Stretching, Connective Tissue, Chronic Pain, and Cancer

this program is presented by university of california television like what you learn visit our website or follow us on Facebook and Twitter to keep up with the latest UC TV programs welcome I am absolutely delighted to welcome all of you to the Osher Center for Integrative Medicine today this is a much-anticipated occasion we have the launch of the can bar lecture on innovations in integrative medicine today this is our inaugural lecture and we have a fantastic inaugural guest speaker and I have the pleasure now of introducing two people first of all the gentleman who has made this series possible and I want to begin by acknowledging mr. Ken Barr who I'm delighted is here with us today and acknowledge and thank him for his vision and the tremendous generosity that he has shared through supporting the OSHA Centers living endowment fund which is making possible this series as well as a whole host of opportunities that we can share both with UCSF and through modern technology with the rest of the world so thank you so much mr. ken bar now I can't let you get off that easy because you're just too fascinating a person and I want to share a few things so that people understand what a remarkable human being you are mr. ken bar is a graduate in 1952 of Philadelphia University it was then known as the Philadelphia textile Institute and he studied materials science now when I say that he's a remarkable human being I am NOT being inappropriately effusive he is an inventor he's an entrepreneur he's an author he's a film producer he's well known for many inventions and they are as wide-ranging as his interests he has more than 50 patents for a whole variety of things that he has invented and I want to give you just a few examples so you understand what I mean by this broad scope one of my favorites he invented the de fuzz it comb for sweaters he invented tangos puzzle game now listen to the rest of this the safety glide hypodermic needle protector a cryogenic cataract remover a new LED traffic light he created New York's first multiplex cinema the quad cinema and another personal favorite of mine zip notes which are rolled sticky notes that have a centerline adhesive strip and are a huge advance on on posta sand I have one of these in my office of thank you for that I'm happy to write you all short notes and share that with you then continuing terms of this breadth he also produced an animated film hoodwinked and 2006's when it came out and there's also an interesting range of consumables that you'll appreciate now over lunch on the one hand he brought to market something called sue food or super food which is a meal of grains and rice and lentils and what some might consider on the other end of the spectrum he developed a hangover proof vodka sky vodka and Blue Angel vodka something tells me you're most known for that Mister can bar also is the author of secrets from an inventor's notebook came out in 2002 I I commend that to you and and this is just a characteristically royalties from the sales of the book go to the New York University School of film where there is the Canberra Institute for of film and TV now mister can bars generosity in philanthropy are legendary and UCSF and again just to name a couple of different things very familiar to those of us at UCSF he established the UCSF can bar Center for advanced simulation in education that was in 2006 and that is a program equipment and a space that is used by all health professional students at the University and there isn't an educator among the thousands of us at UCSF who are not grateful for that innovation mister Canberra also created the Canberra Cardiac Center at the California Pacific Medical Center and the Kaiser Performing Arts Center which is home of the san francisco girls chorus the list goes on and on and I do want to get to my second introductions so I'll just say that mr. ken Barr is truly the the quintessential innovator he's endlessly curious he's constantly seeking ways to improve the way we do things some of us notice things that need fixing and then leave it at that and mister can bar looks closely and discovers what can be done to improve so everybody please join me in welcoming and thanking mr. ken bar for his support and now I have the opportunity to introduce another sort of innovator dr. Ellen Leung Javon do a quick quick bio because the only thing more interesting than hearing about your accomplishments is hearing from you so move to that quickly dr. Langevin earned her degree in medicine from McGill and she completed a postdoctoral research fellowship in neuro chemistry in Cambridge England at the Medical Research Council neuro chemical pharmacology unit and she completed her residency in internal medicine and a fellowship in endocrinology and metabolism at Johns Hopkins in her free time dr. Vaughn Javan was appointed director of the osher Center for Integrative Medicine at Harvard Medical School and Brigham and Women's Hospital in 2012 this is one of our our sister Osher Center sites out of the out of the five in existence and she's the Bernard Osher professor and residents of complementary and integrative medical therapies she's also visiting professor of neurology orthopaedics and rehabilitation at the University of Vermont College of Medicine she you are probably best known for discovering cellular and molecular mechanisms involved in the field of acupuncture and I love the quote from the Boston Globe describing you as a celebrity in the world of acupuncture a field not known necessarily for ever celebrities but you absolutely encompass the dr. Langevin has been the principal investigator of several NIH funded studies investigating the role of connective tissue and chronic pain and the mechanisms of acupuncture and manual and movement based therapies so that's sort of the CV I want to say in a personal note and everyone that works with Ellen knows that your innovation your creative intellect your ceaseless curiosity make you an ideal collaborator and ideal teammate and a wonderful person to learn from so thank you so much Ellen thank you so much Shelley is this on yeah it's on now thank you so much for this kind introduction and I want to extend my thanks to mr. Ken bar for making it possible for me to to be here today which really means a lot to me and I also want to really say how grateful we are to the Osher foundation for making the work that I'm going to present today possible and this is this is really quite remarkable because as Shelley mentioned these these work the work that I'm going to talk about is