Person: Fredberg, Jeffrey
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Fredberg
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Jeffrey
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Fredberg, Jeffrey
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Publication Reduced Baseline Airway Caliber Relates to Larger Airway Sensitivity to Rostral Fluid Shift in Asthma(Frontiers Media S.A., 2017) Bhatawadekar, Swati A.; Keller, Gabriel; Francisco, Cristina O.; Inman, Mark D.; Fredberg, Jeffrey; Tarlo, Susan M.; Stanbrook, Mathew; Lyons, Owen D.; Yadollahi, AzadehBackground: We have previously shown that when asthmatics go supine, fluid shifts out of the legs, accumulates in the thorax, and exacerbates lower airway narrowing. In the retrospective analysis of our previous work presented here, we test the hypothesis that the sensitivity of this process relates inversely to baseline caliber of the lower airways. Methods: Eighteen healthy (six women) and sixteen asthmatic subjects (nine women) sat for 30 min, and then lay supine for 30 min. While supine, lower body positive pressure (LBPP, 40 mm Hg) was applied to displace fluid from the legs similar in amount to the overnight fluid shift. Respiratory resistance and reactance at 5 Hz (R5 and X5) and leg and thoracic fluid volumes (LFV and TFV) were measured at the beginning and end of the supine period. Results: With LBPP, healthy, and asthmatic subjects had similar changes in the LFV and TFV (p = 0.3 and 0.1, respectively). Sensitivity to fluid shift, defined by ΔR5/ΔTFV, was larger in the asthmatics than in the healthy subjects (p = 0.0001), and correlated with baseline R5 in the supine position in the asthmatics (p = 0.7, p = 0.003). No such association was observed in the healthy subjects (p = 0.6). In the asthmatics, women showed a greater reduction in X5 than men with LBPP (p = 0.009). Conclusions: Smaller baseline airway caliber, as assessed by larger R5, was associated with increased sensitivity to fluid shift in the supine position. We conclude that asthmatics with narrower small airways such as obese asthma patients, women with asthma and those with severe asthma may be more sensitive to the effects fluid shift while supine as during sleep.Publication Altered mechanobiology of Schlemm's canal endothelial cells in glaucoma(Proceedings of the National Academy of Sciences, 2014) Overby, Darryl R.; Zhou, Enhua; Vargas-Pinto, Rocio; Pedrigi, Ryan M.; Fuchshofer, Rudolf; Braakman, Sietse T.; Gupta, Ritika; Perkumas, Kristin M.; Sherwood, Joseph M.; Vahabikashi, Amir; Dang, Quynh; Kim, Jae Hun; Ethier, C. Ross; Stamer, W. Daniel; Fredberg, Jeffrey; Johnson, MarkIncreased flow resistance is responsible for the elevated intraocular pressure characteristic of glaucoma, but the cause of this resistance increase is not known. We tested the hypothesis that altered biomechanical behavior of Schlemm’s canal (SC) cells contributes to this dysfunction. We used atomic force microscopy, optical magnetic twisting cytometry, and a unique cell perfusion apparatus to examine cultured endothelial cells isolated from the inner wall of SC of healthy and glaucomatous human eyes. Here we establish the existence of a reduced tendency for pore formation in the glaucomatous SC cell—likely accounting for increased outflow resistance—that positively correlates with elevated subcortical cell stiffness, along with an enhanced sensitivity to the mechanical microenvironment including altered expression of several key genes, particularly connective tissue growth factor. Rather than being seen as a simple mechanical barrier to filtration, the endothelium of SC is seen instead as a dynamic material whose response to mechanical strain leads to pore formation and thereby modulates the resistance to aqueous humor outflow. In the glaucomatous eye, this process becomes