- Identify the cardinal signs of inflammation
- List the body’s response to tissue injury
- Explain the process of tissue repair
- Discuss the progressive impact of aging on tissue
- Describe cancerous mutations’ effect on tissue
Tissues of all types are vulnerable to injury and, inevitably, aging. In the former case, understanding how tissues respond to damage can guide strategies to aid repair. In the latter case, understanding the impact of aging can help in the search for ways to diminish its effects.
Tissue Injury and Repair
Inflammation is the standard, initial response of the body to injury. Whether biological, chemical, physical, or radiation burns, all injuries lead to the same sequence of physiological events. Inflammation limits the extent of injury, partially or fully eliminates the cause of injury, and initiates repair and regeneration of damaged tissue. Necrosis, or accidental cell death, causes inflammation. Apoptosis is programmed cell death, a normal step-by-step process that destroys cells no longer needed by the body. By mechanisms still under investigation, apoptosis does not initiate the inflammatory response. Acute inflammation resolves over time by the healing of tissue. If inflammation persists, it becomes chronic and leads to diseased conditions. Arthritis and tuberculosis are examples of chronic inflammation. The suffix “-itis” denotes inflammation of a specific organ or type, for example, peritonitis is the inflammation of the peritoneum, and meningitis refers to the inflammation of the meninges, the tough membranes that surround the central nervous system
The four cardinal signs of inflammation—redness, swelling, pain, and local heat—were first recorded in antiquity. Cornelius Celsus is credited with documenting these signs during the days of the Roman Empire, as early as the first century AD. A fifth sign, loss of function, may also accompany inflammation.
Upon tissue injury, damaged cells release inflammatory chemical signals that evoke local vasodilation, the widening of the blood vessels. Increased blood flow results in apparent redness and heat. In response to injury, mast cells present in tissue degranulate, releasing the potent vasodilator histamine. Increased blood flow and inflammatory mediators recruit white blood cells to the site of inflammation. The endothelium lining the local blood vessel becomes “leaky” under the influence of histamine and other inflammatory mediators allowing neutrophils, macrophages, and fluid to move from the blood into the interstitial tissue spaces. The excess liquid in tissue causes swelling, more properly called edema. The swollen tissues squeezing pain receptors cause the sensation of pain. Prostaglandins released from injured cells also activate pain neurons. Non-steroidal anti-inflammatory drugs (NSAIDs) reduce pain because they inhibit the synthesis of prostaglandins. High levels of NSAIDs reduce inflammation. Antihistamines decrease allergies by blocking histamine receptors and as a result the histamine response.
After containment of an injury, the tissue repair phase starts with removal of toxins and waste products. Clotting (coagulation) reduces blood loss from damaged blood vessels and forms a network of fibrin proteins that trap blood cells and bind the edges of the wound together. A scab forms when the clot dries, reducing the risk of infection. Sometimes a mixture of dead leukocytes and fluid called pus accumulates in the wound. As healing progresses, fibroblasts from the surrounding connective tissues replace the collagen and extracellular material lost by the injury. Angiogenesis, the growth of new blood vessels, results in vascularization of the new tissue known as granulation tissue. The clot retracts pulling the edges of the wound together, and it slowly dissolves as the tissue is repaired. When a large amount of granulation tissue forms and capillaries disappear, a pale scar is often visible in the healed area. A primary union describes the healing of a wound where the edges are close together. When there is a gaping wound, it takes longer to refill the area with cells and collagen. The process called secondary union occurs as the edges of the wound are pulled together by what is called wound contraction. When a wound is more than one quarter of an inch deep, sutures (stitches) are recommended to promote a primary union and avoid the formation of a disfiguring scar. Regeneration is the addition of new cells of the same type as the ones that were injured (Figure 1).
Watch this video to see a hand heal over the course of 30 days.
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You can watch another video here: Bad hand laceration time lapse. [Warning! This video is more graphic than the first.]