is it's kind of unusual in a sense that it's not a lot of it takes it takes a special kind of environment to be able to support research that's a little bit kind of out of the ordinary and and we are very fortunate to have this kind of support in order to be able to do that so it's very very important to us we're very thankful so I'm gonna be talking about stretching connective tissue chronic pain and cancer quite disparate set of words but I'm gonna start with a riddle and I'm gonna ask what do yoga acupuncture and manuals we have in common and if you go back to the title of the lecture I think you'll probably have an idea that it has something to do with stretching and indeed when we when we stretch our bodies when we do exercise like yoga for example or when we have a massage you know it's it's easy to imagine that there's some kind of stretching of tissues that takes place both via the hands of the practitioner and and the actual movements of the person themselves but it's a little bit less obvious about about acupuncture so this is something that got me really interested in a long time ago very that kind of prompted the whole research projects on acupuncture is the idea that acupuncture needles stretch tissues and the way they do that is by kind of manipulating the tissues almost almost stretching from the inside once the acupuncture needle is inserted it kind of the tissues grab around the needle and then when you rotate the needle it's kind of I I like to think about it just like forget spaghetti winding around a fork and then once that has happened every direction that you move your needle the tissue moves with it so it's a way to sort of grab onto the tissue and stretch it it's a very interesting thing and so all those both yoga acupuncture and manual therapies or massage result in some kind of stretching and of connective tissue and this little lovely little cat up here is there to remind us that stretching is something that it's not just us animals do it and they do it spontaneously and babies also and in people too human we stretch why because it feels good but the purpose of the whole talk you'll see its to it's to explore the idea that stretching not only does it feel good but it's actually good for us and what happens when we stretch and and and all the the work that we've done to try to uncover that so the big focus of my lab is on connective tissue and the reason for that was because of that original observation with the acupuncture needles it got us really intrigued as to what happens when you stretch connective tissue and connective tissue is I think it's like I consider it to be like they on an unsung hero of the body we don't pay enough attention to it we really should and be and the one of the reasons is that connective tissue is is one of these things that's named tells us it's a connector it connects things you can draw a map if it forms a network through your whole body you can draw a line going through any point of your body to any other point of your body via a path of connective tissue right it surrounds everything around every muscle every bone every nerve and it goes inside organs inside your liver your heart there's like a web of connective tissue connects everything it's a middle it's amazing and so it's part of the musculoskeletal system because it in it goes around the muscles it's part of the muscles because it goes inside the muscles at web as well forms the structure of the muscle but you wouldn't know that by looking at textbooks of orthopedics for example or Rheumatology which are the two disciplines of medicine that are supposed to be interested in the musculoskeletal system you're lucky if you find a paragraph on connective tissue it's it's really very strange to me the other thing that's interesting about connective tissue is it's also part of the immune system and that is again something we have to stop and think about why and the reason is that the immune system with when we think of the immune system we think of like white blood cells right that patrol the body that go around the body and check out to look for bad things bacteria or antigens things that are that we want to get rid of or even even cancer cells they look around for trouble and then what they do is they come back to the lymphatics and to the lymph nodes and the spleen and then they report the information that they found and but all of this patrolling around getting the information going back to this all happens in connective tissue connective tissue is actually the terrain it's the area it's the housing of of the of much of the immune system and we don't often think about that so I'm going to be talking a lot about the intersection between musculoskeletal function and immune function how does how does the movements the stretching the all the stuff that we do how does that influence the immune system so one of the things that we also are very interested in the connective tissue is because it's involved in in in a musculoskeletal system and also it must feel skeletal pain musculoskeletal pain is something that we know very very little about and a lot of times for example people will have low back pain terrible back pain and disabled can't work and they go to they have a an x-ray MRI everything is fine their spine is nor a molder no protruding this the person still has back pain why is that and in the last I would say 1020 years people have gotten very interested in the role of tissues outside of the spine and tissues of the back and the connective tissues here particularly did this huge structure here in the back called the thoracolumbar fascia and fashio is another word for connective tissue and the structure in the back we know now contains sensory nerve endings and and we are starting to understand that a lot of back pain has to do with the dirac of faster longer fascia and its relationship to the muscles of the back so in my lab we got really interested in the thoracolumbar fascia some years ago we did an ultrasound study and we looked at what the thoracolumbar fascia looks like in ultrasound so this is just to orient you this is a picture of ultrasound picture of someone's back here's the skin here's the black stuff here is the subcutaneous fat and underneath this big thick white band here that's that thoracolumbar fashion we're seeing it in cross-section this is what it looks like in a normal person but then we started noticing this some people where it looks the fashion looks thicker and then it might even look like that sort of disorganized and sort of not good looking right and we wondered could this has something to do with