1 Department of Physiology, College of Medicine, and School of Biomedical Engineering, University of Tennessee Health Science Center, Memphis, Tennessee 38163; 2 Department of Medicine, Feinberg School of Medicine, Northwestern University, and Veterans Affairs Chicago Health Care System-Lakeside Division, Chicago, Illinois 60611; 3 Department of Surgery, University of Toronto, and Thoracic Surgery Research Laboratory, University Health Network Toronto General Hospital, Toronto, Ontario, Canada M5G 2C4; and 4 Physiology Program, Harvard School of Public Health, Boston, Massachusetts 02115
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ABSTRACT |
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Mechanical forces affect both the function and phenotype of cells in the lung. In this symposium, recent studies were presented that examined several aspects of biomechanics in lung cells and their relationship to disease. Wound healing and recovery from injury in the airways involve epithelial cell spreading and migration on a substrate that undergoes cyclic mechanical deformation; enhanced green fluorescent protein-actin was used in a stable cell line to examine cytoskeletal changes in airway epithelial cells during wound healing. Eosinophils migrate into the airways during asthmatic attacks and can also be exposed to cyclic mechanical deformation; cyclic mechanical stretch caused a decrease in leukotriene C4 synthesis that may be dependent on mechanotransduction mechanisms involving the production of reactive oxygen species. Recent studies have suggested that proinflammatory cytokines are increased in ventilator-induced lung injury and may be elevated by overdistention of the lung tissue; microarray analysis of human lung epithelial cells demonstrated that cyclic mechanical stretch alone profoundly affects gene expression. Finally, airway hyperresponsiveness is a basic feature of asthma, but the relationship between airway hyperresponsiveness and changes in airway smooth muscle (ASM) function remain unclear. New analysis of the behavior of the ASM cytoskeleton (CSK) suggests, however, that the CSK may behave as a glassy material and that glassy behavior may account for the extensive ASM plasticity and remodeling that contribute to airway hyperresponsiveness. Together, the presentations at this symposium demonstrated the remarkable and varied roles that mechanical forces may play in both normal lung physiology as well as pathophysiology.
actin remodeling; 5-lipoxygenase; inflammatory cytokines; mechanical properties
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INTRODUCTION |
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THE LUNG IS A MECHANICALLY dynamic organ, and cells in the lung are subjected to many different types of physical forces. For example, endothelial cells are subjected to shear stress due to fluid flow, and epithelial cells lining the airways and alveoli are exposed to tensile and compressive forces during the respiratory cycle. In the last ten years, it has become apparent that most cells throughout the body sense their mechanical environment and respond to changes (8, 18, 22, 33, 69). Some of these responses include changes in intracellular ion concentrations, cytoskeletal rearrangement, and changes in gene expression. Although there are significant changes in lung mechanics during mechanical ventilation and in airway diseases such as asthma, little is known about how such changes affect cellular functions in the lung. In addition, the mechanisms by which cells in the lung transduce mechanical signals into biological signals are not well understood. Some of these issues were featured in a symposium at the Experimental Biology Meeting in New Orleans, LA, on April 22, 2002. The presentations, summarized in this report, explored recent findings in cellular mechanotransduction in the lung, including state-of-the-art techniques for subjecting cells to physical forces and monitoring functional changes. The symposium was sponsored by the Respiration Section of the American Physiological Society.
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BIOMECHANICS AND WOUND HEALING IN AIRWAY EPITHELIAL CELLS1 |
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Ventilator-induced lung injury (VILI) is a significant problem for patients that can result in damage to the airway epithelium. Damage to the epithelium can occur during mechanical ventilation through a variety of mechanisms, including repeated collapse and reopening of airways (10). Restoration of the epithelial integrity is essential for recovering barrier function to protect the lungs, and wound healing in the airways occurs on a substrate that undergoes cyclic mechanical deformation.
In previous studies, we examined wound healing during cyclic mechanical
stretch and compression (47, 66, 67). Airway epithelial
cells, including normal human bronchial epithelial cells and
transformed lines of human bronchial epithelial cells (16HBE14o), were grown on collagen-coated Silastic
membranes. Wounds were induced with a spatula, and wound closure was
measured using videomicroscopy. Wounded monolayers were subjected to
cyclic strain using either the Flexercell device or our custom-designed
biaxial stretching device (66). We found that wound
closure was significantly inhibited by both cyclic stretch and cyclic
compression. The extent of inhibition was dependent on the magnitude of
the strain and the frequency of cyclic strain. In the latter case, the
inhibition was specifically related to the time of relaxation between
stretch or compression, with shorter relaxation times corresponding to
greater inhibition. Three primary mechanisms are responsible for wound
healing of epithelial cells: cell spreading, cell migration, and cell
proliferation (26, 27, 47, 72-74). In many of our
studies, wound closure occurred within 10-12 h so that significant
cell proliferation was unlikely. By measuring cell migration velocities
at the wound edge, we found that both cyclic stretch and cyclic
compression decreased cell motility. In addition, measurements of cell
area at the wound edge demonstrated that cyclic stretch prevents cell spreading, and cyclic compression actually resulted in a decrease in
cell size.
