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)
22821059. Wolfson MR, Wu J, Hubert TL, Gregory TJ, Mazela J, Shaffer TH, Lucinactant attenuates pulmonary inflammatory response, preserves lung structure, and improves physiologic outcomes in a preterm lamb model of RDS. Pediatr Res 72:4(375-83)2012 Oct
21142524. Hubert TL, Lindemann R, Wu J, Agnew C, Shaffer TH, Wolfson MR, Prototype hybrid systems for neonatal warming: in vitro comparisons to standard of care devices. Biomed Instrum Technol 44:6(523-7)2010 Nov-Dec
20724665. Kilpatrick LE, Standage SW, Li H, Raj NR, Korchak HM, Wolfson MR, Deutschman CS, Protection against sepsis-induced lung injury by selective inhibition of protein kinase C-d (d-PKC). J Leukoc Biol 89:1(3-10)2011 Jan
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
12591068. Miller L, Banson FL, Bazir K, Korimilli A, Liu Ji, Dewan R, Wolfson M, Panganamamula KV, Carrasquillo J, Schwartz J, Chaker AE, Black M, Risk of esophageal variceal bleeding based on endoscopic ultrasound evaluation of the sum of esophageal variceal cross-sectional surface area. Am J Gastroenterol 98:2(454-9)2003 Feb
12394959. Shashikant MP, Badellino MM, Cooper B, Shaffer TH, Myers SI, Wolfson MR, Physicochemical properties of perfluorochemical liquids influence ventilatory requirements, pulmonary mechanics, and microvascular permeability during partial liquid ventilation following intestinal ischemia/reperfusion injury. Crit Care Med 30:10(2300-5)2002 Oct
11453320. Chappell SE, Wolfson MR, Shaffer TH, A comparison of surfactant delivery with conventional mechanical ventilation and partial liquid ventilation in meconium aspiration injury. Respir Med 95:7(612-7)2001 Jul
11181591. Miller TF, Milestone B, Stern R, Shaffer TH, Wolfson MR, Effects of perfluorochemical distribution and elimination dynamics on cardiopulmonary function. J Appl Physiol 90:3(839-49)2001 Mar
10834696. Al-Rahmani A, Awad K, Miller TF, Wolfson MR, Shaffer TH, Effects of partial liquid ventilation with perfluorodecalin in the juvenile rabbit lung after saline injury. Crit Care Med 28:5(1459-64)2000 May
10603625. Cullen AB, Cox CA, Hipp SJ, Wolfson MR, Shaffer TH, Intra-tracheal delivery strategy of gentamicin with partial liquid ventilation. Respir Med 93:11(770-8)1999 Nov
10587539. Shaffer TH, Wolfson MR, Greenspan JS, Liquid ventilation: current status. Pediatr Rev 20:12(e134-42)1999 Dec
10459422. Philips CM, Weis C, Fox WW, Wolfson MR, Shaffer TH, On-line techniques for perfluorochemical vapor sampling and measurement. Biomed Instrum Technol 33:4(348-55)1999 Jul-Aug
10380093. Miller TF, Milestone B, Stern R, Shaffer TH, Wolfson MR, Effect of single versus multiple dosing on perfluorochemical distribution and elimination during partial liquid ventilation. Pediatr Pulmonol 27:6(410-8)1999 Jun
10360217. Heckman JL, Hoffman J, Shaffer TH, Wolfson MR, Software for real-time control of a tidal liquid ventilator. Biomed Instrum Technol 33:3(268-76)1999 May-Jun
10360216. Wolfson MR, Miller TF, Peck G, Shaffer TH, Multifactorial analysis of exchanger efficiency and liquid conservation during perfluorochemical liquid-assisted ventilation. Biomed Instrum Technol 33:3(260-7)1999 May-Jun
10360214. Shaffer TH, Wolfson MR, Liquid ventilation state-of-the-art, Part I. Biomed Instrum Technol 33:3(251-2)1999 May-Jun
9887157. Driska SP, Laudadio RE, Wolfson MR, Shaffer TH, A method for isolating adult and neonatal airway smooth muscle cells and measuring shortening velocity. J Appl Physiol 86:1(427-35)1999 Jan
9710279. Wolfson MR, Greenspan JS, Shaffer TH, Liquid-assisted ventilation: an alternative respiratory modality. Pediatr Pulmonol 26:1(42-63)1998 Jul
9614640. Chan L, Miller TF, Yuxin J, Farina C, Chander A, Shaffer TH, Wolfson MR, Antenatal triiodothyronine improves neonatal pulmonary function in preterm lambs. J Soc Gynecol Investig 5:3(122-6)1998 May-Jun
9504789. Davidson A, Heckman JL, Donner RM, Miller TF, Shaffer TH, Wolfson MR, Cardiopulmonary interaction during partial liquid ventilation in surfactant-treated preterm lambs. Eur J Pediatr 157:2(138-45)1998 Feb
9475875. Wolfson MR, Kechner NE, Roache RF, DeChadarevian JP, Friss HE, Rubenstein SD, Shaffer TH, Perfluorochemical rescue after surfactant treatment: effect of perflubron dose and ventilatory frequency. J Appl Physiol 84:2(624-40)1998 Feb
9292491. Shaffer TH, Foust R 3rd, Wolfson MR, Miller TF Jr, Analysis of perfluorochemical elimination from the respiratory system. J Appl Physiol 83:3(1033-40)1997 Sep
9261458. Milestone BN, Miller T Jr, Wolfson MR, Stern RG, Shaffer TH, Virtual bronchoscopy with perfluoronated hydrocarbon enhancement. Acad Radiol 4:8(583-6)1997 Aug
9177987. Zelinka MA, Wolfson MR, Calligaro I, Rubenstein SD, Greenspan JS, Shaffer TH, A comparison of intratracheal and intravenous administration of gentamicin during liquid ventilation. Eur J Pediatr 156:5(401-4)1997 May
9176643. Kimless-Garber DB, Wolfson MR, Carlsson C, Shaffer TH, Halothane administration during liquid ventilation. Respir Med 91:5(255-62)1997 May
8959271. Gabriel JL, Miller TF Jr, Wolfson MR, Shaffer TH, Quantitative structure-activity relationships of perfluorinated hetero-hydrocarbons as potential respiratory media. Application to oxygen solubility, partition coefficient, viscosity, vapor pressure, and density. ASAIO J 42:6(968-73)1996 Nov-Dec
8839744. Shaffer TH, Wolfson MR, Liquid ventilation: an alternative ventilation strategy for management of neonatal respiratory distress. Eur J Pediatr 155 Suppl 2:(S30-4)1996 Aug
8726157. Foust R 3rd, Tran NN, Cox C, Miller TF Jr, Greenspan JS, Wolfson MR, Shaffer TH, Liquid assisted ventilation: an alternative ventilatory strategy for acute meconium aspiration injury. Pediatr Pulmonol 21:5(316-22)1996 May
8632927. Wolfson MR, Greenspan JS, Shaffer TH, Pulmonary administration of vasoactive substances by perfluorochemical ventilation. Pediatrics 97:4(449-55)1996 Apr
8795104. Shaffer TH, Wolfson MR, Greenspan JS, Hoffman RE, Davis SL, Clark LC Jr, Liquid ventilation in premature lambs: uptake, biodistribution and elimination of perfluorodecalin liquid. Reprod Fertil Dev 8:3(409-16)1996
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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