Tissue and Aging
According to poet Ralph Waldo Emerson, “The surest poison is time.” In fact, biology confirms that many functions of the body decline with age. All the cells, tissues, and organs are affected by senescence, with noticeable variability between individuals owing to different genetic makeup and lifestyles. The outward signs of aging are easily recognizable. The skin and other tissues become thinner and drier, reducing their elasticity, contributing to wrinkles and high blood pressure. Hair turns gray because follicles produce less melanin, the brown pigment of hair and the iris of the eye. The face looks flabby because elastic and collagen fibers decrease in connective tissue and muscle tone is lost. Glasses and hearing aids may become parts of life as the senses slowly deteriorate, all due to reduced elasticity. Overall height decreases as the bones lose calcium and other minerals. With age, fluid decreases in the fibrous cartilage disks intercalated between the vertebrae in the spine. Joints lose cartilage and stiffen. Many tissues, including those in muscles, lose mass through a process called atrophy. Lumps and rigidity become more widespread. As a consequence, the passageways, blood vessels, and airways become more rigid. The brain and spinal cord lose mass. Nerves do not transmit impulses with the same speed and frequency as in the past. Some loss of thought clarity and memory can accompany aging. More severe problems are not necessarily associated with the aging process and may be symptoms of underlying illness.
As exterior signs of aging increase, so do the interior signs, which are not as noticeable. The incidence of heart diseases, respiratory syndromes, and type 2 diabetes increases with age, though these are not necessarily age-dependent effects. Wound healing is slower in the elderly, accompanied by a higher frequency of infection as the capacity of the immune system to fend off pathogen declines.
Aging is also apparent at the cellular level because all cells experience changes with aging. Telomeres, regions of the chromosomes necessary for cell division, shorten each time cells divide. As they do, cells are less able to divide and regenerate. Because of alterations in cell membranes, transport of oxygen and nutrients into the cell and removal of carbon dioxide and waste products from the cell are not as efficient in the elderly. Cells may begin to function abnormally, which may lead to diseases associated with aging, including arthritis, memory issues, and some cancers.
The progressive impact of aging on the body varies considerably among individuals, but Studies indicate, however, that exercise and healthy lifestyle choices can slow down the deterioration of the body that comes with old age.
Cancer is a generic term for many diseases in which cells escape regulatory signals. Uncontrolled growth, invasion into adjacent tissues, and colonization of other organs, if not treated early enough, are its hallmarks. Health suffers when tumors “rob” blood supply from the “normal” organs.
A mutation is defined as a permanent change in the DNA of a cell. Epigenetic modifications, changes that do not affect the code of the DNA but alter how the DNA is decoded, are also known to generate abnormal cells. Alterations in the genetic material may be caused by environmental agents, infectious agents, or errors in the replication of DNA that accumulate with age. Many mutations do not cause any noticeable change in the functions of a cell; however, if the modification affects key proteins that have an impact on the cell’s ability to proliferate in an orderly fashion, the cell starts to divide abnormally.
As changes in cells accumulate, they lose their ability to form regular tissues. A tumor, a mass of cells displaying abnormal architecture, forms in the tissue. Many tumors are benign, meaning they do not metastasize nor cause disease. A tumor becomes malignant, or cancerous, when it breaches the confines of its tissue, promotes angiogenesis, attracts the growth of capillaries, and metastasizes to other organs (Figure 2).
The specific names of cancers reflect the tissue of origin. Cancers derived from epithelial cells are referred to as carcinomas. Cancer in myeloid tissue or blood cells form myelomas. Leukemias are cancers of white blood cells, whereas sarcomas derive from connective tissue. Cells in tumors differ both in structure and function. Some cells, called cancer stem cells, appear to be a subtype of cell responsible for uncontrolled growth. Recent research shows that contrary to what was previously assumed, tumors are not disorganized masses of cells, but have their own structures.
Watch this video to learn more about tumors. What is a tumor?
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Cancer treatments vary depending on the disease’s type and stage. Traditional approaches, including surgery, radiation, chemotherapy, and hormonal therapy, aim to remove or kill rapidly dividing cancer cells, but these strategies have their limitations. Depending on a tumor’s location, for example, cancer surgeons may be unable to remove it. Radiation and chemotherapy are difficult, and it is often impossible to target only the cancer cells. The treatments inevitably destroy healthy tissue as well. To address this, researchers are working on pharmaceuticals that can target specific proteins implicated in cancer-associated molecular pathways.
Comparative biology of tissue repair, regeneration and aging
The Symposium on the Comparative Biology of Tissue Repair, Regeneration and Aging, held 26 June to 28 June 2015 at the MDI Biological Laboratory in Salisbury Cove, Maine, brought together a diverse group of biologists with a common interest in understanding why regenerative capacity varies among animal species, why it is progressively lost in senescence, and how answers obtained from studies that address those questions might be applied in regenerative medicine.