Because both cell spreading and cell migration depend on cytoskeletal remodeling, we sought to visualize the distribution of actin in cells at the wound edge. When we examined rhodamine-phalloidin staining of F-actin in static cells, we observed a consistent band of actin bundles spanning the length of the wound edge. This pattern of actin at a wound edge has been observed previously by others and is referred to as "purse-string" contraction (35). In addition to the purse-string pattern, lamellapodial extensions containing actin filaments extend forth from purse-string bands into the denuded area. Previous studies have suggested that purse strings are important in the healing of small wounds, whereas lamellae predominate in larger wounds (2). We found that both mechanisms appear to be important in our studies of moderately sized wounds (~1 mm). In cells exposed to cyclic stretch, the actin band could be observed at the wound edge, but it was not nearly as broad, and fewer lamellapodia could be seen.
One of the limitations of rhodamine-phalloidin staining is that one
cannot observe dynamic changes in actin distribution. To visualize
actin remodeling in living cells to distinguish between wound healing
mechanisms in cyclically stretched cells, we developed a cell line that
expresses enhanced green fluorescent protein (EGFP)-actin. With the use
of a vector from Clontech (Palo Alto, CA) that encodes a fusion protein
of EGFP and human actin, we transfected 16HBE14o cells
and selected cells expressing EGFP-actin using G418. Using a
stable clone of these cells, we fixed and stained the cells with
rhodamine-phalloidin. An overlay of fluorescent images demonstrated partial overlap between fluorescence due to EGFP and fluorescence due
to rhodamine. Also, Western blots showed differences in expression of
EGFP-actin in different clones and an increase in cytosolic EGFP-actin
relative to insoluble EGFP-actin when compared with the ratio of
unlabeled actin. We were able to visualize changes in actin
distribution in live cells exposed to cytochalasin D and observed
severing of actin filaments. We also tracked actin remodeling at wound
edges in static cells and observed the formation of purse-string actin
bands and lamellae. We have also modified a stretching device so that
we can observe changes in actin during stretch. The combination of this
stable cell line expressing EGFP-actin and the device for stretching
cells on a microscope stage will be used in future studies to examine
the dynamics of actin remodeling during cyclic stretch and wound healing.
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CYCLIC MECHANICAL STRAIN AND EOSINOPHIL LEUKOTRIENE SYNTHESIS2 |
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Cells in the airway wall undergo mechanical strain as the airways distend and elongate during the ventilatory cycle. Thus many investigators in recent years have examined the effects of mechanical stretch on the function of various cells of the airway wall as well as the distal lung (33). Virtually all of these studies have focused on parenchymal airway or lung cells, including epithelial cells, endothelial cells, smooth muscle cells, and fibroblasts. By contrast, the influence of mechanical factors on inflammatory cells present in the lung has received almost no attention. Recently, we have begun to investigate the effects of cyclic mechanical stretch on the function of adherent eosinophils. The eosinophil is the predominant inflammatory cell infiltrating the airway wall and lumen in asthma (4). Eosinophils bind extracellular matrix (ECM) proteins and other cells in the airway wall via integrins (65). We reasoned that these integrin-mediated contacts with the ECM and with other cells would allow airway eosinophils to sense and respond to mechanical stretch, as has been demonstrated for parenchymal airway cells.
We have focused our studies on the ability of cyclic mechanical stretch to alter synthesis of the cysteinyl leukotriene C4 (LTC4) by adherent human eosinophils. LTC4 and its derivatives, LTD4 and LTE4, are potent bronchoconstrictors and proinflammatory mediators that play an important role in asthma pathogenesis (30). The leukotrienes are lipid mediators derived from arachidonic acid and are rapidly synthesized and released by eosinophils after agonist stimulation in vitro. To assess the effect of cyclic mechanical stretch on eosinophil leukotriene synthesis, we adhered purified human blood eosinophils to fibronectin-coated Silastic membranes and subjected the cells to cyclic stretch using the Flexercell strain unit. Our initial experiments showed that cyclic stretch does not activate LTC4 synthesis in adherent eosinophils. We next examined the effect of cyclic stretch on formation of LTC4 by adherent eosinophils stimulated with known agonists of LTC4 synthesis. Interestingly, these experiments showed that short-term (15-min) cyclic stretch actually inhibits LTC4 synthesis in eosinophils stimulated simultaneously with either calcium ionophore A-23187 or the chemotactic peptide N-Formyl-Met-Leu-Phe. Cyclic stretch also inhibited agonist-stimulated LTC4 synthesis in eosinophils adhered to collagen-coated wells. Stretch-induced inhibition of LTC4 synthesis was observed in eosinophils subjected to short-term cyclic stretch of varying magnitude (10-30% maximum strain) and frequency (5-30 cycles/min). Notably, cyclic stretch-induced inhibition of LTC4 synthesis was not associated with any measurable eosinophil cytotoxicity and was fully reversible after overnight incubation.
Synthesis of cysteinyl leukotrienes requires three sequential enzymatic steps: release of arachidonic acid from membrane phospholipids by cytosolic phospholipase A2 (cPLA2), conversion of arachidonic acid by 5-lipoxygenase to the unstable intermediate LTA4, and conjugation of LTA4 with glutathione by LTC4 synthase to form LTC4. Analysis of each of these steps revealed that cyclic stretch inhibited both cPLA2-mediated arachidonic acid release and the activity of 5-lipoxygenase but did not affect LTC4 synthase activity in adherent eosinophils.
