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Ventilator-induced Lung Injury

Role of Protein–Protein Interaction in Mechanosensation

Thoracic Surgery Research Laboratory, University Health Network Toronto General Hospital, Department of Surgery, University of Toronto, Toronto, Ontario, Canada

Correspondence and requests for reprints should be addressed to Dr. Mingyao Liu, Professor of Surgery, Toronto General Hospital, Room: MBRC5R422, 200 Elizabeth Street, Toronto, ON, M5G 2C4 Canada. E-mail: mingyao.liu{at}utoronto.ca

ABSTRACT

For critically ill patients, mechanical ventilation is a commonly used life-supporting modality, but ventilation per se could also induce lung injury. Mechanical forces–induced cell damage and inflammatory responses have been considered as one of major mechanisms of ventilator-induced lung injury (VILI). Mechanotransduction related to VILI has been the subject of several recent reviews, which focused on the mechanical force–induced signal cascades. In this article, we will discuss the initial processes, mechanosensation, by which physical forces can be sensed by the cells and converted into biochemical reactions for intracellular signaling. In addition to suggested mechanosensors, such as stretch-activated ion channels, extracellular matrix–integrin–cytoskeleton complex, and growth factor receptors, we would like to introduce a new concept of intracellular mechanosensation through specific protein–protein interactions. Proteins associated with the cytoskeleton could transmit physical forces, and bind with signaling-related enzymes through specific functional domains and motifs. These interactions could lead to activation or inactivation of the enzymes, and subsequently alter the signal transduction processes in the cells. Understanding these mechanisms will help us to develop new strategies for the management of VILI.

Key Words: acute lung injury • mechanical ventilation • mechanosensors • mechanotransduction

Treatment of acute respiratory distress syndrome (ARDS) has been one of the major challenges in critical care medicine. Although many therapeutic approaches have been developed clinically, the mortality and morbidity associated with ARDS remains very high. A clinical trial organized by National Institutes of Health has shown that the mortality of patients with ARDS was significantly decreased by reducing tidal volume of the ventilator setting (1). This important observation establishes ventilator-induced lung injury (VILI) as one of the most important components in the pathogenesis of acute lung injury (ALI) and ARDS. Increasing evidence suggests that mechanical stretch could stimulate production of cytokines, chemokines, and other inflammatory mediators through specific intracellular signal transduction pathways. The increased awareness of this issue has been credited to the addition of the term "mechanotransduction" to the dictionary of critical care medicine. Moreover, many excellent review articles have been published on cellular responses to mechanical stimuli and related intracellular signal transduction pathways. However, how physical forces are being sensed and converted into the biochemical reactions of intracellular signal transduction is largely unknown. Because the intracellular signal transduction pathways initiated by mechanical forces and proinflammatory mediators share similarity, identifying the initiation steps of mechanotransduction may help design specific treatment strategies that block the sensation of lung cells to mechanical forces, which may reduce ventilator-induced cell damage—thus altering the course of ALI and improve outcome in patients. In this review, we will briefly summarize the mechanosensory mechanisms described in the literature. Particularly, we will highlight a new concept of intracellular mechanosensation. We hope that the translational nature of this article will attract more clinicians, physiologists, and cell biologists toward working together, to advance our knowledge in mechanotransduction, in order to develop new strategies for the management of VILI and ARDS.

VILI: THE ROLE OF ALVEOLAR EPITHELIAL CELLS

Although still controversial, it has been commonly accepted that the increased production of cytokines, chemokines, and other inflammatory mediators is one of the major mechanisms of VILI (2–4). By applying physical forces on cultured cells, the consequences of mechanical forces on lung cell function (5), surfactant metabolism (6), cell proliferation, apoptosis, and cytokine production have been extensively studied and subjected to excellent reviews (7–13).