Human skeletal muscle is about 40 % of the body mass and is formed by bundle of contractile multinucleated muscle fibers, resulting from the fusion of myoblasts. Satellite cells (SC) are skeletal muscle stem cell located between the plasma membrane of myofibers and the basal lamina. Their regenerative capabilities are essential to repair skeletal muscle after injury (Hurme and Kalimo 1992 Lipton and Schultz 1979) (Sambasivan et al. 2011 Dumont et al. 2015a). In adult muscles, SC are found in a quiescent state and represent, depending on species, age, muscle location, and muscle type, around 5 to 10 % of skeletal muscle cells (Rocheteau et al. 2015). After injury, SC become activated, proliferate and give rise to myogenic precursor cells, known as myoblasts. After entering the differentiation process, myoblasts form new myotubes or fuse with damaged myofibers, ultimately mature in functional myofibers.
Skeletal muscle injuries can stem from a variety of events, including direct trauma such as muscle lacerations and contusions, indirect insults such as strains and also from degenerative diseases such as muscular dystrophies (Huard et al. 2002 Kasemkijwattana et al. 2000 Kasemkijwattana et al. 1998 Menetrey et al. 2000 Menetrey et al. 1999 Crisco et al. 1994 Garrett et al. 1984 Lehto and Jarvinen 1991 Jarvinen et al. 2005 Cossu and Sampaolesi 2007). Skeletal muscle can regenerate completely and spontaneously in response to minor injuries, such as strain. In contrast, after severe injuries, muscle healing is incomplete, often resulting in the formation of fibrotic tissue that impairs muscle function. Although researchers have extensively investigated various approaches to improve muscle healing, there is still no gold standard treatment.
This concise review provides a sight about the various phases of muscle repair and regeneration, namely degeneration, inflammation, regeneration, remodeling and maturation. We also give an overview of research efforts that have focused on the use of stem cell therapy, growth factors and/or biological scaffolds to improve muscle regeneration and repair. We also address the therapeutic potential of mechanical stimulation and of anti-fibrotic therapy to enhance muscle regeneration and repair.
Soft tissue injuries
By Phil Mack
Consultant Sports Physiotherapist
What is a soft tissue injury?
Soft tissue injuries (STI) are when trauma or overuse occurs to muscles, tendons or ligaments. Most soft tissue injuries are the result of a sudden unexpected or uncontrolled movement like stepping awkwardly off a curb and rolling over your ankle. These are injuries our Physiotherapists see every day at our Edinburgh physiotherapy and sports injury clinics. However, soft tissue damage can also occur from excessive overuse or chronically fatigued structures, especially muscles and tendons. For example, if you were to do a long run when already fatigued (from a previous run or exercise), then it is possible to cause trauma or a strain to key running musculoskeletal structures like your calf muscles or achilles tendons, also see: “How to prevent running injuries”.
What are the most common soft tissue injuries?
- Ankle Spain (see exercise routine below)
- Back Strain (see article on back pain)
- Calf Strain
- Golfers/Tennis elbow
- Hamstring strain
What is the difference between a strain and a sprain?
Tendons are fibrous bands that attach muscles to bone. Trauma to muscles or tendons due to overstretching is referred to as a ‘strain’. Ligaments are also fibrous bands that hold bones together. Trauma by over-stretching of ligaments is referred to as a ‘sprain’. Strains and sprains are both very common and can occur from accidents during sport, at home or at work.
There are three levels or grades of severity:
Grade 1 strain or sprain (mild)
- Minimal over-stretching. Possible minor microscopic tearing of fibres
- Mild tenderness and minimal swelling
Grade 2 strain or sprain (moderate)
- Partial tear of fibres
- Moderate pain, tenderness and swelling
- Unable to apply loading to injured area without pain
Grade 3 strain or sprain (severe)
- Complete rupture of structure
- Significant pain and swelling
- Inability to use the injured structure
- Instability of the affected joint
Suffering from a soft Tissue Injury? Click to call 07738 304238 to speak to a Physiotherapist
What are the symptoms of soft tissue injuries?