The cytoskeleton has been implicated as a transducer of mechanical signals in a variety of experimental systems (33). We therefore examined the effects of cytochalasin D and latrunculin A, which disrupt actin microfilaments, on inhibition of LTC4 synthesis by cyclic stretch. Both agents attenuated stretch-induced inhibition of LTC4 synthesis, suggesting that mechanical signal transduction depends on an intact actin cytoskeleton in adherent eosinophils. The role of the cytoskeleton in stretch-induced inhibition of LTC4 synthesis is potentially important from another standpoint as well. Upon cell stimulation, cPLA2 and 5-lipoxygenase both translocate to the nuclear envelope, where leukotriene synthesis takes place (5, 41). Membrane translocation of both enzymes appears to involve interactions with cytoskeletal proteins (43, 62). Thus the enzymes required for LTC4 synthesis that are inhibited by cyclic stretch, cPLA2 and 5-lipoxygenase, are those that undergo cytoskeleton-dependent translocation to the nuclear envelope. On the other hand, LTC4 synthase, which was not inhibited by cyclic stretch, is an integral membrane protein in the nuclear envelope and is not known to move within the cell.
Mechanical stimulation of endothelial cells has been shown to cause generation of reactive oxygen species (ROS) (20, 71). Because we showed previously that oxidants inactivate 5-lipoxygenase and inhibit leukotriene synthesis in alveolar macrophages (53), we sought to determine whether ROS played a role in cyclic stretch-induced inhibition of eosinophil leukotriene synthesis. First, we found that the antioxidants N-acetyl cysteine and catalase attenuate inhibition of LTC4 synthesis by cyclic stretch. Next, we found evidence of oxidative modification of multiple cellular proteins and oxidative damage to DNA in adherent eosinophils subjected to cyclic stretch, but not in those cultured under static conditions. Oxidative damage to DNA in stretched eosinophils was inhibited by cytochalasin D, suggesting that stretch-induced oxidant generation occurs downstream of mechanical signaling involving the cytoskeleton.
The experimental studies reviewed in this section represent our initial characterization of the influence of short-term cyclic stretch on synthesis of LTC4, an important eosinophil-derived mediator of bronchoconstriction and airway inflammation in asthma. We conclude from these studies that mechanical stimulation can have major effects on the function of inflammatory cells in the airway and, in particular, that cyclic stretch inhibits synthesis of LTC4 in adherent eosinophils through a complex, regulated pathway involving the cytoskeleton and intracellular oxidant generation. The significance of the finding that cyclic stretch inhibits eosinophil LTC4 synthesis remains to be established. It seems possible that inhibition of LTC4 synthesis by cyclic stretch could be a physiological mechanism for downregulation of inflammation in the asthmatic airway. On the other hand, bronchoconstriction, mucus plugging, air trapping, and airway remodeling all might decrease airway distensibility in asthma. This could result in decreased cyclic airway stretch, "failure" to inhibit airway eosinophil LTC4 synthesis, and amplification of airway inflammation in asthma. In future studies, we will seek to address these possibilities.
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MECHANICAL STRETCH AND CYTOKINE PRODUCTION IN LUNG CELLS3 |
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A recent National Institutes of Health trial showed that ventilation with lower tidal volumes reduces the mortality of patients with acute respiratory distress syndrome (ARDS) (1). This is one of the most important breakthroughs in the management of acute lung injury and ARDS. However, one of the controversial questions is the role of cytokines in VILI (9).
VILI and cytokine production.
There is increasing evidence to suggest that proinflammatory cytokines
are mediators of VILI (10, 60), which may cause or
exacerbate lung injury by an inflammatory response (32). Tumor necrosis factor- (TNF-
) mRNA levels were increased in cells
isolated from bronchoalveolar lavage (BAL) fluid after conventional ventilation (55). Tremblay and coworkers (59)
used an ex vivo rat lung ventilation model and demonstrated that
injurious ventilation regimens increased BAL concentrations of several
cytokines, including TNF-
, interleukin (IL)-1
, IL-6, IL-10,
macrophage inflammatory protein-2 (MIP-2), and interferon-
. Von
Bethmann and colleagues (64) used an isolated-perfused
mouse lung model and reported that hyperventilation induces release of
TNF-
and IL-6 from the lung into the perfusate. In a randomized
clinical study, Ranieri and colleagues (45) found that
patients ventilated with a protective strategy had a reduction in
concentrations of polymorphonuclear cells, TNF-
, IL-1
, soluble
TNF-
receptor 55, and IL-8 in the BAL compared with patients with
conventional ventilation. Excessive ventilator settings, a high
concentration of oxygen, and prematurity are the most important factors
for bronchopulmonary dysplasia in preterm infants (56,
57), especially in infants with very low birth weight (VLBW)
(25). Mechanical ventilation increased proinflammatory
mediators in air space samples from VLBW infants (16).
Blockade of the function of proinflammatory cytokines, such as IL-1
(39) or TNF-
(21), attenuated the severity
of VILI in animals.
Cell stretch as models to cytokine studies.