impaired. Together, these observations support the idea of SC cell stiffness—and its biomechanical effects on pore formation—as a therapeutic target in glaucoma.Publication The actin regulator zyxin reinforces airway smooth muscle and accumulates in airways of fatal asthmatics(Public Library of Science, 2017) Rosner, Sonia R.; Pascoe, Christopher D.; Blankman, Elizabeth; Jensen, Christopher C.; Krishnan, Ramaswamy; James, Alan L.; Elliot, John G.; Green, Francis H.; Liu, Jeffrey C.; Seow, Chun Y.; Park, Jin-Ah; Beckerle, Mary C.; Paré, Peter D.; Fredberg, Jeffrey; Smith, Mark A.Bronchospasm induced in non-asthmatic human subjects can be easily reversed by a deep inspiration (DI) whereas bronchospasm that occurs spontaneously in asthmatic subjects cannot. This physiological effect of a DI has been attributed to the manner in which a DI causes airway smooth muscle (ASM) cells to stretch, but underlying molecular mechanisms–and their failure in asthma–remain obscure. Using cells and tissues from wild type and zyxin-/- mice we report responses to a transient stretch of physiologic magnitude and duration. At the level of the cytoskeleton, zyxin facilitated repair at sites of stress fiber fragmentation. At the level of the isolated ASM cell, zyxin facilitated recovery of contractile force. Finally, at the level of the small airway embedded with a precision cut lung slice, zyxin slowed airway dilation. Thus, at each level zyxin stabilized ASM structure and contractile properties at current muscle length. Furthermore, when we examined tissue samples from humans who died as the result of an asthma attack, we found increased accumulation of zyxin compared with non-asthmatics and asthmatics who died of other causes. Together, these data suggest a biophysical role for zyxin in fatal asthma.Publication Assessing the impact of engineered nanoparticles on wound healing using a novel in vitro bioassay(Future Medicine Ltd, 2014) Zhou, Enhua; Watson, Christa; Pizzo, Richard; Cohen, Joel; Dang, Quynh; Ferreira de Barros, Pedro Macul; Park, Chan Young; Chen, Cheng; Brain, Joseph; Butler, James; Ruberti, Jeffrey W; Fredberg, Jeffrey; Demokritou, PhilipAIM: As engineered nanoparticles (ENPs) increasingly enter consumer products, humans become increasingly exposed. The first line of defense against ENPs is the epithelium, the integrity of which can be compromised by wounds induced by trauma, infection, or surgery, but the implications of ENPs on wound healing are poorly understood. MATERIALS & METHODS: Herein, we developed an in vitro assay to assess the impact of ENPs on the wound healing of cells from human cornea. RESULTS & DISCUSSION: We show that industrially relevant ENPs impeded wound healing and cellular migration in a manner dependent on the composition, dose and size of the ENPs as well as cell type. CuO and ZnO ENPs impeded both viability and wound healing for both fibroblasts and epithelial cells. Carboxylated polystyrene ENPs retarded wound healing of corneal fibroblasts without affecting viability. CONCLUSION: Our results highlight the impact of ENPs on cellular wound healing and provide useful tools for studying the physiological impact of ENPs.Publication Geometric constraints during epithelial jamming(Springer Science and Business Media LLC, 2018-04-02) Atia, Lior; Bi, Dapeng; Sharma, Yasha; Mitchel, Jennifer; Gweon, Bomi; Koehler, Stephan; DeCamp, Stephen; Lan, Bo; Kim, Jae Hun; Hirsch, Rebecca; Pegoraro, Adrian; Lee, Kyu Ha; Starr, Jacqueline; Weitz, David; Martin, Adam; Park, Jin-Ah; Butler, James; Fredberg, JeffreyPublication Airway and Parenchymal Strains during Bronchoconstriction in the Precision Cut Lung Slice(Frontiers Media S.A., 2016) Hiorns, Jonathan E.; Bidan, Cécile M.; Jensen, Oliver E.; Gosens, Reinoud; Kistemaker, Loes E. M.; Fredberg, Jeffrey; Butler, Jim P.; Krishnan, Ramaswamy; Brook, Bindi