When soft tissue is damaged, there is usually immediate pain along with immediate or delayed swelling (excessive swelling can slow the healing process – see treatment below). Stiffness is also very common as a result of the trauma and swelling. Bruising may also develop after 24-48 hours.
In the case of moderate to severe soft tissue injuries of muscles, tendons and ligaments around a joint, there may be instability experienced, especially to weight-bearing joints like the hip, knee and ankle.
How long will it take to recover from a soft tissue injury?
The recovery time from grade 1 soft tissue injuries in one to two weeks and three to four weeks for a grade 2. Grade three soft tissue injuries require immediate assessment and treatment, with much longer recovery times. Recovery times can also depend on your age, general health and occupation. If you are not sure of the nature or extent of your injury, contact an experienced Specialist Physiotherapist for advice.
Should I go to a hospital with a soft tissue injury?
With severe trauma, there may also be a fracture and as with all severe trauma, it is advisable to go directly to A&E for a detailed assessment and diagnosis. A good gauge for when a soft tissue injury requires a full examination is, for example, if:
- You are unable to put any weight on the injured structure
- There is an unusual deformity or shape
- You heard a pop or crack at the time of injury
- Any surrounding bony structures are painful
- There is presence of neurological signs like numbness or pins and needles (either at the injury site or anywhere else)
Treatment for soft tissue injuries:
There are principally three stages of treatment and recovery from soft tissue injuries like ankle sprains
Stage one: During the first 24-72 hours, it is important to protect the injured area, gain an accurate diagnosis and follow the PRICE regime (see below). If possible, gentle pain free movement should be encouraged.
Stage two: Reduce swelling and stiffness and begin to regain normal movement.
Stage three: Regaining of normal function and return to normal activities.
PRICE Regime for Soft Tissue Injuries
Minimise using the affected area the area and initially avoid stretching which could further weaken the damaged tissue.
If trauma is severe, protect the injury from further damage. Stop any activity that will aggravate the injury. Use of crutches to take the weight off an injured knee, hip or ankle injury may be necessary. A sling may help to protect an arm or shoulder.
Rest and avoid activities that cause significant pain (for example walking, raising your arm). Allow sufficient rehab time for even small injuries. Choose alternative.
Wrap ice cubes in a damp tea towel, use frozen peas or a sports ice pack. Use the ice pack for 15–20 minutes every three to four hours when awake.
Very cold products can induce hypothermia or cold burns so wrapping the ice in a cloth is advisable.
Apply a firm bandage that does not restrict circulation or cause additional pain. The bandage should cover the whole joint.
Raise the limb above the level of your heart, if possible in order to help reduce the swelling. Support the limb with cushions or a sling to keep it raised when not walking or using the limb.
Pain relief may also be required. If you are not sure what medication to use, your Specialist Physiotherapist, Pharmacist or GP can advise you.
What to avoid when you have a soft tissue injury?
In the first 48-72 hours, it is important to avoid the following:
Increases blood flow and swelling.
Increases blood flow and swelling, and will slow up the healing process.
Promotes blood flow and can increase swelling and can, therefore, increase damage if begun too early.
Physiotherapy treatment for soft tissue injuries
An experienced Physiotherapist can assess your injury, and confirm both the diagnosis and extent of damage. They will provide you with advice, hands-on treatment and exercises which will promote a prompt and effective recovery, as well as reduce the risk of further injury in the future. (see also “how to avoid running injuries”) Your Specialist Physiotherapist will also advise you on a progressive return to normal activities and alternative exercises to follow whilst you are injured.
What Exercises are there for Soft Tissue Injuries?
There are so many different types of soft tissue injuries it would be impossible to list the exercises for all of them in this article. Here is an example of an exercise routine after an ankle injury. The program begins with the easiest exercise progressing the hardest as your ankle gets stronger.
Initial Post Ankle Injury Exercise
Tie a length of resistance elastic in front of you at waist level and hold the elastic tightly in one hand.
Lift one leg up (elastic side) and pull the elastic towards you as far as possible, by bringing your shoulder blades together and moving your arm back.
Maintain your balance on one leg with your shoulders back and your trunk stable during the exercise. Slowly return to the initial position and repeat.
Begin with 1 set of 4-6 reps or less depending on how the ankle feels. Progressively build up to 3 sets of 8 reps.
Regaining Balance After an Ankle Injury
Stand up with the injured leg on the rounded part of a Bosu (you can begin with balancing on both legs, to begin with, if the ankle is too sore).