To study the cellular and molecular mechanisms of ventilation-induced
cytokine production from the lung, several groups have employed cell
culture models to study mechanical stretch-induced cytokine production.
Pugin and coworkers (44) have shown that after 8- to 32-h
stretch at 20 cycles/min, production of IL-8 increased in human
macrophages, and the same stretch regimen also enhanced LPS-induced
TNF- and IL-6 production from macrophages. Because
ventilation-derived mechanical stretch is primarily applied to alveolar
epithelial cells, which could produce a variety of cytokines and
chemokines (40, 52), Pugin and coworkers (44) also applied the same stretch regimen to human lung epithelial A549
cells; however, the increase in IL-8 was not significant. Vlahakis and
coworkers (63) compared the effects of different stretch
regimens on IL-8 production from A549 cells and found that 30% (but
not 20%) stretch at 20 or 40 cycles/min increased IL-8 after
12-48 h. With the use of a different stretch apparatus, Tsuda and
coworkers (61) reported that after 8 h in culture, stretch alone did not affect IL-8 production; however, in the presence
of glass fibers or crocidolite asbestos, stretch significantly increased IL-8 production from A549 cells. Mourgeon and colleagues (38) applied mechanical stretch to primary cultured fetal
rat lung cells in an organotypic culture to simulate effects of
ventilation on premature lungs and to study the effect of mechanical
stretch on MIP-2 production. MIP-2 is a rodent homolog of the human
IL-8, and both are important mediators for neutrophil recruitment and activation (12, 36, 54). The mRNA levels of MIP-2 were
increased only on LPS stimulation and not by stretch, and pretreatment
of cells with cycloheximide to block protein synthesis did not inhibit stretch-induced release of MIP-2 (38). Therefore,
stretch-induced deformation of the cytoskeleton may facilitate the
secretion process of MIP-2. Indeed, it has been shown that both
microfilament (24) and microtubule (23)
systems are involved in MIP-2 secretion from pneumocytes.
Microarray analysis on stretch-induced gene expression related to
VILI.
In most of the studies described above, cell stretch alone did not show
significant effects on cytokine gene expression. Most cytokines studied
were chosen on the basis of animal studies and clinical observations
and were thus limited to several molecules. Can mechanical stretch
alone regulate expression of genes related to cytokine, chemokine,
inflammatory mediators, or proteins that are involved in intracellular
signaling of acute inflammatory responses? To answer this question,
several research groups have used microarray technique combined with
bioinformatics analysis. Preliminary results have demonstrated that
mechanical stretch alone has a profound effect on mRNA levels of
multiple genes in human lung epithelial cells. After 1 h of
stretch (18% elongation, 30 cycles/min), mRNA levels of >35 genes
were significantly increased, while mRNA levels of >300 genes
decreased. Interestingly, most of the commonly studied cytokine genes,
such as IL-1, IL-6, IL-1R
, and TNF-R1 were not affected by
stretch, whereas mRNA levels of IL-1R
, IL-1RA, TNF-
, and TNF-R2
were decreased. Genes encoding several novel cytokines and inflammatory
mediators, which have not been studied in VILI, are significantly up-
or downregulated by mechanical stretch. These results, of course, need
to be confirmed by other techniques and need to be examined with animal
studies as well as with clinical studies. However, these preliminary
data are very encouraging, providing the starting point for further investigation of VILI.
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FRAGILE OBJECTS: SMOOTH MUSCLE, SOFT GLASSES, AND AIRWAY HYPERRESPONSIVENESS4 |
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Airway hyperresponsiveness is the term used to describe airways that narrow too easily and too much in response to challenge with nonspecific contractile agonists (70). Airway hyperresponsiveness is the basic feature that underlies the excessive airway narrowing characteristic of asthma, but its mechanism remains unknown (28). Although asthma is usually defined as an inflammatory disease, the link between the immunological phenotype and the resulting mechanical phenotype associated with disease presentation, including airway hyperresponsiveness, remains unclear (6, 7, 19, 29). It remains equally unclear whether airway hyperresponsiveness is due to fundamental changes in smooth muscle phenotype, plasticity (remodeling) of airway smooth muscle (ASM) cytoskeletal architecture, structural and/or mechanical changes in the noncontractile elements of the airway wall, or alterations in the relationship of the airway wall to the surrounding lung parenchyma (28, 37).
It was thought, until recently, that the role of ASM in airway narrowing was functionally specified by its static force-length curve. To the contrary, we now know that even modest agitation, such as the imposed length changes caused by the tidal action of breathing, profoundly perturb the binding of myosin to actin and plastically remodel the cytoskeletal (CSK) lattice. The contractile state is dynamically equilibrated, and the associated cytoskeletal scaffolding is evanescent, being rapidly demolished in some circumstances and reconstructed in others (15, 17, 42, 49, 50). Several related phenomena have been noted, including the failure of deep inspirations to dilate the asthmatic but not the normal airway, the latch state, and the roles of heat shock protein 27, Rho, and calponin in muscle plasticity (49). Together, however, these phenomena seem to be mostly unconnected, each from the other, and remain largely unexplained. Moreover, each mechanism proposed addresses only a subset of the questions necessary for a comprehensive theory of airway hyperresponsiveness, and all contain large explanatory gaps.