with the reason why some people may have back there's something wrong with the fascia so we did a study of a hundred seven subjects and we measured how thick this fashion was so we measured that the subcutaneous tissue and we also measured the this fashion here which is this area that I highlighted in green when we measured the whole thickness between the skin and the muscle you can see that it was thicker here and also what we call the echogenicity in that's the this is an ultrasound term that and that denotes how many echoes they're generated by the ultrasound and so the people with back pain here in black had a thicker and more echogenic thoracolumbar fascia this is the whole thickness when we looked at the subcutaneous thickness here is the same but when we looked at the peri muscular which is the fashio right around the muscle that's where that difference came from so people with back pain had a thicker fashio than pigs people without that thing we didn't know why but we were curious as to whether this thicker in fashion may have something to do with perhaps an old injury that hadn't healed or some inflammation or something that was causing the fashio to get stuck and not move properly so we did another study where we looked at the different layers the important thing to realize is this fashion is composed of many different layers and they're all supposed to move so in the next style I'm going to show you how that how that happens so if if you could click the first movie this is a movie of somebody who's lying down on a table face down and the table feet is moving up and down and you can see here that this this their back is essentially the person is moving like this passively up and down and their fashio is getting stretched and you can see that the layers within the fashio are gliding they're not moving all at the same rate can you can you see that these layers are not moving at the same there's kind of movement between those layers a little bit like stuff slipping and sliding right that's normal now if you could please click the video of the person with back pain this person doesn't quite look so sliding you see how it kind of looks like it's pulling and tugging and it's not really doesn't look quite as as happy and as as as kind of fluid right and so we hypothesized that this is something that may have to be associated with back pain so we measured this movement using a technique of elastography where you can actually take those images and measure the relative motion between the tissue layers and we found that lo and behold it was reduced in the people with back pain compared with controls we also found interesting difference between men and women so the females in general had higher movement than the males but in both males and females it was reduced in people with back pain so it's not something that's restricted to either men or women everybody gets it if you have back pain it tends to get reduced so why would that be well we know that if you have an injury anywhere what happens is that the body tends to heal the injury and so this is an example of cross-section through the skin and this is the subcutaneous muscle and this is the fashion ear and this is the the underneath the muscle and this is a tiny little injury that affected these two layers and you can see that once the injury has healed the two layers have stuck together they're become fused and this is what we call an adhesion and adhesions mean that layers are adherent they're not they're not independent they can't move and we think that maybe that's what's happening in the people with back pain is that somehow maybe they they were shoveling snow perhaps some day and they kind of you know how you say oh I wrenched my back you know and but we don't know there nothing shows up on x-rays their back hurts like hell but they're they kind of you know hobble along for a couple of days and then they get better well we think that what happens during these little sort of micro injuries that make cause some little sort of a little bit of tearing and these are not big tears but over time they may kind of result in some loss of function the ability of the body to heal wounds is vital right if if we didn't have that we would die like for example if you were a lion in the John for example and you have a big cut on the side of your of your back there's no there's nobody there to stitch you up right so in the old prehistoric times when we did not have you know surgery and you know at the ability to stitch wounds if a wound was gaping open and was not able to heal itself and close then that then the person or the animal would literally not survive so this is a very very very important mechanism that is essential for survival and we don't want to think about it where you cut yourself and after a couple of days at first you have some pain and you have a little scab and then somehow your tissues are able to regenerate that gap across the the cut and they produce what we call fibrous tissues that form essentially a scar right and this is a very complicated and and well orchestrated a reaction that allows the tissues to essentially mend themselves and inflammation right is the first step of this you cannot heal the wound until but if you do not have a proper inflammatory response so the first step is these inflammatory cells are going to get called or over and they're gonna come to the area and they're gonna start to secrete all kinds of molecules and chemicals to sort of mount this whole kind of response and then eventually heal so what happens then next well eventually this inflammation has to go away it has to what we call resolve itself and so eventually if everything goes well all of this stuff gets cleaned out and what you're left with is a tiny little essentially scar but the tissues are eventually normal right they go back to normal except for the fact that they had this little scar and perhaps they've lost a little bit of that of mobility you've all had you know little scars here and there but it doesn't interfere with with your with with anything however there are times when this resolution mechanism fails and this whole inflammatory response that was essential to heal the wound persists and continues for days and weeks on end and what you get now is what's called chronic inflammation and that's not good because chronic inflammation has really nose business being there it shouldn't be there anymore that the job is done and this it should clear away but somehow it stays and the consequence of chronic inflammation is something that we cause fibrosis which is essentially a spreading of