As mechanical stretch derived from injurious ventilation is primarily applied to alveolar epithelium, we questioned whether the alveolar epithelial cells sense nonphysiologic mechanical forces and become a source of proinflammatory mediators. Using one of the most important proinflammatory cytokines, tumor necrosis factor- (TNF-), as an example, we first demonstrated that primary cultured rat lung alveolar epithelial cells could produce TNF- in response to lipopolysaccharide (LPS) stimulation (14). Furthermore, TNF- mediates LPS-induced production of macrophage inflammatory protein-2 (MIP-2) (15), a rodent homolog of human interleukin-8 (IL-8) (16). Using a computerized Bio-Stretch system developed in our laboratory (17), we studied the effects of mechanical stretch on primary cultured fetal rat lung cells, a model system that emulates mechanical ventilation on premature infants, and demonstrated that the major effect of mechanical stretch on MIP-2 production is to stimulate its secretion (18). Considering that the direct effect of mechanical force on cells is the deformation of the cytoskeletal structure, this result was in agreement with the observation that the cytoskeleton system is involved in TNF- and MIP-2 secretion from lung epithelial cells rather than the regulation of transcription of these two genes (19–21). Several groups have used microarray approach to explore genes related to ARDS and VILI (22). A synergistic effect of mechanical stretch and TNF- on gene expression has been described in human lung epithelial cells (23). These studies suggested that alveolar epithelial cells have the ability to act as mechanosensory cells in the lung and are involved in VILI by increasing the production and response to proinflammatory cytokines.

Since 2000, hundreds of review articles have been published worldwide on the subject of VILI. One of the major purposes of these reviews was to portray the mechanisms underlying mechanical ventilation–induced lung jury (9, 13). Activation of protein kinases, especially protein tyrosine kinases, mitogen-activated protein kinases, and transcription factor NF-B, have been proposed to be the major pathways that mediate mechanical force–induced production of cytokine, chemokine, and other inflammatory mediators in the lung cells (24–28). These molecules contribute to the regulation of inflammatory responses and tissue injury. In the present article, instead of focusing on different signaling pathways, we mainly discuss the different ways in which cells sense mechanical stimuli, and the mechanisms by which physical forces are converted into the biochemical reactions of signal transduction. We also comment on the relationship between mechanosensation and VILI.

MECHANOSENSATION: THE INITIAL STEP OF MECHANOTRANSDUCTION

Sensing physical forces is a fundamental response for living cells that is preserved throughout evolution. One example of an early formed response mechanism is the mechanosensitive ion channel. Identified and cloned in bacteria, mechanosensitive ion channels are known to open or close after specific mechanical stimuli (29). Another example of how organisms may sense mechanical stimuli is illustrated by the ability of wind to activate intracellular signals in plants. A contact-sensitive plant, Minosa pudica L., closes its leaves and points its petiole downward away from the stimulus when touched. It has been shown that the degree of actin tyrosine phosphorylation and the degree of bending of its petioles are closely correlated (30). As will be discussed later, protein phosphorylation is one of the major means of intracellular signal transduction in mammalian cells.

Sensing physical stimuli, such as light, temperature, and forces, is essential for living organisms. In highly organized life-forms, specialized structures have been formed for mechanosensation—for example, touch receptors in C. elegans (31, 32), bristle receptors in Drosophila (33, 34), and hair cells of the inner ear (35). A protein called brain sodium channel 1 has been reported to be essential for detection of light touch, and is a central component of a mechanosensory complex in the skin (36). Cell membrane proteins, called polycystins, are important in mediating mechanosensation in the primary cilium of kidney cells (37). In the lungs, rapidly adapting receptors (RARs) are another perfect example of specialized mechanoreceptors. RARs occur throughout the respiratory tract from the nose to the bronchi. They have thin myelinated nerve fibers that respond to mechanical and chemical irritants, and to many inflammatory and immunologic mediators. The RARs of the trachea and larger bronchi are mechanosensitive; they cause cough, bronchoconstriction, and airway mucus secretion (38, 39). Voltage-gated ion channels selective for K⁺ and Na⁺ (for the generation and conduction of action potentials), and ion channels selective for other ions such as Ca²⁺ or Cl^–, are thought to play distinctive roles in the activation of RARs (40). These specialized mechanosensory apparati in the body commonly consist of a transduction channel connected to intracellular and extracellular anchors, which control the entry of ions, and thus convert a mechanical stimulus into an intracellular signal (41).