At this symposium, it was suggested that this untidy constellation of diverse findings and multiple potential mechanisms may drop into a unified pattern when the CSK of the ASM cell is thought of as being a glassy material. Generically, a glass is any material that has the disordered molecular state of a liquid and, at the same time, the rigidity of a solid. A glass arises in a liquid that solidifies too fast for structural elements to form an ordered array and a corresponding solid state, as would an ordinary solid (3, 13, 14, 31, 58, 68). Even though the state of least free energy would be ordered, the interactions among elements are too complex and too weak to form ordered structures spontaneously (13). Rather, as the system is rapidly quenched, each element finds itself trapped in a cage formed by its neighbors. In that cage (equivalently, an energy well), elements are trapped away from energy minima, and, therefore, the system is not at a thermodynamic equilibrium.
In glassy systems, microscale jostling caused by thermal agitation (and perhaps ongoing protein conformational changes in the case of certain cytoskeletal proteins) might cause a microscale element to hop out of its current cage and fall into a nearby cage (3, 31, 58, 68). If so, each element would not oscillate about a fixed spatial address as it would in an ordinary solid matrix. Rather, the existence of ongoing hopping events would imply that the links among elements are impermanent (metastable) and that the elements are constantly rearranging themselves in a never-ending search for order. It follows logically that if individual elements can hop, then the matrix as a whole can flow, reorganize internal structures, and become internally disordered. However, if the microscale jostling is decreased, then energy becomes ever less available, the weak bonds between elements constrain the motion more and more, and the rate of hopping slows. If the jostling is reduced enough that hopping virtually ceases, then individual elements become trapped in place, the matrix can no longer flow or reorganize, and the material becomes simply elastic. This is called the glass transition (3, 31, 58, 68).
In this symposium, it was shown how microscale jostling can be expressed as an effective temperature of the CSK matrix, and methods were demonstrated by which this effective temperature can be measured. Although the precise nature of this effective temperature remains quite unclear, these data provide strong evidence that the living ASM cell satisfies all empirical criteria that define the special class of soft glassy materials. Data provided were also consistent with the hypothesis that the living cell can modulate its mechanical properties and reorganize its microstructure by moving between glassy states that are "hot," melted, and liquidlike and ones that are "cold," frozen, and solidlike. If true, the outstanding question then becomes, Does the cell modulate its mechanical properties and reorganize its internal structures in much the same way a glassblower shapes a work of glass? Instead of modulating thermodynamic (bath) temperature, does the cell change its mechanical properties by modulating an effective temperature representing the level of microscale agitation? Finally, can the remarkable mechanical plasticity/remodeling of the ASM CSK that has recently come to the fore in airway biology be accounted for by the hypothesis of glassy behavior?
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CONCLUSIONS |
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The presentations at this symposium demonstrated the remarkable and varied roles that mechanical forces may play in both normal lung physiology as well as pathophysiology. Mechanical forces in the lung are significantly altered during mechanical ventilation, during exercise, and in diseases such as asthma, emphysema, cystic fibrosis, and ARDS. It is clear that there are tremendous gaps in our knowledge of how cells in the lung sense mechanical forces, alter their phenotype or function, and potentially contribute to pathophysiology. As demonstrated by this symposium, research in this field will be advanced by multidisciplinary approaches, including expertise in pulmonary physiology, molecular biology, bioengineering, immunology, and clinical medicine.
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ACKNOWLEDGEMENTS |
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We thank the American Physiological Society for support of this symposium.
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FOOTNOTES |
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The research reported in this symposium was supported by National Heart, Lung, and Blood Institute (NHLBI) Grant HL-64981 (to C. M. Waters), a Merit Review award from the Department of Veterans Affairs and the American Lung Association of Metropolitan Chicago (to P. H. S. Sporn), Canadian Institutes of Health Research Grants MOP-13270 and MOP-42546 (to M. Liu), and NHLBI Grants P01-HL-33009 and R01-HL-65960 (to J. J. Fredberg).
Address for reprint requests and other correspondence: C. M. Waters, Dept. of Physiology, Univ. of Tennessee Health Science Center, 894 Union Ave. - 426 Nash, Memphis, TN 38163 (E-mail: cwaters{at}physio1.utmem.edu).
1 Presented by Christopher Waters.
2 Presented by Peter Sporn.
3 Presented by Mingyao Liu.
4 Presented by Jeffrey Fredberg.
10.1152/ajplung.00141.2002
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REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Acute Respiratory Distress Syndrome Network.
Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury, and the acute respiratory distress syndrome.
N Engl J Med
342:
1301-1308,
2000
2.
Bement, WM,
Forscher P,
and
Mooseker MS.
A novel cytoskeletal structure involved in purse string wound closure and cell polarity maintenance.
J Cell Biol
121:
565-578,
1993[Abstract].
3.
Bouchaud, J.
Weak ergodicity breaking and aging in disordered systems.
J Phys I
2:
1705-1713,
1992.
4.
Bousquet, J,
Chanez P,
Lacoste JY,
Barneon G,
Ghavanian N,
Enander I,
Venge P,
Ahlstedt S,
Simony-Lafontaine J,
Godard P,
and
Michel FB.
Eosinophilic inflammation in asthma.
N Engl J Med
323:
1033-1039,
1990[Abstract].
