Inflamation drh. M. Arfan Lesmana, M.Sc. Fakultas Kedokteran Hewan, Universitas Brawijaya Email: [email protected] Remember our old friends, rubor, tumor, calor et dolor? Plus functio laesa too. Introduction • Inflammation is the response of living tissue to injury. • Some form of an inflammatory response is seen in virtually all living organisms, but the higher life forms have the unique ability to use the blood vascular system to deposit fluid and cells in the extravascular space. • The acute inflammatory response has 3 main functions. • The affected area is flooded by a mixture of blood and tissue components collectively called the acute inflammatory exudate. The exudate carries proteins, fluid and cells from local blood vessels into the damaged area to mediate local defenses. • If a causative agent (e.g. bacteria, foreign body) is present in the damaged area, it can be destroyed and eliminated by components of the exudate. • The damaged tissue is broken down and partially liquefied, and the debris removed from the site of damage and the healing process begins. • The inflammatory response is continuous with the process of repair. Acute inflammation is short, lasting only a few hours to days. Longer inflammatory responses are referred to as chronic inflammation. • The hallmark of chronic inflammation is the presence of predominantly macrophages in the exudates and perhaps also the formation of fibrous connective tissue. This fibrous connective tissue formation results in organization or scar formation. • There is an intermediate stage of inflammation that has not begun to organize yet, but is past the acute stage. This form of inflammation is known as subacute inflammation. Causes of Inflammation • One of the most common causes of inflammation is microbial infection. These microbes include viruses, bacteria, protozoa, fungi and various parasites. Viruses lead to death of individual cells by intracellular multiplication. Bacteria release synthesized exotoxins or cell wall components (endotoxin) that specifically initiate inflammation Hypersensitivity reactions • A hypersensitivity reaction occurs when an altered state of immunological responsiveness causes an inappropriate or excessive immune reaction which damages the tissues. The types of reaction will be discussed in more detail later. Physical agents • Tissue damage leading to inflammation may occur through physical trauma, ultraviolet or other ionizing radiation, burns or excessive cooling ('frostbite') Irritant and corrosive chemicals • Corrosive chemicals (acids, alkalis, oxidizing agents) provoke inflammation through direct tissue damage. These chemical irritants cause tissue damage that leads directly to inflammation Renal infarct. Necrotic tissue will be surrounded by neutrophils. Death of tissues from lack of oxygen or nutrients resulting from inadequate blood flow (infarction) is a potent inflammatory stimulus. The edge of a recent infarct often shows an acute inflammatory response. Effects of Inflammation • The effects of inflammation can be both local and systemic. The systemic effects of acute inflammation include fever, leukocytosis and vascular changes. These will be discussed in more detail later in this unit. The local effects are usually clearly beneficial, for example the destruction of invading microorganism, but at other times they appear to serve no obvious function, or may even be harmful. Beneficial effects • Both the fluid and cellular exudates may have useful effects. Beneficial effects of the fluid exudate are as follows: Entry of antibodies. Increased vascular permeability allows antibodies to enter the extravascular space, where they may lead either to lysis of microorganisms, through the participation of complement, or to phagocytosis by opsonization. Antibodies are also important in neutralization of toxins. Fibrin formation. Fibrin formation from exuded fibrinogen may mechanically impede the movement of micro-organisms, trapping them and so facilitating phagocytosis. Stimulation of immune response. The drainage of this fluid exudate into the lymphatics allows particulate and soluble antigens to reach the local lymph nodes where they may stimulate the immune response. Harmful effects • As we all know however, the inflammatory response has significant harmful effects. Most of these are caused by release of lysosomal enzymes by inflammatory cells. Some of these harmful effects include: • Destruction of normal tissues. Enzymes such as collagenases, elastases and other proteases may degrade normal tissues, resulting in their destruction. For example in type III hypersensitivity reactions and in some types of glomerulonephritis small vessels are damaged. • Swelling. The swelling of acutely inflamed tissues may be harmful. At right is a dog with a swollen face due to an anaphylactic reaction. If that swelling occurs in the larynx, VERY BAD. Inflammatory swelling is especially serious when it occurs in an enclosed space such as the cranial cavity. Thus, acute meningitis or an intra-cerebral abscess may raise intracranial pressure to the point where blood cannot move easily in the brain, there is depression of cardiac and respiratory centers and OOPS, death Inappropriate inflammatory response. Sometimes, acute inflammatory responses appear inappropriate, such as those which occur in type I hypersensitivity reactions where the provoking environmental antigen (e.g. pollen) otherwise poses no threat to the individual. Clinical Aspects of Acute Inflammation • The four principal effects of inflammation were described nearly 2,000 years ago by Celsus: • Redness (rubor). An acutely inflamed tissue appears red, for example skin affected by sunburn, or the eye in acute conjunctivitis. This is due to dilatation of small blood vessels within the damaged area. Remember hyperemia? Hyperemic scrotum of a bull that has a skin infection (see the crustiness at the bottom). • Heat (calor). Increase in temperature is readily detected in the skin. It is due to increased blood flow (hyperemia) through the region, resulting