S.The precision-cut lung slice (PCLS) is a powerful tool for studying airway reactivity, but biomechanical measurements to date have largely focused on changes in airway caliber. Here we describe an image processing tool that reveals the associated spatio-temporal changes in airway and parenchymal strains. Displacements of sub-regions within the PCLS are tracked in phase-contrast movies acquired after addition of contractile and relaxing drugs. From displacement maps, strains are determined across the entire PCLS or along user-specified directions. In a representative mouse PCLS challenged with 10−4M methacholine, as lumen area decreased, compressive circumferential strains were highest in the 50 μm closest to the airway lumen while expansive radial strains were highest in the region 50–100 μm from the lumen. However, at any given distance from the airway the strain distribution varied substantially in the vicinity of neighboring small airways and blood vessels. Upon challenge with the relaxant agonist chloroquine, although most strains disappeared, residual positive strains remained a long time after addition of chloroquine, predominantly in the radial direction. Taken together, these findings establish strain mapping as a new tool to elucidate local dynamic mechanical events within the constricting airway and its supporting parenchyma.Publication Homogenizing cellular tension by hepatocyte growth factor in expanding epithelial monolayer(Nature Publishing Group, 2017) Jang, Hwanseok; Notbohm, Jacob; Gweon, Bomi; Cho, Youngbin; Park, Chan Young; Kee, Sun-Ho; Fredberg, Jeffrey; Shin, Jennifer H.; Park, YongdooHepatocyte growth factor (HGF) induces cell migration and scattering by mechanisms that are thought to tip a local balance of competing physical forces; cell-to-cell and cell-to-substrate forces. In this local process, HGF is known to attenuate local cadherin-dependent adhesion forces for cell-cell junction development and enhance local integrin-dependent contractile forces for pulling neighboring cells apart. Here we use an expanding island of confluent Madin-Darby canine kidney (MDCK) cells as a model system to quantify the collective cell migration. In the absence of HGF, cell trajectories are highly tortuous whereas in the presence of HGF, they become far less so, resembling free expansion of a gas. At the level of cell-to-cell junctions, HGF attenuates the linkage of stress fibers to cell-to-cell junctions with concomitant decrease in intercellular stress. At the level of cell-to-substrate junctions, HGF augments the linkage of stress fibers to cell-to-substrate junctions with no apparent effect on traction. Together, HGF induces both structural changes in the actin-bound junctional protein complex and physical forces spanning multicellular clusters, which further promotes the expansion of confluent cellular layer.Publication Unjamming and cell shape in the asthmatic airway epithelium(Nature Publishing Group, 2015) Park, Jin-Ah; Kim, Jae Hun; Bi, Dapeng; Mitchel, Jennifer; Qazvini, Nader Taheri; Tantisira, Kelan; Park, Chan Young; McGill, Maureen; Kim, Sae-Hoon; Gweon, Bomi; Notbohm, Jacob; Steward Jr, Robert; Burger, Stephanie; Randell, Scott H.; Kho, Alvin; Tambe, Dhananjay; Hardin, Corey; Shore, Stephanie; Israel, Elliot; Weitz, David; Tschumperlin, Daniel J.; Henske, Elizabeth; Weiss, Scott; Manning, Mary; Butler, James; Drazen, Jeffrey; Fredberg, JeffreyFrom coffee beans flowing in a chute to cells remodelling in a living tissue, a wide variety of close-packed collective systems— both inert and living—have the potential to jam. The collective can sometimes flow like a fluid or jam and rigidify like a solid. The unjammed-to-jammed transition remains poorly understood, however, and structural properties characterizing these phases remain unknown. Using primary human bronchial