MECHANOSENSORS ON CYTOPLASMA MEMBRANE

In addition to these specialized cells or apparati, it is believed that all cell types in the body are able to respond to mechanical force applied to them or generated internally. Stretch-activated ion channels (42), extracellular matrix (ECM)–integrin–cytoskleton network (43), growth factor receptors (44), and cell–cell adhesion molecules (45) have been considered as mechanosensors localized on the cytoplasma membrane (Figure 1). These mechanisms have been reviewed extensively in the literature; thus, we will discuss them only briefly.

View larger version (49K): [in this window] [in a new window]   Figure 1. Mechanosensors on the cytoplasma membrane. Stretch-activated ion channel, receptors for growth factors and other ligands, ECM–integrin–cytoskeletal complex are commonly accepted as mechanosensors on the cytoplasm membrane. Intercellular cell–cell adherens junctions and gap junctions are also involved in mechanical force–induced signaling.

ECM–Integrin–Cytoskeleton Complex
Cells attach to ECM via proteins called integrins, which connect the ECM to the cytoskeleton (Figure 1). Mechanical loads could be transmitted across the cell surface by these physically interconnected structures. A "tensegrity" model was proposed by Ingber and Jamieson to describe the role of this complex in maintaining cellular mechanics and mechanotransduction (52). This model considers the cytoskeletal components (microfilaments, microtubule, and intermediate filaments) to form an interconnected network, whereas the microfilaments and intermediate filaments bear tension and the microtubules bear compression. This model explains the ability of the cell to execute complex processes such as spreading, migration, and how forces applied locally on the cell result in responses throughout the whole cell (53). Dynamic formation of new connections between integrins and their specific ECM ligands could be a mechanism in relaying the signals induced by physical forces, such as shear stress, to intracellular signals (44). This area of research has been subjected to many excellent reviews (54–57). Its particular role in VILI is not clear; however, it has been proposed that ventilator-induced increase in pulmonary permeability could be mediated through this mechanism (10).

Growth Factor Receptors
There is evidence to suggest that receptor tyrosine kinases can serve as mechanosensors (58). It has been demonstrated that mechanical forces can activate platelet-derived growth factor (PDGF) receptor in vascular smooth muscle cells, which was shown not to operate through an autocrine mechanism and could not be blocked by antibodies against PDGF receptors (59). The authors speculated that physical forces as energy could be absorbed by the receptor, by nonprotein or protein components of the plasma membrane, or by molecules at some other site of the cell, followed by transfer of the signal to the plasma membrane (59). In fetal rat lung cells, PDGF and its receptors were also shown to be involved in stretch-induced cell proliferation, but it was considered through an autocrine or paracrine mechanism (60). It has been recently reported that compressive stress shrinks the lateral intercellular space surrounding airway epithelial cells, increasing local ligand concentrations, which triggers cellular signaling via autocrine binding of epidermal growth factor family ligands to the epidermal growth factor receptor in airway epithelial cells (61) (Figure 1). This mechanism may explain the airway spasm–induced intracellular signal transduction related to asthma. When mechanical ventilation is used for patients with severe asthma, this mechanosensory mechanism may play a role in both asthma and VILI.

Intercellular Mechanical Signaling
For multicellular tissues, the mechanical force–induced signals that transmit from one cell to another are essential in order for cells to synchronize their responses. One example is the mechanical stimulation–induced intercellular Ca²⁺ signaling in airway epithelial cells (62, 63). The intercellular calcium propagation is mediated through gap junction proteins, connexins (64) (Figure 1). The adherens junction could also function as mechanosensors. Ko and coworkers demonstrated that mechanical forces applied to adherens junctions in fibroblasts activate stretch-sensitive calcium-permeable channels and increase actin polymerization; these effects appear to be mediated via N-cadherins (45) (Figure 1). The adherens junction and gap junction may interact in mechanotransduction (65). Considering the importance of integrity of alveolar epithelium in maintaining the barrier function in the lung, cell–cell interaction may play an important role in mechanotransduction, especially during mechanical ventilation. Furthermore, when VILI occurs, local tissue damage and inflammatory responses may significantly affect the intercellular mechanosensation and mechanotransduction.