Move the opposite leg in a half circle motion to challenge your balance. Maintain a balanced and upright posture throughout the exercise.
Begin with 3-5 x 10-second balances and progressively built to 3 x 30 seconds.
Mobility and Early Strengthening Exercise
With your knee at hip width and arms overhead, take a step forward and bend your knee and hip to 90 degrees.
Keep your torso and your hip stable and the foot aligned with the knee and the hip. Return in control to the starting position and repeat.
Begin with 1 set of 3-5 reps and progressively build up the 3 sets of 6.
Sit in a chair with a physio resistance band tied around your foot and against a stable object.Begin with an easy resistance and progressively increase when your ankle feels ready.
Keep your knee still and your heel in contact with the floor while you move the sole of your foot towards the outside. Return slowly and repeat.
Begin with 1 set of 4-6 reps and progressively increase this to 3 sets of 8 as the ankle allows.
Phil has over 17 years of experience working with professional and international athletes and teams throughout UK, Australia and South Africa, including the South African Springboks, Leicester Tigers and Ulster Rugby as well as the South African Triathlon Team.
MDI Biological Laboratory Scientist Identifies Signaling Underlying Regeneration
BAR HARBOR, MAINE — Many salamanders can readily regenerate a lost limb, but adult mammals, including humans, cannot. Why this is the case is a scientific mystery that has fascinated observers of the natural world for thousands of years.
Now, a team of scientists led by James Godwin, Ph.D., of the MDI Biological Laboratory in Bar Harbor, Maine, has come a step closer to unraveling that mystery with the discovery of differences in molecular signaling that promote regeneration in the axolotl, a highly regenerative salamander, while blocking it in the adult mouse, which is a mammal with limited regenerative ability.
“Scientists at the MDI Biological Laboratory have been relying on comparative biology to gain insights into human health since its founding in 1898,” said Hermann Haller, M.D., the institution’s president. “The discoveries enabled by James Godwin’s comparative studies in the axolotl and mouse are proof that the idea of learning from nature is as valid today as it was more than one hundred and twenty years ago.”
Instead of regenerating lost or injured body parts, mammals typically form a scar at the site of an injury. Because the scar creates a physical barrier to regeneration, research in regenerative medicine at the MDI Biological Laboratory has focused on understanding why the axolotl doesn’t form a scar – or, why it doesn’t respond to injury in the same way that the mouse and other mammals do.
“Our research shows that humans have untapped potential for regeneration,” Godwin said. “If we can solve the problem of scar formation, we may be able to unlock our latent regenerative potential. Axolotls don’t scar, which is what allows regeneration to take place. But once a scar has formed, it’s game over in terms of regeneration. If we could prevent scarring in humans, we could enhance quality of life for so many people.”
The axolotl as a model for regeneration
The axolotl, a Mexican salamander that is now all but extinct in the wild, is a favorite model in regenerative medicine research because of its one-of-a-kind status as nature’s champion of regeneration. While most salamanders have some regenerative capacity, the axolotl can regenerate almost any body part, including brain, heart, jaws, limbs, lungs, ovaries, spinal cord, skin, tail and more.
Since mammalian embryos and juveniles have the ability to regenerate – for instance, human infants can regenerate heart tissue and children can regenerate fingertips – it’s likely that adult mammals retain the genetic code for regeneration, raising the prospect that pharmaceutical therapies could be developed to encourage humans to regenerate tissues and organs lost to disease or injury instead of forming a scar.
In his recent research, Godwin compared immune cells called macrophages in the axolotl to those in the mouse with the goal of identifying the quality in axolotl macrophages that promotes regeneration. The research builds on earlier studies in which Godwin found that macrophages are critical to regeneration: when they are depleted, the axolotl forms a scar instead of regenerating, just like mammals.
The recent research found that although macrophage signaling in the axolotl and in the mouse were similar when the organisms were exposed to pathogens such as bacteria, funguses and viruses, when it came to exposure to injury it was a different story: the macrophage signaling in the axolotl promoted the growth of new tissue while that in the mouse promoted scarring.