5.
Brock, TG,
Anderson JA,
Fries FP,
Peters-Golden M,
and
Sporn PHS
Decreased leukotriene C4 synthesis accompanies adherence-dependent nuclear import of 5-lipoxygenase in human blood eosinophils.
J Immunol
162:
1669-1676,
1999
6.
Bryan, SA,
O'Connor BJ,
Matti S,
Leckie MJ,
Kanabar V,
Khan J,
Warrington SJ,
Renzetti L,
Rames A,
Bock JA,
Boyce MJ,
Hansel TT,
Holgate ST,
and
Barnes PJ.
Effects of recombinant human interleukin-12 on eosinophils, airway hyper-responsiveness, and the late asthmatic response.
Lancet
356:
2149-2153,
2000[ISI][Medline].
7.
Crimi, E,
Spanevello A,
Neri M,
Ind PW,
Rossi GA,
and
Brusasco V.
Dissociation between airway inflammation and airway hyperresponsiveness in allergic asthma.
Am J Respir Crit Care Med
157:
4-9,
1998
8.
Davies, PF.
Flow-mediated endothelial mechanotransduction.
Physiol Rev
75:
519-560,
1995
9.
Dos Santos, CC,
and
Slutsky AS.
Invited review: mechanisms of ventilator-induced lung injury: a perspective.
J Appl Physiol
89:
1645-2084,
2000
10.
Dreyfuss, D,
and
Saumon G.
Ventilator-induced lung injury: lessons from experimental studies.
Am J Respir Crit Care Med
157:
294-323,
1998
12.
Driscoll, KE.
Macrophage inflammatory proteins: biology and role in pulmonary inflammation.
Exp Lung Res
20:
473-490,
1994[ISI][Medline].
13.
Durian, D,
and
Diamant H.
Condensed-matter physics. In search of soft solutions.
Nature
412:
391-392,
2001[ISI][Medline].
14.
Ediger, M.
Movies of the glass transition.
Science
287:
604-605,
2000
15.
Fredberg, JJ,
Inouye DS,
Mijailovich SM,
and
Butler JP.
Perturbed equilibrium of myosin binding in airway smooth muscle and its implications in bronchospasm.
Am J Respir Crit Care Med
159:
1-9,
1999
16.
Groneck, P,
and
Speer CP.
Inflammatory mediators and bronchopulmonary dysplasia.
Arch Dis Child
73:
F1-F3,
1995[ISI].
17.
Gunst, SJ,
and
Wu MF.
Selected contribution: plasticity of airway smooth muscle stiffness and extensibility: role of length-adaptive mechanisms.
J Appl Physiol
90:
741-749,
2001
18.
Hamill, OP,
and
Martinac B.
Molecular basis of mechanotransduction in living cells.
Physiol Rev
81:
685-740,
2001
19.
Holloway, JW,
Beghe B,
and
Holgate ST.
The genetic basis of atopic asthma.
Clin Exp Allergy
29:
1023-1032,
1999[ISI][Medline].
20.
Howard, AB,
Alexander RW,
Nerem RM,
Griendling KK,
and
Taylor WR.
Cyclic strain induces an oxidative stress in endothelial cells.
Am J Physiol Cell Physiol
272:
C421-C427,
1997
21.
Imai, Y,
Kawano T,
Iwamoto S,
Nakagawa S,
Takata M,
and
Miyasaka K.
Intratracheal anti-tumor necrosis factor- antibody attenuates ventilator-induced lung injury in rabbits.
J Appl Physiol
87:
510-515,
1999
22.
Ingber, DE.
Tensegrity: the architectural basis of cellular mechanotransduction.
Annu Rev Physiol
59:
575-599,
1997[ISI][Medline].
23.
Isowa, N,
Keshavjee SH,
and
Liu M.
Role of microtubules in LPS-induced macrophage inflammatory protein-2 production from rat pneumocytes.
Am J Physiol Lung Cell Mol Physiol
279:
L1075-L1082,
2000
24.
Isowa, N,
and
Liu M.
Role of LPS-induced microfilament depolymerization in MIP-2 production from rat pneumocytes.
Am J Physiol Lung Cell Mol Physiol
280:
L762-L770,
2001
25.
Jobe, AH,
and
Ikegami M.
Mechanisms initiating lung injury in the preterm.
Early Hum Dev
53:
81-94,
1998[ISI][Medline].
26.
Kheradmand, F,
Folkesson HG,
Shum L,
Derynk R,
Pytela R,
and
Matthay MA.
Transforming growth factor- enhances alveolar epithelial cell repair in a new in vitro model.
Am J Physiol Lung Cell Mol Physiol
267:
L728-L738,
1994
27.
Kim, JS,
McKinnis VS,
Nawrocki A,
and
White SR.
Stimulation of migration and wound repair of guinea-pig airway epithelial cells in response to epidermal growth factor.
Am J Respir Cell Mol Biol
18:
66-74,
1998
28.
King, GG,
Pare PD,
and
Seow CY.
The mechanics of exaggerated airway narrowing in asthma: the role of smooth muscle.
Respir Physiol
118:
1-13,
1999[ISI][Medline].
29.