essentially scarring out of control and people can get fibrosis in various parts of their bodies in their kidneys their lungs their there and and and and these are these are serious pathologies when they happen and there's a lot of effort trying to understand the mechanism underlying fibrosis now in the musculoskeletal system we don't know a whole lot about this yet but we know that when you get chronic inflammation and fibrosis somewhere which we think is happening in the case of our thickened thoracolumbar fascia remember this causes increased stiffness the tissues are not as you not only do now glide as well but they're also stiffer and so that restricts movement and that's not good why because if you have pain you're also not going to water move because it hurts to move and therefore you will have what we call fear of movement and there's there's if this is a very understood now as being an important component of back pain because people just don't want to burn their back bend their back because it hurts and therefore they will avoid moving the area that hurts which contributes further to restricting the mobility and so you have restricted mobility coming from two different directions from the increased stiffness from the injury the inflammation the fibrosis and also from the behavior of the person contributing to somebody ending up with connective tissue that's not happy at all because connective tissue needs to move in order to be healthy so we're gonna talk some more about that so I also want to talk about another area where connective tissue is extremely important and that's and it used to be years ago we used to think that cancer is about tumor cells right growing out of control somehow invading the body we now know that it's not just that cancer leads something to grow onto it needs a bed and that bed that it grows on to is guess what connective tissue that it has a name we call it stroma and it's the tumor stroma you can see this is an example of a tumor that has so the tumor cells are what you see here in these little pockets but the stroma are this kind of these sort of strands of connective tissue that can essentially hold the tumor together and a feed they help the tumor grow so the tumor is essentially hijacking the connective tissue of the person to help it to grow into a bigger tumor and there's there are cases where this becomes very extreme you can see here this is an example of a tumor where this pink stuff is the connective tissue this is essentially fibrosis and we call it even though it's Cod there's a name for it it's called a dismal plastic reaction and these tumors that have very strong amount of fibrosis tend to have a bad prognosis they don't do as well and there's some very very elegant research happening at the university of wisconsin's right now in the lab of dr. Patricia Keeley where they have shown that there are these if you look very carefully at this stroma this is the connective tissue inside the tumor whenever you see these wavy kind of lines that's actually not bad when you see these straight lines that point directly into the tumor cells that's bad and these are the air the areas of connective tissue that are helping the tumor grow if they're going around the tumor it's not so much but once they start not so not so bad of prognosis but when they start going into the tumor and what they found is that these they they provide these little highways for the tumor cells to grow out of and it promotes the spreading and the dissemination of the cancer cell so this - stroma is extremely important now if we go back to our connective tissue stiffness for a minute here resulting from chronic inflammation and fibrosis we know that both chronic information and fibrosis are our predisposing factors for cancer growth I mean and so this is a serious thing and not only does inflammation and fibrosis help the cancer as I said but in return the cancer secretes molecules that further increase the stiffness of the tissue so it it becomes a self sort of feeding a sort of cycle where the the cancer promotes the stiffness and the stiffness promotes the cancer so stiffness is not good all right so let's go back to our stretching so when we talk about stress okay we a lot of people in this audience are very interested in stress right what do we talk about when we talk about stress we talk about mostly stress that we experience in our lives but the word stress also has a very specific meaning in biomechanics stress right when you stress a piece of material the amount of stress is the force that you exert on the material divided by the cross-sectional of the area of the material if you apply a very very small force on a very small amount of area you're gonna have a bigger stress okay and strain is something we think about is we think about strain like the strain of sort of you know difficult you need to do different clothes things but in in biomechanics strain means the amount of deformability how and here I'm gonna use a prop that actually mr. can bar just gave me before the lecture which is this rubber band so if you have a rubber band right that is really really stiff okay and it's hard to deform okay I'm gonna have I'm gonna put a large amount of force and therefore large the rubber band is going to experience a lot of stress but there's going to be low strain not a lot of deformation if on the other hand I have a piece of really sort of loose fabric for example that is very very loose think of sweater and you're gonna deform it the sweater is gonna be very compliant so the stress is not going to be large but the strain will be a large because the the the the the the sweater is going to deform so something that is very stiff will have a low high stress and low strain okay and so everything that we do in our body interacts with the connective tissue and depending on how stiff it is it's going to influence the what we call the stress and strain relationship between the the effects of the mechanical force so that's important but another thing that's really important is that we are not rubber bands right we are living bodies and therefore our tissues respond to the mechanical forces and by having biological reactions that then change the the the the tissue itself so this whole thing is this whole relationship of body movements to in applied forces to stiffness and to the amount of the moving and the deformation of the body is something that's constantly in evolution every time you move every time you have a massage or an acupuncture treatment somehow it's tweaking your connective tissue and the connective tissue can change in