The paper on the research, entitled “Distinct TLR Signaling in the Salamander Response to Tissue Damage” was recently published in the journal Developmental Dynamics. In addition to Godwin, authors include Nadia Rosenthal, Ph.D., of The Jackson Laboratory Ryan Dubuque and Katya E. Chan of the Australian Regenerative Medicine Institute (ARMI) and Sergej Nowoshilow, Ph.D., of the Research Institute of Molecular Pathology in Vienna, Austria.
Godwin, who holds a joint appointment with The Jackson Laboratory, was formerly associated with ARMI and Rosenthal is ARMI’s founding director. The MDI Biological Laboratory and ARMI have a partnership agreement to promote research and education on regeneration and the development of new therapies to improve human health.
Specifically, the paper reported that the signaling response of a class of proteins called toll-like receptors (TLRs), which allow macrophages to recognize a threat such an infection or a tissue injury and induce a pro-inflammatory response, were “unexpectedly divergent” in response to injury in the axolotl and the mouse. The finding offers an intriguing window into the mechanisms governing regeneration in the axolotl.
Being able to ‘pull the levers of regeneration’
The discovery of an alternative signaling pathway that is compatible with regeneration could ultimately lead to regenerative medicine therapies for humans. Though regrowing a human limb may not be realistic in the short term, significant opportunities exist for therapies that improve clinical outcomes in diseases in which scarring plays a major role in the pathology, including heart, kidney, liver and lung disease.
“We are getting closer to understanding how axolotl macrophages are primed for regeneration, which will bring us closer to being able to pull the levers of regeneration in humans,” Godwin said. “For instance, I envision being able to use a topical hydrogel at the site of a wound that is laced with a modulator that changes the behavior of human macrophages to be more like those of the axolotl.”
Godwin, who is an immunologist, chose to examine the function of the immune system in regeneration because of its role in preparing the wound for repairs as the equivalent of a first responder at the site of an injury. His recent research opens the door to further mapping of critical nodes in TLR signaling pathways that regulate the unique immune environment enabling axolotl regeneration and scar-free repair.
Godwin’s research is supported by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under grant numbers P20GM103423 and P20GM104318 to the MDI Biological Laboratory. ARMI is supported by grants from the State Government of Victoria, Australia. The mouse studies were supported by Jackson Laboratory institutional funds.
Lycopene counteracts the hepatic response to 7,12-dimethylbenz[a]anthracene by altering the expression of Bax, Bcl-2, caspases, and oxidative stress biomarkers
Context: Lycopene is a carotenoid found in tomato, watermelon, pink grapefruit, and guava in high concentration. Dietary intake of lycopene has been proposed to inversely correlate with the risk of cancer. It has also been reported to provide protection against cellular damage caused by reactive oxygen species, which makes it worthwhile to study the effect of lycopene on liver damage in rat model.
Objective: In this study, we report the effect of lycopene on 7,12-dimethylbenz[a]-anthracene (DMBA)-induced expression of Bax, Bcl-2, caspases, and oxidative stres biomarkers in the liver.
Materials and methods: Lycopene was administered orally at 20 mg/kg body weight for 20 weeks followed by the intraperitoneal injection of DMBA (50 mg/kg body weight) on day 1 and day 30 of the experiment. Control rats received vehicle (olive oil) or DMBA alone. Rats were sacrificed after completion of the treatment.
Results: We observed that the levels of Bax, caspase-3, and caspase-9 decreased to 44, 67, and 43%, respectively, and Bcl-2 increased by 80% in DMBA-treated rats. Lycopene reversed the changes in the respective groups, and decreased the level of Bcl-2 to 25%, while increasing the Bax to 42% when compared to DMBA control. Lycopene increased the expression of caspase-3 (82.09%) and caspase-9 (58.96%), and attenuated the level of hepatic malondialdehyde (41%) and 8-isoprostane (40%) when compared to the respective controls. Glutathione (GSH) decreased significantly in DMBA group (15.89%), but reached the normal level in lycopene-treated animals. Hepatic lycopene concentration in treated rats was 8.2 nmol/g tissue.
Conclusion: The study reports that lycopene counteracts the hepatic response to DMBA by altering the expression of Bax, Bcl-2, caspases, and oxidative stress biomarkers in animal model.
Two common skin disorders are eczema and acne. Eczema is an inflammatory condition and occurs in individuals of all ages. Acne involves the clogging of pores, which can lead to infection and inflammation, and is often seen in adolescents. Other disorders, not discussed here, include seborrheic dermatitis (on the scalp), psoriasis, cold sores, impetigo, scabies, hives, and warts.
