low heat capacity and respiratory compromise, respectively. As an alternative, we have partnered with industry to explore the use of PFC liquids as a relatively non-invasive and expedient means for selective cerebral hypothermia for neuroprotection against insults secondary to clinical scenarios such as stroke, head trauma, and cardiac compromise.
Nasal continuous positive airway pressure (nCPAP) has become an increasingly popular alternative for preterm infants who do not initially require endotracheal intubation and positive pressure ventilation. While nCPAP avoids the potential morbidity associated with endotracheal intubation and mechanical ventilation, it has not been possible to effectively deliver exogenous surfactant to the lung due to limitations related to surfactant inactivation and aerosol technology. In addition bolus delivery of exogenous surfactants requires some form of intubation, often requiring an initial increase in driving pressures to facilitate alveolarization, and often involves ventilator disconnection during administration. Dr. Wolfson's laboratory has assumed a leadership role in performing studies in preterm preparation to develop drug/device combination, using a precision engineered, peptide-containing synthetic surfactant and a novel aerosol generator to potentially deliver large quantities of active surfactant to the lung when coupled with a CPAP generator or mechanical ventilator. This technology would allow delivery of aerosolized surfactant to preterm infants receiving nCPAP or those on a ventilator.
Recent Medically Related Publications, Obtained from PubMed (Click on PubMed ID to view abstract)
19434687. Laudadio RE, Wolfson MR, Shaffer TH, Driska SP, Developmental differences in the contractile response of isolated ovine tracheal smooth muscle cells. Pediatr Pulmonol 44:6(602-12)2009 Jun
18841530. Wolfson MR, Funanage VL, Kirwin SM, Pilon AL, Shashikant BN, Miller TL, Shaffer TH, Recombinant human Clara cell secretory protein treatment increases lung mRNA expression of surfactant proteins and vascular endothelial growth factor in a premature lamb model of respiratory distress syndrome. Am J Perinatol 25:10(637-45)2008 Nov
18689464. Venegas B, Wolfson MR, Cooke PH, Chong PL, High vapor pressure perfluorocarbons cause vesicle fusion and changes in membrane packing. Biophys J 95:10(4737-47)2008 Nov 15
18496275. Wolfson MR, Hirschl RB, Jackson JC, Gauvin F, Foley DS, Lamm WJ, Gaughan J, Shaffer TH, Multicenter comparative study of conventional mechanical gas ventilation to tidal liquid ventilation in oleic acid injured sheep. ASAIO J 54:3(256-69)2008 May-Jun
18266110. Wolfson MR, Malone DJ, Wu J, Hoffman J, Rozenberg A, Shaffer TH, Barbut D, Intranasal perfluorochemical spray for preferential brain cooling in sheep. Neurocrit Care 8:3(437-47)2008
17436327. Cullen AB, Cooke PH, Driska SP, Wolfson MR, Shaffer TH, Correlation of tracheal smooth muscle function with structure and protein expression during early development. Pediatr Pulmonol 42:5(421-32)2007 May
17149150. Miller TL, Shashikant BN, Pilon AL, Pierce RA, Shaffer TH, Wolfson MR, Effects of recombinant Clara cell secretory protein (rhCC10) on inflammatory-related matrix metalloproteinase activity in a preterm lamb model of neonatal respiratory distress. Pediatr Crit Care Med 8:1(40-6)2007 Jan
16534184. Cullen AB, Cooke PH, Driska SP, Wolfson MR, Shaffer TH, The impact of mechanical ventilation on immature airway smooth muscle: functional, structural, histological, and molecular correlates. Biol Neonate 90:1(17-27)2006
16276338. Miller TL, Shashikant BN, Melby JM, Pilon AL, Shaffer TH, Wolfson MR, Recombinant human Clara cell secretory protein in acute lung injury of the rabbit: effect of route of administration. Pediatr Crit Care Med 6:6(698-706)2005 Nov
16210850. Miller TL, Shashikant BN, Pilon AL, Pierce RA, Shaffer TH, Wolfson MR, Effects of an intratracheally delivered anti-inflammatory protein (rhCC10) on physiological and lung structural indices in a juvenile model of acute lung injury. Biol Neonate 89:3(159-70)2006
16081627. Shashikant BN, Miller TL, Welch RW, Pilon AL, Shaffer TH, Wolfson MR, Dose response to rhCC10-augmented surfactant therapy in a lamb model of infant respiratory distress syndrome: physiological, inflammatory, and kinetic profiles. J Appl Physiol 99:6(2204-11)2005 Dec
15911457. Wolfson MR, Shaffer TH, Pulmonary applications of perfluorochemical liquids: ventilation and beyond. Paediatr Respir Rev 6:2(117-27)2005 Jun
15891342. Shashikant BN, Miller TL, Jeng MJ, Davis J, Shaffer TH, Wolfson MR, Differential impact of perfluorochemical physical properties on the physiologic, histologic, and inflammatory profile in acute lung injury. Crit Care Med 33:5(1096-103)2005 May
15678504. Miller TL, Palmer C, Shaffer TH, Wolfson MR, Neonatal chest wall suspension splint: a novel and noninvasive method for support of lung volume. Pediatr Pulmonol 39:6(512-20)2005 Jun
14717869. Wolfson MR, Shaffer TH, Liquid ventilation: an adjunct for respiratory management. Paediatr Anaesth 14:1(15-23)2004 Jan
14717868. Shaffer TH, Wolfson MR, Panitch HB, Airway structure, function and development in health and disease. Paediatr Anaesth 14:1(3-14)2004 Jan
12797896. Foust R 3rd, Cullen AB, Wolfson MR, Shaffer TH, Meconium aspiration injury: Uncoupling between the in vivo physiologic and in vitro inflammatory responses. Pediatr Crit Care Med 2:1(93-8)2001 Jan
12797891. Foust R 3rd, Cox C, Davis JM, Wolfson MR, Miller TF, Horowitz S, Shaffer TH, Pulmonary antioxidant enzyme activity during early development: Effect of ventilation. Pediatr Crit Care Med 2:1(63-68)2001 Jan
12780988. Jeng MJ, Oliver R, Wolfson MR, Shaffer TH, Partial liquid ventilation: Effect of initial dose and redosing strategy in acute lung injury. Pediatr Crit Care Med 3:2(163-170)2002 Apr
12780971. Cox CA, Fox WW, Weiss CM, Wolfson MR, Shaffer TH, Liquid ventilation: Gas exchange, perfluorochemical uptake, and biodistribution in an acute lung injury. Pediatr Crit Care Med 3:3(288-296)2002 Jul
Commonwealth of Pennsylvania, Health Research Formula Fund Award (Tobacco Settlement Fund) “Pulmonary and Systemic Cytoprotective Ventilatory Strategies in the Immature Neonate” (Principal Investigator)
National Institutes of Health HLBI, 64158, Consortium Agreement; “Delivery of Antioxidant Enzymes and Genes to Neonatal Lung” (Co-Investigator)
BeneChill, Inc. “Perfluorochemical Induced Hypothermia: Induction and Maintenance for Neuroprotection” (Principal Investigator)
National Institutes of Health 1 P20 RR020173 “Center for Pediatric Research Excellence” (Collaborator/Mentor)
Respironics Inc.; “Measurement of Chest Wall and Pulmonary Function: Use of an external splint to improve chest wall stability”. (Principal Investigator)
Claragen Inc. “Recombinant Human CC10 as a Therapy in ARDS” (Co- Principal Investigator)
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