epithelial cells, we show that the jamming transition in asthma is linked to cell shape, thus establishing in that system a structural criterion for cell jamming. Surprisingly, the collapse of critical scaling predicts a counter-intuitive relationship between jamming, cell shape and cell–cell adhesive stresses that is borne out by direct experimental observations. Cell shape thus provides a rigorous structural signature for classification and investigation of bronchial epithelial layer jamming in asthma, and potentially in any process in disease or development in which epithelial dynamics play a prominent role.Publication AllerGen’s 8th research conference(BioMed Central, 2016) Arrieta, Marie-Claire; Arevalos, Andrea; Stiemsma, Leah; Chico, Marta E.; Sandoval, Carlos; Jin, Minglian; Walter, Jens; Cooper, Phil; Finlay, Brett; Bernatchez, Emilie; Gold, Matthew J.; Langlois, Anick; Blais-Lecours, Pascale; Duchaine, Caroline; Marsolais, David; McNagny, Kelly M.; Blanchet, Marie-Renée; Brubacher, Jordan; Chhetri, Bimal; Sabaliauskas, Kelly; Bassil, Kate; Kwong, Jeff; Coates, Frances; Takaro, Tim K.; Chow, Angela; Miller, Gregory E.; Chen, Edith; Mandhane, Piushkumar J.; Turvey, Stuart E.; Elliott, Susan J.; Becker, Allan B.; Subbarao, Padmaja; Sears, Malcolm R.; Kozyrskyj, Anita L.; Dubeau, Aimée; Lu, Zihang; Balkovec, Susan; Kowalik, Krzysztof; Gustafsson, Per; Ratjen, Felix; Edgar, Rachel D.; Bush, Nicole R.; MacIssac, Julie L.; McEwen, Lisa M.; Boyce, Thomas W.; Kobor, Michael S.; Emmerson, Melanie; Shen, Bingqing; Moraes, Theo J.; Gabrielli, Sofianne; Clarke, Ann; Eisman, Harley; Morris, Judy; Joseph, Lawrence; LaVieille, Sebastien; Ben-Shoshan, Moshe; Islam, Sumaiya A.; Brückmann, Christof; Nieratschker, Vanessa; Jamieson, Kyla C.; Proud, David; Kanagaratham, Cynthia; Camateros, Pierre; Kopriva, Frantisek; Henri, Jennifer; Hajduch, Marian; Radzioch, Danuta; Kang, Liane J.; Koleva, Petya T.; Field, Catherine J.; Konya, Tedd; Scott, James A.; Konya, Theodore; Azad, Meghan B.; Brook, Jeff; Guttman, David; Kumari, Manjeet; Bridgman, Sarah L.; Tun, Mon H.; Mandal, Rupasri; Wishart, David S.; Lee, Amy H. Y.; Xia, Jeff; Gill, Erin; Hancock, Bob; Maestre, Danay; Sutherland, Darren; Hirota, Jeremy; Pena, Olga; Carlsten, Christopher; Jones, Meaghan J.; MacIsaac, Julia L.; Dow, William H.; Rosero-Bixby, Luis; Rehkopf, David H.; Morimoto, Takeshi; Smith, Steven G.; Oliveria, John-Paul; Beaudin, Suzanne; Schlatman, Abbey; Howie, Karen; Obminski, Caitlin; Nusca, Graeme; Sehmi, Roma; Gauvreau, Gail M.; O’Byrne, Paul M.; North, Michelle; Peng, Cheng; Sanchez-Guerra, Marco; Byun, Hyang-Min; Ellis, Anne K.; Baccarelli, Andrea; Okeme, Joseph O.; Dhal, Suman; Saini, Aman; Diamond, Miriam L.; Olesovsky, Christopher J.; Salter, Brittany M.; Wang, Michael; Lacy, Paige; O’Sullivan, Michael J.; Park, Chan Young; Fredberg, Jeffrey; Lauzon, Anne-Marie; Martin, James G.; Ryu, Min Hyung; Mookherjee, Neeloffer; Simons, Elinor; Lefebvre, Diana; Dai, David; Singh, Amrit; Shannon, Casey P.; Kim, Young Woong; Yang, Chen Xi; Mark FitzGerald, J.; Boulet, Louis-Philippe; Tebbutt, Scott J.; Singhera, Gurpreet K.; JasemineYang, S.; Dorscheid, Delbert R.; Sinnock, Hasantha; Goruk, Susan; Tavakoli, Hamid; Lynd, Larry D.; Sadatsafavi, Mohsen; Tenn, Mark W.; Thiele, Jenny; Adams, Daniel E.; Steacy, Lisa M.; Torabi, Bahar; De Schryver, Sarah; Lejtenyi, Duncan; Baerg, Ingrid; Chan, Edmond S.; Mazer, Bruce D.; Tran, Maxwell M.; Dai, Wei Hao; Lou, Wendy; Chari, Radha S.; Conway, Edward M.; Neighbour, Helen; Larché, Mark; Tebbutt, Scott JPublication Corrigendum: Airway and Parenchymal Strains during Bronchoconstriction in the Precision Cut Lung Slice(Frontiers Media S.A., 2017) Hiorns, Jonathan E.; Bidan, Cécile M.; Jensen, Oliver E.; Gosens, Reinoud; Kistemaker, Loes E. M.; Fredberg, Jeffrey; Butler, Jim P.; Krishnan, Ramaswamy; Brook, Bindi S.