MECHANOSENSATION INSIDE THE CELLS: THE ROLE OF PROTEIN–PROTEIN INTERACTION

All these models mentioned above focus on the proteins associated with plasma membrane of the cells. Recent studies have shown that mechanical forces could also be converted into biochemical signals inside the cells through protein–protein interaction.

Specialized Intracellular Mechanosensor
In myocardial cells, muscle LIM protein (MLP) in the Z-disc complex has been proposed as a stretch sensor. MLP has been shown to bind to -actin in the Z-disc, as well as to have the ability to interact and colocalize with telethonin, a titin interacting protein. A human MLP mutation has been found to be associated with dilated cardiomyopathy, which was attributed to marked defect in MLP interaction with telethonin (66). This complex could be considered as a specialized intracellular sensor for mechanical stretch in the heart.

Force Transduction by the Cytoskeleton
Sawada and Sheetz used a Triton buffer to remove cytoplasm and cellular membrane, and then applied a transient mechanical stretch to Triton-insoluble cytoskeleton. They then added biotinylated cytoplasmic proteins back, and demonstrated stretch-dependent binding of paxillin, focal adhesion kinase, and p130Cas to the cytoskeleton (67). Because the ion channels were removed from the apical plasma membrane, the intracellular concentrations of calcium and other ions were not subjected to dynamic exchange, yet the biochemical reactions for signal transduction still occurred. In effect, the transient mechanical stretch altered enzymatic activity and phosphorylation status of certain proteins associated with the cytoskeleton and enabled these molecules to interact with cytoplasm proteins added back to the culture system. Alenghat and coworkers recently showed that alteration of the cytoskeletal force balance in renal epithelial cells by disruption of microfilaments, microtubules, or integrin-dependent extracellular matrix adhesions, inhibited or eliminated fluid shear stress–induced increase of intracellular calcium, indicating that the mechanotransduction response in these cells is governed by global mechanical cues, including isometric tension within the entire cytoskeleton and intact adhesions to extracellular matrix (68). In other words, the function of mechanosensitive ion channels is predetermined by the integrity of the cytoskeleton. These studies demonstrated the essential role of the cytoskeleton in mechanotransduction, but they did not explain how mechanical forces change the enzymatic activity and how the cytoskeleton control the activity of ion channels.

Specific Protein–Protein Interaction in Mechanosensation
Through molecular cloning and protein chemistry studies, it has been found that the structure of proteins can be dissected as functional domains and motifs (69) (Figure 2A). The importance of protein–protein interactions through these functional modules is one of the basic concepts in intracellular signal transduction. We propose that these interactions play an important role in mechanosensation.

View larger version (49K): [in this window] [in a new window]   Figure 2. Schematic model of protein–protein interaction through specific binding as a mechanism for intracellular mechanosensation. (A) Proteins are built by functional modules. Protein tyrosine kinase c-Src and actin-filament associated protein (AFAP) are used as examples to illustrate the specific binding and interaction between proteins. Bmf: binding motifs. (B) Physical force transmitted via the cytoskeleton may increase the contact between AFAP and c-Src. The high-affinity Src binding sites on AFAP may competitively bind to c-Src, and lead to its activation by SH2 or SH3 domain displacement. Other proteins and mechanosensitive enzymes may interact similarly. Panel B is reproduced with permission from The Journal of Biological Chemistry (88).

It is noteworthy that Parker and coworkers have shown that phosphotyrosine phosphatase inhibition increased the susceptibility of rat lungs to high peak inflation pressure injury, and tyrosine kinase inhibition attenuated the injury (79). Therefore, activation of protein tyrosine kinases may contribute to the pathophysiologic processes related to VILI. The role of protein tyrosine kinases, especially Src family members, in VILI merits further investigation.

Crystallographic structure studies (80–82) revealed that the kinase activity of c-Src is maintained at a low basal level by two major intramolecular interactions. One is the binding of its SH3 domain to the linker between the SH2 domain and the kinase domain; another is the binding of its SH2 domain to the phsophorylated tyrosine residue 527 in its C-terminal tail (Figure 2B). AFAP contains two proline-rich motifs that may bind to the Src SH3 domain (83), and several putative consensus tyrosine phosphorylation motifs that may bind to Src SH2 domain (84). Further, AFAP contains an actin-binding motif (85) (Figure 2A); thus, it is well suited to sense mechanical stretch-induced cytoskeletal deformation. As an adaptor protein AFAP links signaling molecules to actin filaments, and it is also involved in the actin-filament organization and Src-related intracellular signal transduction (86).