stiffness as a result of that because it's that's that's how connective tissue is it's plastic so this is very important to remember so all of our our our treatments are having an interaction with this but the million-dollar question is what how does these how do these mechanical forces and tissue deformation interact with this inflammation and fibrosis and cancer what is the relationship between those things so we decided to address this in our lab it's quite some time ago with some animal models and here I'm going to make sure that people understand that you know the animal models that I'm going to describe here first of all they are very important we think they're important in order to be able to study this this very important subject but they're all very humane we don't make the animals suffer in any way other than very very mild mild amount of discomfort when we not sure I'll show you the two different techniques that we use one is what we called a micro injury so we're literally causing an injury that's literally in the millimeter range something that you can only see under the microscope and we this is the injury that I showed you before we essentially cut the connections between the connective tissue planes in the back and then we let it heal and it causes this scar and we follow what we call the resolution of the injury and this is important because we can follow the different types of cells first the neutrophils which are the cells that are the big attackers at the beginning and then what we call the m1 macrophages which is the macrophages that kind of take it to the next stage where the resolution starts and then the m2 macrophages they are essentially cleaning up the mess and then so they come and they've cleaned up the degree and they help to create a nice new healthy tissue okay so that's our first model this is what we call acute self-limited inflammation now we also have another model which is chronic now that's on purpose we want a model where this nice resolution doesn't happen so instead of doing a little injury we inject a tiny tiny little amount of this thing called carrageenan now carrageenan I hate to say is something that's in the yogurt just that you eat or the ice cream or ice it's it's amazing I said it's a lot of food products it's a it's a prote it's a it's a molecule another proteins it's derived from seaweed and it's something that if you eat it apparently it's it's fine I've stopped eating I've started reading a lot of yogurt labels actually since we started doing this this research but when you injected subcutaneously it's not it it actually causes this tiny tiny little amount again microscopic you know you're talking about something a millimeter but that continues and persists so this shows you this is 24 hours you've got acute inflammation here two weeks six weeks even ten weeks later you still see some inflammation so this is a tiny little essentially injury if you could call it that that continues and persists kind of mimics chronic inflammation that happens you know in people when inflammation doesn't go away you can see here that the first phase of inflammation is pretty much the same those polymorphonuclear these are the neutrophils the m1 macrophages instead of kind of going away here stay and then the m2 macrophages the cleaner-uppers they don't never actually take over you can see here that here there's all that's left here is m2 here they're trying but they're not quite succeeding and so that's why this inflammation what we call failed resolution it doesn't succeed okay so the first thing we wanted to know is okay if you just create this little let's well now that we're going to talk about the first model right the little injury model if you stretch the animal every day does that help this injury heal so this was a method that we developed here at the lab at the University of Vermont quite some time ago and this is this little method where we hold the animal very very gently by the chair the animal then grabs the edge of the table and stretches their body and this is something they do spontaneously and they they kind of hold their far feet forward and their back feet backwards and look at this they stick their back feet out and they stretch and we one of my technicians kind of figured this out once and they said I think I actually enjoy it because they don't complain they don't squeak they don't struggle they just stretch and we think they actually feel good doing it because they really don't struggle and it's funny because they can do it from about five to ten minutes and then after that amount of time they've had enough then they kind of start to wriggle and then we know it's time and then we stop so it's really interesting so we we looked we used a special kind of stain to look at the amount of newly formed collagen what that means is this is the new collagen that's put down in order to form the scar and this red indicates that and you can see here this is the non stretched animal so the non stretched animal is simply taken out of its cage for the same amount of time and just basically kind of handled but not stretched the non stretched animal you can see there's a lot more of this Procol in the injured compared to the non injured animal but look at the stretched animal it's almost the same there's no longer a statistically significant difference between the injured and the non injured so it has really reduced the amount of scar that took place so that was interesting we then thought well this is actually something I'm skipping ahead in time and I apologize this slide is a little bit washed out but I'll talk you through it this is a wee-wee we did this more recently at the Brigham's but it fits there nicely because this is a model of fibrosis so this is now a disease model of fibrosis and there's a disease called scleroderma and third derma is an autoimmune disease where people develop fibrosis all over their bodies their hands become so tight that cannot bend their fingers and their face and so if this is a serious illness that people try to figure out how can we prevent this and so we wondered would stretching help there's an animal model of it's called GVHD graft-versus-host disease which is also when people get bone-marrow transplants they get an illness very similar to if they're if the transplant rejects the patient they can get something that looks just like their derma and so these at this mouse model is is like this and so the red and blue are the of this are the scleroderma animals and the black and green are the normals and we measured both the thickness we use the same ultrasound