Leckie, MJ,
ten Brinke A,
Khan J,
Diamant Z,
O'Connor BJ,
Walls CM,
Mathur AK,
Cowley HC,
Chung KF,
Djukanovic R,
Hansel TT,
Holgate ST,
Sterk PJ,
and
Barnes PJ.
Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response.
Lancet
356:
2144-2148,
2000[ISI][Medline].
30.
Leff, AR.
Role of leukotrienes in bronchial hyperresponsiveness and cellular responses in airways.
Am J Respir Crit Care Med
161:
S125-S132,
2000
31.
Liu, A,
and
Nagel S.
Jamming is not just cool anymore.
Nature
396:
21,
1998[ISI].
32.
Liu, M,
and
Slutsky AS.
Anti-inflammatory therapies: application of molecular biology techniques in intensive care medicine.
Intensive Care Med
23:
718-731,
1997[ISI][Medline].
33.
Liu, M,
Tanswell AK,
and
Post M.
Mechanical force-induced signal transduction in lung cells.
Am J Physiol Lung Cell Mol Physiol
277:
L667-L683,
1999
35.
Lotz, MM,
Rabinovitz I,
and
Mercurio AM.
Intestinal restitution: progression of actin cytoskeleton rearrangements and integrin function in a model of epithelial wound healing.
Am J Pathol
156:
985-996,
2000
36.
Luster, AD.
Chemokines-chemotactic cytokines that mediate inflammation.
N Engl J Med
338:
436-445,
1998
37.
Milanese, M,
Crimi E,
Scordamaglia A,
Riccio A,
Pellegrino R,
Canonica GW,
and
Brusasco V.
On the functional consequences of bronchial basement membrane thickening.
J Appl Physiol
91:
1035-1040,
2001
38.
Mourgeon, E,
Isowa N,
Keshavjee S,
Zhang X,
Slutsky AS,
and
Liu M.
Mechanical stretch stimulates macrophage inflammatory protein-2 secretion from fetal rat lung cells.
Am J Physiol Lung Cell Mol Physiol
279:
L699-L706,
2000
39.
Narimanbekov, IO,
and
Rozycki HJ.
Effect of IL-1 blockade on inflammatory manifestations of acute ventilator-induced lung injury in a rabbit model.
Exp Lung Res
21:
239-254,
1995[ISI][Medline].
40.
Paine, R, III,
and
Simon RH.
Expanding the frontiers of lung biology through the creative use of alveolar epithelial cells in culture.
Am J Physiol Lung Cell Mol Physiol
270:
L484-L486,
1996
41.
Peters-Golden, M,
and
Brock TG.
Intracellular compartmentalization of leukotriene synthesis: unexpected nuclear secrets.
FEBS Lett
487:
323-326,
2001[ISI][Medline].
42.
Pratusevich, VR,
Seow CY,
and
Ford LE.
Plasticity in canine airway smooth muscle.
J Gen Physiol
105:
73-94,
1995[Abstract].
43.
Provost, P,
Samuelsson B,
and
Radmark O.
Interaction of 5-lipoxygenase with cellular proteins.
Proc Natl Acad Sci USA
96:
1881-1885,
1999
44.
Pugin, J,
Dunn I,
Jolliet P,
Tassaux D,
Magnenat JL,
Nicod LP,
and
Chevrolet JC.
Activation of human macrophages by mechanical ventilation in vitro.
Am J Physiol Lung Cell Mol Physiol
275:
L1040-L1050,
1998
45.
Ranieri, VM,
Suter PM,
Tortorella C,
De Tullio R,
Dayer JM,
Brienza A,
Bruno F,
and
Slutsky AS.
Effect of mechanical ventilation on inflammatory mediators in patients with acute respiratory distress syndrome: a randomized controlled trial.
JAMA
282:
54-61,
1999
46.
Ricard, JD,
Dreyfuss D,
and
Saumon G.
Production of inflammatory cytokines in ventilator-induced lung injury: a reappraisal.
Am J Respir Crit Care Med
163:
1176-1180,
2001
47.
Savla, U,
and
Waters CM.
Mechanical strain inhibits repair of airway epithelium in vitro.
Am J Physiol Lung Cell Mol Physiol
274:
L883-L892,
1998
49.
Seow, CY,
and
Fredberg JJ.
Historical perspective on airway smooth muscle: the saga of a frustrated cell.
J Appl Physiol
91:
938-952,
2001
50.
Seow, CY,
Pratusevich VR,
and
Ford LE.
Series-to-parallel transition in the filament lattice of airway smooth muscle.
J Appl Physiol
89:
869-876,
2000
51.
Simon, BA.
Message in a model.
Am J Respir Crit Care Med
163:
1043-1044,
2001
52.
Simon, RH,
and
Paine R, III.
Participation of pulmonary alveolar epithelial cells in lung inflammation.
J Lab Clin Med
126:
108-118,
1995[ISI][Medline].
53.
Sporn, PHS,
and
Peters-Golden M.
Hydrogen peroxide inhibits alveolar macrophage 5-lipoxygenase metabolism in association with depletion of ATP.
J Biol Chem
263:
14776-14783,
1988
54.
Strieter, RM,
Standiford TJ,
Huffnagle GB,
Colletti LM,
Lukacs NW,
and
Kunkel SL.