Eczema is an allergic reaction that manifests as dry, itchy patches of skin that resemble rashes (Figure 4.21). It may be accompanied by swelling of the skin, flaking, and in severe cases, bleeding. Many who suffer from eczema have antibodies against dust mites in their blood, but the link between eczema and allergy to dust mites has not been proven. Symptoms are usually managed with moisturizers, corticosteroid creams, and immunosuppressants.
Acne is a skin disturbance that typically occurs on areas of the skin that are rich in sebaceous glands (face and back). It is most common along with the onset of puberty due to associated hormonal changes, but can also occur in infants and continue into adulthood. Hormones, such as androgens, stimulate the release of sebum. An overproduction and accumulation of sebum along with keratin can block hair follicles. This plug is initially white. The sebum, when oxidized by exposure to air, turns black. Acne results from infection by acne-causing bacteria (Propionibacterium and Staphylococcus), which can lead to redness and potential scarring due to the natural wound healing process (Figure 4.22).
A burn results when the skin is damaged by intense heat, radiation, electricity, or chemicals. The damage results in the death of skin cells, which can lead to a massive loss of fluid. Dehydration, electrolyte imbalance, and renal and circulatory failure follow, which can be fatal. Burn patients are treated with intravenous fluids to offset dehydration, as well as intravenous nutrients that enable the body to repair tissues and replace lost proteins. Another serious threat to the lives of burn patients is infection. Burned skin is extremely susceptible to bacteria and other pathogens, due to the loss of protection by intact layers of skin.
Burns are sometimes measured in terms of the size of the total surface area affected. This is referred to as the “rule of nines,” which associates specific anatomical areas with a percentage that is a factor of nine (Figure 1).
Figure 1. The size of a burn will guide decisions made about the need for specialized treatment. Specific parts of the body are associated with a percentage of body area.
Burns are also classified by the degree of their severity:
- A first-degree burn is a superficial burn that affects only the epidermis. Although the skin may be painful and swollen, these burns typically heal on their own within a few days. Mild sunburn fits into the category of a first-degree burn.
- A second-degree burn goes deeper and affects both the epidermis and a portion of the dermis. These burns result in swelling and a painful blistering of the skin. It is important to keep the burn site clean and sterile to prevent infection. If this is done, the burn will heal within several weeks.
- A third-degree burn fully extends into the epidermis and dermis, destroying the tissue and affecting the nerve endings and sensory function. These are serious burns that may appear white, red, or black they require medical attention and will heal slowly without it.
- A fourth-degree burn is even more severe, affecting the underlying muscle and bone.
Oddly, third and fourth-degree burns are usually not as painful because the nerve endings themselves are damaged. Full-thickness burns cannot be repaired by the body, because the local tissues used for repair are damaged and require excision (debridement), or amputation in severe cases, followed by grafting of the skin from an unaffected part of the body, or from skin grown in tissue culture for grafting purposes.
Skin grafts are required when the damage from trauma or infection cannot be closed with sutures or staples. Watch this video to learn more about skin grafting procedures.
Scientists reset biological clock to restore vision in old mice
A team of scientists at Harvard Medical School have turned back the clock on aged eye cells in the retina to reverse vision loss in elderly mice with a condition mimicking human glaucoma, according to a study published in Nature on December 2.
This proof-of-concept study demonstrates the epigenetic reprogramming of complex tissues, such as the nerve cells of the eye, to a younger age when they can repair and replace tissue damaged from age-related conditions and diseases. The approach paves the way for therapies to promote tissue repair of various organs to reverse aging and age-related diseases in humans.
“That ageing (the loss of cellular functions over time) can (at least in a mouse) be safely reversed in a complex tissue such as the eye to restore its youthful functions. It implies that, in mammals, there is a reset switch that can erase many of the problems that accumulate with ageing. It implicates the epigenome (gene regulation), specifically epigenetic noise that accumulates over time, as a central cause of ageing,” said senior author Dr David Sinclair, professor of genetics in the Blavatnik Institute and co-director of the Paul F. Glenn Center for Biology of Aging Research at Harvard Medical School, in an email.
“If affirmed through further studies, these findings could be transformative for the care of age-related vision diseases like glaucoma and to the fields of biology and medical therapeutics for disease at large,” Dr Sinclair said.