method the reason why this is interesting is because we use the same method that we used in our humans to look at the thickness of their connective tissue and also their mobility you know how this just gliding back and forth so we first looked at the thickness and you can see with the scleroderma animal the skin becomes much thicker at two weeks that's when they have a lot of inflammation and then it kind of goes back and then it kind of atrophies because the model kind of wears out and so but the stretched animals are in red you see their return to normal faster than the blue animals which are the non stretched so these stretched animals got better faster well and they they got stretched the same way as our previous one ten minutes every day now here's its bottom graph is the mobility this is this the displacement when we measure this with our ultrasound machine the same way we measure it with the humans is we measure the relative mobility between the muscle and the skin and we see here these are the scleroderma non stretched the mobility is greatly reduced the blue that's bad and the stretched animals are almost normal so they the mobility of these stretched animals is indistinguishable from the non scleroderma animals so in this case it looks like stretched attenuated the pathology and we think this is really important it's really suggested patients with lurid dermis should really have very you know physiotherapy as part of their of their treatment and right now that's not part of the very well-established standard of care the other thing we looked at in these same animals is some genes we looked at many genes that are associated with fibrosis and and and and so we we found that in these particular genes for example tgf-beta these are all genes that are associated with fibrosis and we wanted to know that it's stretching improve those and in most of them it it like for example tgf-beta did not stretch it this is a stretch this is a non-stretch scleroderma but it that was the exception pretty much all the other ones stretching improve them the ones where it improved the most and these these were statistically significant was the something called adam ate and ccl2 and these are important molecules where you can see the stretched slurred Amaro are closer to normal than their non stretched and these are very interesting molecules because they have to do do with interactions between the cell and the extracellular matrix which is the collagen matrix so we're we're going to be very interested in looking at that to see whether these can be used as markers that we can follow these animals so this is a very recent research we haven't published this yet so now i'm going to go back in time a little bit and i'm going to talk about another model of that if that second model of inflammation that I talked about with the yogurt you know the carrageenan and this was this was research that was done in my lab at UVM by Corie who was a postdoctoral fellow here some time ago and she was interested in applying this stretching method to rats that had the little carrageenan in until she's the one who did that for the first time and she was interested to know if these animals had any pain as a result of the inflammation and so she did very painstakingly testing on their backs with a little poking their backs to see if they had pain sensitivities called von Frey testing takes a lot of patience and she did that really nicely and she found that these animals had increased pain sensitivity you see these are the non stretched animals and the stretched animals had decreased pain sensitivity here a higher score is worse so they got better she also noticed they were walking a little funny because the carrageenan was kind of causing them to limp just a little bit and so she measured the stride length how big a step they took and she saw the stretched animals were taking bigger steps compared with the non-stretch so it helped them so the stretching helped these animals in a behavioral way and she also looked at their tissue macrophages so these are the inflammatory cells and they were much reduced in the stretched animal so it looked like this stretching was having an effect on the inflammation in the tissues we still were little curious though because we were wondering well this stretching method is kind of you know the animals doing a lot of things besides stretching right it's being a little bit stressed because you know it's being restrained so maybe it's getting like a flood of cortisol you know hormones in the system maybe that's what's doing it maybe has nothing to do with stretching the tissues themselves the muscles are activated perhaps it's a muscle thing maybe has nothing to do with connective tissue so we did an experiment where we compared active stretching which is what I showed you two passive stretching where we just anesthetize the animal and then we just stretch it you know passively with this by the same amount and then the control was anesthesia only stopped controlled for all the stress and other things right and then we found that the passive stretch were almost was almost as good as the active stretch they were both better than anesthesia only so we think maybe active stretching is a little bit better but we think that stretching of the tissues is part at least an important component of this and we measured this with ultrasound again so okay going back to our inflammation resolution mechanism we know that this inflammation resolution of inflammation gets started the program that starts this resolution starts as soon as the inflammation starts it's in the first couple of hours something happens that helps turning the resolution the inflammation off so we wanted to know okay so far we looked at something that was two weeks down the line right let's look right away so the first thing we did is we did we looked at acute inflammation so 48 hours after you inject the carrageenan this is when the neutrophils these are the initial responders right the first they go and they try to respond to the inflammation let's see if that gets affected and it did so here again we're looking at the thickness and inflammatory lesion measured with ultrasound it was reduced in the stretch animal the inflammatory lesion cross-sectional area was reduced the totals inflammatory cell counts were introduced and the total number of neutrophils we were surprised by that because we thought that this response was going to be something that occurred like more with the macrophages and the ones that are doing the the resolution but no apparently it involves the neutrophils themselves and