"The good, the bad, and the ugly." The role of chemokines in models of human disease.
J Immunol
156:
3583-3586,
1996[ISI][Medline].
55.
Takata, M,
Abe J,
Tanaka H,
Kitano Y,
Doi S,
Kohsaka T,
and
Miyasaka K.
Intraalveolar expression of tumor necrosis factor- gene during conventional and high-frequency ventilation.
Am J Respir Crit Care Med
156:
272-279,
1997
56.
Tanswell, AK,
Buch S,
Liu M,
and
Post M.
Factors mediating cell growth in lung injury.
In: Chronic Lung Disease in Early Infancy, edited by Bland RD,
and Coalson J.. New York: Dekker, 1999, p. 493-534.
57.
Tanswell, AK,
Liu M,
and
Post M.
Bronchopulmonary dysplasia: strategies for therapeutic intervention.
In: Intensive Care in Childhood: A Challenge to the Future, edited by Tibboel D,
and van der Voort E.. Berlin: Springer, 1996, p. 53-65.
58.
Torquato, S.
Hard Knock for thermodynamics.
Nature
405:
521-522,
2000[ISI][Medline].
59.
Tremblay, L,
Valenza F,
Ribeiro SP,
Li J,
and
Slutsky AS.
Injurious ventilatory strategies increase cytokines and c-fos m-RNA expression in an isolated rat lung model.
J Clin Invest
99:
944-952,
1997
60.
Tremblay, LN,
and
Slutsky AS.
Ventilator-induced injury: from barotrauma to biotrauma.
Proc Assoc Am Physicians
110:
482-488,
1998[ISI][Medline].
61.
Tsuda, A,
Stringer BK,
Mijailovich SM,
Rogers RA,
Hamada K,
and
Gray ML.
Alveolar cell stretching in the presence of fibrous particles induces interleukin-8 responses.
Am J Respir Cell Mol Biol
21:
455-462,
1999
62.
Tzima, E,
Trotter PJ,
Hastings AD,
Orchard MA,
and
Walker JH.
Investigation of the relocation of cytosolic phospholipase A2 and annexin V in activated platelets.
Thromb Res
97:
421-429,
2000[ISI][Medline].
63.
Vlahakis, NE,
Schroeder MA,
Limper AH,
and
Hubmayr RD.
Stretch induces cytokine release by alveolar epithelial cells in vitro.
Am J Physiol Lung Cell Mol Physiol
277:
L167-L173,
1999
64.
Von Bethmann, AN,
Brasch F,
Nusing R,
Vogt K,
Volk HD,
Muller KM,
Wendel A,
and
Uhlig S.
Hyperventilation induces release of cytokines from perfused mouse lung.
Am J Respir Crit Care Med
157:
263-272,
1998
65.
Wardlaw, AJ,
Symon FS,
and
Walsh GM.
Eosinophil adhesion in allergic inflammation.
J Allergy Clin Immunol
94:
1163-1171,
1994[ISI][Medline].
66.
Waters, CM,
Glucksberg MR,
Lautenschlager EP,
Lee CW,
Van Matre RM,
Warp RJ,
Savla U,
Healy KE,
Moran B,
Castner DG,
and
Bearinger JP.
A system to impose prescribed homogenous strains on cultured cells.
J Appl Physiol
91:
1600-1610,
2001
67.
Waters, CM,
and
Savla U.
Keratinocyte growth factor accelerates wound closure in airway epithelium during cyclic mechanical strain.
J Cell Physiol
181:
424-432,
1999[ISI][Medline].
68.
Weeks, ER,
Crocker JC,
Levitt AC,
Schofield A,
and
Weitz DA.
Three-dimensional direct imaging of structural relaxation near the colloidal glass transition.
Science
287:
627-631,
2000
69.
Wirtz, HR,
and
Dobbs LG.
The effects of mechanical forces on lung functions.
Respir Physiol
119:
1-17,
2000[ISI][Medline].
70.
Woolcock, AJ,
and
Peat JK.
Epidemiology of bronchial hyperresponsiveness.
Clin Rev Allergy Immunol
7:
245-256,
1989.
71.
Yeh, LH,
Park YJ,
Hansalia RJ,
Ahmed IS,
Deshpande SS,
Goldschmidt-Clermont PJ,
Irani K,
and
Alevriadou BR.
Shear-induced tyrosine phosphorylation in endothelial cells requires Rac1-dependent production of ROS.
Am J Physiol Cell Physiol
276:
C838-C847,
1999
72.
Zahm, JM,
Chevillard M,
and
Puchelle E.
Wound repair of human surface respiratory epithelium.
Am J Respir Cell Mol Biol
5:
242-248,
1991[ISI][Medline].
73.
Zahm, JM,
Kaplan H,
Herard AL,
Doriot F,
Pierrot D,
Somelette P,
and
Puchelle E.
Cell migration and proliferation during the in vitro wound repair of the respiratory epithelium.
Cell Motil Cytoskeleton
37:
33-43,
1997[ISI][Medline].
74.
Zahm, JM,
Pierrot D,
Chevillard M,
and
Puchelle E.
Dynamics of cell movement during the wound repair of human surface respiratory epithelium.
Biorheology
29:
459-465,
1992[ISI][Medline].