Glaucoma is an optic neuropathy marked by progressive degeneration of the optic nerve and is the second leading cause of irreversible blindness, after cataract. The study is the first to demonstrate that it is possible to reverse vision loss, rather than stop its progress, in animals with a condition mimicking human glaucoma.
Dr Sinclair and his team used an adeno-associated virus (AAV) as a vehicle to deliver into the retinas of mice three youth-restoring genes—Oct4, Sox2 and Klf4—that are normally switched on during embryonic development. The three genes, together with a fourth one, which was not used in this work, are collectively known as Yamanaka factors. This promoted nerve regeneration following optic-nerve injury in mice with damaged optic nerves, reversed vision loss in animals with a condition mimicking human glaucoma, and reversed vision loss in aging animals without glaucoma.
“The (Yamanaka) factors have been used to make pluripotent stem cells in the dish and used to make cells that are returned to the body. They cause cancer or kill animals when turned on. We show it is possible to use a subset of them to reverse aging, and in existing cells within the body,” said Dr Sinclair. The treatment resulted in a two-fold increase in the number of surviving retinal ganglion cells after the injury and a five-fold increase in nerve regrowth.
“Previous studies identified factors that can promote retinal ganglion cells survival and regeneration, but none showed restoration of vision. Sinclair’s group very cleverly used only three (Oct4, Sox2, Klf4) of the four ‘Yamanaka factors’ and restored eyesight after damage to the optic nerve. Thus, avoiding unwanted tumors growth or cell death by not using the c-Myc. Although this study provides proof of principle in mice, it is a huge step forward for the field of regenerative medicine,” said Prof Keshav K Singh, professor of Genetics, pathology and environmental health at the University of Alabama at Birmingham, who has done extensive work in mitochondrial genetics, including reversing skin aging in mice.
Lead author Yuancheng Lu, research fellow in genetics at Harvard Medical Lab and a former doctoral student in Sinclair’s lab, builds on the Nobel-winning discovery of Shinya Yamanaka, who identified the four transcription factors, Oct4, Sox2, Klf4, c-Myc, that could erase epigenetics markers on cells and return these cells to their primitive embryonic state from which they can develop into any other type of cell. Subsequent studies identified two major setbacks -- the four Yamanaka factors could induce tumour growth when used in adult mice, which made them unsafe, and could also erase the cell’s identity by resetting the cellular state to its most primitive.
Lu and colleagues circumvented these hurdles by dropping the gene c-Myc to deliver the remaining three Yamanaka genes, Oct4, Sox2 and Klf4. The modified approach successfully reversed cellular aging without fuelling tumour growth or losing their identity.
The findings set the stage for treatment of various age-related diseases in humans. “The study has significance for regenerative medicine towards slowing down or reversing aging related decline in organ function. Yes, gene therapy holds promise to promote tissue repair and reverse age-related diseases in due course, after relevant safety and efficacy studies,” said Dr Anurag Agrawal, director, Council of Scientific and Industrial Research-Institute of Genomics and Integrative Biology, New Delhi.
“The Yamanaka factors can be potentially used to treat neurodegeneration, arthritis, organ deterioration, and other age-related conditions,” said Dr Sinclair.
Kathryn W. Davis Center for Regenerative Biology and Aging
Scientists in the Davis Center use diverse animal models and cell systems to define the genetic mechanisms underlying tissue repair and regeneration and how the activity of various genes influences lifespan. Choosing the best animal model for every experiment is a cornerstone of the research approach taken by Davis Center scientists.
For example, the zebrafish, a common aquarium specimen, possesses the remarkable ability to rapidly replace damaged and lost body parts including limbs, heart, and nervous system, making it an ideal model for defining the genetic mechanisms of regeneration and healing and for identifying drug candidates for use in regenerative medicine. The tiny roundworm C. elegans shares over 40% of its genetic information with humans and its short lifespan makes it especially well-suited for defining genes that influence healthy lifespan.
Research in the Davis Center is designed to lead to the identification of therapies that will enhance repair and regenerative processes in humans. Such therapies hold significant potential for treating devastating diseases and injuries and for slowing or reversing the degenerative changes that occur with chronic disease and aging.
In 2013, the Davis Center was designated a Center of Biomedical Research Excellence (COBRE) by the National Institutes of Health.