this is this is the work of Lisbeth beretta in my lab at the at the Brigham and she she was the one who did the study and we just got this published so okay so what is this resolution mechanism and we're very fortunate to have at the Brigham somebody by the name of Charles Sirhan who is essentially discovered some molecules a very important class of molecules that are derived from omega-3 fatty acids that you eat in your diet so fish oil things like that oily fish and specific kinds of omega-3 epa and DHA these are specific kinds of fatty that get transformed into what we call Pro resolving mediators and these resolving mediators get formed and and released right at the beginning of inflammation and they are the ones that promote the resolution however somehow this needs to be in balance with the attack response right the chemoattractant the person Atlanteans all these other things that are trying to make the inflammation happen right so you don't want this to completely stop the inflammation but you want it to be kind of just in the right amount it's a balancing act and so if for some reason the pro inflammatory mediators prevail if they eventually essentially dominate the situation you then get failed resolution chronic inflammation and fibrosis so what determines that so we wanted to measure that so we looked at these pro resolving and pro inflammatory mediators within the inflammatory of lesion in the same experiment I showed you before 48 hours after carrageenan so this was the we looked at the first thing we did is we said okay let's let's see what happens if you inject is this resolving that's the this resolution molecule let's say let's inject it into the body and see and it mimicked the effect of stretching so this is stretching without the resolving and this is resolving without stretching and you can see that the two have a very similar effect then we thought okay let's look at the tissue and see whether there's resolving being produced in the inflammatory lesion and it did so the inflammatory lesion is making its own resolving and we then looked at the inflammatory component look at Ryan before which was our marker of inflammation that was reduced and then we but that was not by itself statistically significant but when you looked at the ratio between the resolve ins and remember I said that sort of tug of war between the two that was greatly enhanced so here there is the relative amount of resolving to Loco trying is increased and we think that that's really what matters it's the ratio of the two so we then thought okay what is the where who's making the resolve ins we don't know yet right so we think we hypothesize that it's the connective tissue that's making the resolving so we thought okay let's take a piece of connective tissue and and put it in a dish and see if it can make resolving and see if stretching the piece of connective tissue will make it make more resolve it's so we did that we take a piece or this again with Lisbeth's work we took the piece of connective tissue and she designed this absolutely ingenious experiment where she put his piece of connective tissue in she made this little well in the center and then she took neutrophils and she puts them on top of the tissue and then she put at the bottom this chemoattractant something that calls neutrophils and makes them move migrate and then she compared stretched versus non stretched tissue and what she found is that in the stretch tissues the mike the neutrophils were staying put they weren't moving whereas in the non-stretch tissue they were migrating she was measuring the neutrophils at the bottom underneath and so what this showed is stretching actually kind of reduced that the movement of neutrophils through the tissues and then she looked at how much resolve in this tissue had made and it had been increased by the stretching so it looks like this mechanism of resolution can be mimicked outside of the animal so it's not some sort of systemic effect now I talked about cancer well because we know that inflammation is so important in cancer of course it's important to think about and people have been very actively thinking about what what about this inflammation resolution mechanism does that have anything to do with cancer and so there's a group in Japan that did an experiment where they looked at a tumor at the growth of a tumor here and then they injected this analog into the lightbox in analog so the this is a another pro resolving mediator of the same family as the resolved ins and injected that into the animal and you can see how it reduced the growth of the tumor so we wondered okay well what happens would stretching reduce the growth of cancer of tumors and this was done at the University of Vermont we had there was a model this was the lab next door to us that had a model of where they injected a tiny little tumor in the back of the animals at the exact same location where we put our carrageenan so we couldn't resist we had to try this and we injected that instead of injecting the carrageenan into the animal and the subcutaneous right here we injected the tumor cells and then we looked and we waited a month and then we stretched versus non stretch the animals and we compared the size of the tumors so if you look here you can see that on average the stretched mice had the smaller tumors but then there were these a couple of animals here four of them here with the red and this is because these mesothelioma were very aggressive tumors these were not actually supposed to be subcutaneous this is a tumor of the lining of the lung they have a tendency to spread and in those four animals the the tumor had broken beyond the subcutaneous tissue and spread to the peritoneal cavity and we found four though in our stretch group and only one in the no stretch so that got us a little bit worried and we wondered is that is it that the this is actually these difference in the metastasis and the red was not statistically significant it could have been just chanced you know if we could flip a coin five times you could get four heads in one tail but and we had a lot of animals in here we had about 60 and 66 animals but we if you subtract those it were that they're the animals where the tumor only stayed in the subcutaneous space there was a highly significant effect of stretching but because we were worried about this we do not publish these results we wanted to wait and check it in a different model where you did not have a problem with metastasis so we're just doing this now and this is I'm just showing you this side just a sneak preview because I'm very excited about