To determine the molecular structure of AFAP in mammalian cells, we first cloned AFAP from rat lung tissue (87), and later from human lung alveolar epithelial cells (88). The peptide sequences and molecular structure of AFAP proteins are conserved between chicken, rat, and human. All the functional motifs and domains described for chicken AFAP (85) are present in rat and human AFAP proteins in the same order. We further demonstrated that AFAP was able to directly activate c-Src through its SH3 and SH2 domains. The first stretch of proline-rich motif was found to be critical for c-Src binding. A single amino acid mutation at position 71 from proline to alanine significantly reduced binding between AFAP and c-Src, and reduced c-Src activation. Overexpression of this mutant significantly reduced mechanical stretch–induced c-Src translocation from cytoplasm to the cytoskeleton, and prevented stretch-induced activation of c-Src. In addition to the use of AFAP mutant we used small interference RNA to knock-down the endogenous AFAP expression, which also reduced stretch-induced c-Src activation (88). These interesting observations led us to propose a novel mechanism for mechanosenation. We suggest that mechanical stretch–induced cytoskeletal deformation increases the competitive binding between AFAP and c-Src by displacement of SH3 and/or SH2 domains, which in turn induces the configuration change of c-Src and leads to its activation (Figure 2B). Upon the activation of c-Src, a downstream signaling cascade will be initiated.

According to this model, the mechanical stretch–derived cytoskeletal deformation will enable cytoskeleton-associated proteins to sense physical force inside the cells, and convert it into the biochemical reactions of intracellular signal transduction through protein–protein interactions. In this regard, the physical interaction between AFAP and c-Src could serve as an example. Activated c-Src could further enhance tyrosine phosphorylation of AFAP that will further increase their binding through the SH2 domain. This auto-feedback mechanism could be very important in c-Src-related signal transduction.

In addition to AFAP, several other signal transduction proteins, such as focal adhesion kinase (89) and p130Cas (90), also contains Src SH2 and SH3 binding motifs. They also have the potential to be associated with the cytoskeleton. Mechanical forces–derived cytoskeleton deformation may increase or decrease contact of these proteins with their binding partner in a similar fashion, thus they may also sense physical forces and initiate intracellular signaling through the same mechanism. Several other types of enzymes, such as phospholipase A2, phospholipase C (91), and receptor protein tyrosine phosphotase , have been considered as mechanosensitive (92). The molecular modules on these proteins and their binding partners have also been defined. Therefore, protein–protein interaction could be a common mechanism for mechanosensation. This new concept could be applied to further explain how physical forces are transmitted through the ECM–integrin–cytoskeleton complex.

In summary, the importance of VILI in ARDS has been commonly accepted. The mechanotransduction has been the focus of related studies. The mechanosensation, especially the specific protein-protein interaction mediated physico-chemical conversion provides a new insight for our understanding of cellular and molecular mechanisms of VILI. Acute inflammatory responses have been considered as the major mechanism of ARDS. However, blocking inflammation may potentially jeopardize the innate immunity. Using bioinformatics approach several groups have been actively searching for genes related to VILI and/or ARDS (22). By knowing the mechanosensory mechanisms, mechanotransduction pathways and genes specifically regulated by mechanical ventilation and involved in VILI, we may be able to selectively prevent physical force-induced cell damage and inflammatory responses, while maintaining the host defense mechanisms in the lung intact. These molecular studies may reveal more clues for the development and management of VILI, as well as ARDS.

ACKNOWLEDGMENTS

The authors thank Dr. Claudia dos Santos for her critical comments on this manuscript.

FOOTNOTES

This work is supported by operating grants (MT-13270, MOP-42546) from Canadian Institutes of Health Research (CIHR). B.H. is a recipient of CIHR Fellowship. M.L. holds an Ontario Graduate Scholarship. M.L. is a recipient of Premier's Research Excellence Award from the Ontario Government.

Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

(Received in original form January 27, 2005; accepted in final form March 28, 2005)

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