this is a this is a mammary tumor model in mice and you can see we only have done a very few numbers but you can see and there's some variability but we're starting to see the same thing the stretched animal tumor wait the tumor cell count looks like it's reduced we're gonna have to really do more animals here to see if this is real but what got us really excited is we looked at the resolve and concentration in those tumors and they were really higher so that to us is a really hint that maybe we're looking at something that's actually happening so this is all to tell you that you you know integrative medicine in my opinion is a lot about making new connections between things and like I was talking at the beginning you know making connections between the musculoskeletal system and the immune system is very important we want to understand the role of connective tissue in many many different ways and I think we just have begun scratching the surface but also understanding the relationship between movement and health we think it's also extremely important and hopefully there's going to be a lot more to come so as well I want a really first of all acknowledge all the people who have done this work both at the University of Vermont this was the work the older work that I talked about and the more recent work with Lisbeth that I mentioned our technicians sarah ela and our collaborators including dr. Sirhan at the Brigham and of course funding from the Osher foundation that we are so grateful for and funding from the National Center for Complementary and Integrative Health thank you very much yeah that's a whole other talk so we're very very interested in fibroblast responses to mechanical such we'vewe've for a long time being interested in cytoskeletal remodeling in response to stretching and cellular scale role related signaling inside and outside and ATP signaling related to that so yeah we're really really interested in that we think there might actually be a cytoskeletal mechanism that may be coupled we're not sure yet perhaps with the with the sort of metabolite pathway where the resolving ZAR produced but we don't know yet so great question well that's kind of yeah it's a great question could you stretch another part of your body say you have an injury here could I stretch somewhere else right that's what you're asking or systemically yeah so we don't know but we that's why we did that first experiment where we took the tissue out of the animal so that there's no doubt about it there were no muscles there no brain no no nothing else no vascular system and we still saw some some form of we can't really call it anti-inflammatory effect because you know you can't have inflammation without blood vessels but there was certainly a suggestion that the immune system I you know in this case the neutrophils were behaving differently in this case and and so there might still be some systemic effects that we are going to need to look into because certainly the resolving does get into the blood but it's it's not really clear right now where how much of an endocrine effect this is happening but we're yeah for sure it's possible yeah no we're not yes good question we are not set up in the lab to look at that we don't but certainly oxygenation and and sort of you know reactive oxygen you know species and and acid-base all those kinds of things very very important but that's not an area that that that we look at but it very well could be related really good good question so I can't say anything about that unfortunately we spent a lot of time thinking about that as a matter of fact we've just the dose is super-important right what's the right dose how much how often how hard should you stretch and and so of course these is to determine the dose of something you need huge numbers of animals very difficult right you have to determine every single parameter first individually then in combination factorial designs up the wazoo I mean you know crazy so we've decided that the first thing we're gonna try to understand is how long do you need to stretch because if you notice ten minutes our animals I mean you wouldn't most people wouldn't want to stretch for that long and so the first thing we're gonna try to do is stretch last time and see if it still works like with ten seconds enough you know we did a little bit of time interest work in terms of how often so we try doing it every other day it didn't seem to work quite as much the animals get the weekend off and the technicians too so they don't get stretched Saturday and Sunday but five days a week seems to be better than every other day so with that we know and then in terms of how quickly after the injury very important we start right away we think that that's why this 48-hour experiment to me is it's see they only get stretched three times and it look at the effect we got so it seems to be it's right away and I think a lot of like orthopedic surgery or physical therapy they're moving in that drinks used to be the janitor they put you in a cast you know you wouldn't be able to move let alone stretch now they take you out of the cat and start moving I think people start understanding that already you know in terms of practice but we don't know the mechanisms of course so you know now we I think we're getting closer to understanding those you know getting closer anyway to a mechanism oh yeah they stretch for sure but it's not as sustained I mean they still have they still stretch well that's an issue also because sometimes you know certainly the the no stretch animal is not that gets immobilized so it still gets a certain amount of stretch but it looks there that we've seen differences between our groups so even with a sort of yeah and also for the everyday life of the animal these animals are not you know in a mobile you know so yeah we actually have another model where we prevent the animals from stretching that's a whole other story we do that but then we'd want to know what happens when you can't stretch you know but yeah so I think we're going to hold the rest of the questions for now and we'll have a couple more minutes for you thank you again so much dawn for launch our series thank you mister can bar mr. oh sure dr. Bitterman our other guests from the Osher Center leadership board and advisory boards and thank you everybody thanks for joining us you

Channel: University of California Television (UCTV)

Views: 64,229

Rating: 4.90099 out of 5

Keywords: Integrative Medicine, Stretching, Connective Tissue, Chronic Pain, Cancer

Id: 7Gcl7BN6-38

Length: 57min 59sec (3479 seconds)

Published: Mon May 02 2016