from vascular dilatation and the delivery of warm blood to the area. Systemic fever, which results from some of the chemical mediators of inflammation, also contributes to the local temperature • Swelling (tumor). Swelling results from edema, the accumulation of fluid in the extravascular space as part of the inflammatory exudate, and to a much lesser extent, from the physical mass of the inflammatory cells migrating into the area. • Pain (dolor). Pain results partly from the stretching and distortion of tissues due to inflammatory edema and, in part from some of the chemical mediators of acute inflammation, including bradykinin, the prostaglandins and serotonin. • Loss of function (functio laesa). Loss of function, a well-known consequence of inflammation, was added by Virchow (1821-1902) to the list of features drawn up by Celsus. Movement of an inflamed area is consciously and reflexively inhibited by pain, while severe swelling may physically immobilize the affected area. Clinical indicators of inflammation Clinical indications of an inflammatory process usually include one or all of the following: • General malaise • Fever • Pain, often localized to the inflamed area • Leukocytes Cellular changes • An increased leukocyte count with an increase in neutrophil count in the peripheral blood is a typical response to acute inflammation. The leukocytes respond to chemoattractants originating from the site of injury. In inflammation, neutrophils are released from the bone marrow into the blood in larger numbers than are normally present. Therefore, when a blood sample is taken, increased numbers are seen. Often in viral infections, there will be an increase in lymphocytes. Sometimes, increased numbers of monocytes can be present in severe or more chronic inflammation. This is a photomicrograph of a blood smear showing normal neutrophils. These cells are also called polymorphonuclear leukocytes because of the multiple lobulations in the nucleus. In severe cases of inflammation, there may be increased numbers of immature (band) neutrophils. These cells are named for the band like appearance of the nucleus. In neutrophils, lobulation increases with maturity. These young cells are released from the bone marrow before they are completely "ripe", so their their nuclei are not yet fully lobulated Non-cellular changes • Inflammation is mediated in large part by soluble substances (mediators) found in plasma. Specific acute phase proteins, like fibrinogen, may be measured in blood to monitor inflammatory processes. Macroscopic appearance of inflammation • The morphologic appearance of inflammation is modified according to the tissue involved and the type of agent provoking the inflammation. Several descriptive terms are used for the appearances. We'll practice labeling lesions many times over the course of the next three weeks and in all subsequent pathology course Serous inflammation • In serous inflammation, there is abundant protein-rich fluid exudate with a relatively low cellular content. Examples include inflammation of the serous cavities, such as peritonitis, and inflammation of a synovial joint, acute synovitis. Vascular dilatation may be apparent to the naked eye, the serous surfaces appearing injected, i.e. having dilated, blood-laden vessels on the surface, (like the appearance of the conjunctiva in 'blood-shot' eyes). Serous exudate in the thoracic cavity. A "runny nose" is serous exudation. Catarrhal inflammation • When mucus hypersecretion accompanies acute inflammation of a mucous membrane, the appearance is described as catarrhal. This type of inflammation is usually seen in the acute stage of inflammation in organs that have abundant goblet (mucus producing) cells, such as the respiratory tract and the colon. As the disease progresses, other inflammatory components may be seen such as neutrophils (mucopurulent). Catarrhal enteritis. Note mucous flowing out of the intestinal lumen. Cat. A "snotty nose" is catarrhal inflammation. It is a little bit more severe than the serous inflammation. Fibrinous inflammation • When the inflammatory exudate contains abundant fibrinogen, this polymerizes into a thick fibrin coating. This is often seen in acute pericarditis and gives the parietal and visceral pericardium a 'bread and butter' appearance. When you think "bread and butter", think about dropping the bread butter side down on the floor and picking it up again - this is what fibrin can look like. Fibrin on the surface of the spleen. Fibrinous peritonitis; or fibrinous perisplenitis Hemorrhagic inflammation • Hemorrhagic inflammation indicates severe vascular injury. As a result blood predominates in the exudate Here is a little kangaroo (roo actually) that had a hemorrhagic pneumonia due to infection with Toxoplasma. There are numerous areas of local necrosis caused by Toxoplasma, and resulting damage to vessels, so it is hemorrhagic inflammation Suppurative (purulent) inflammation • The terms 'suppurative' and 'purulent' denote the production of pus, which consists of dying and degenerate neutrophils. When you see pus, think bacteria The underside of the brain of this dog has green exudate that contains neutrophils. The diagnosis for this would be purulent meningitis. • The pus may become walled-off by granulation tissue or fibrous tissue to produce an abscess (a localized collection of pus in a tissue). In this pig's brain, a collection of purulent material surrounded by a fibrous connective tissue capsule is located between the cerebrum and the cerebellum. This is a brain abscess. If a hollow viscus fills with pus, this is called empyema, for example, empyema of the gall bladder or of empyema the guttural pouch. When pus fills the thorax, we can call it thoracic empyema. Necrotizing inflammation • The products of inflammation (proteolytic enzymes and other nastiness) and vascular occlusion by thrombosis may result in widespread necrosis of the affected organ. The term necrotizing can be used to describe this kind of inflammation. As with other types of inflammation, necrotizing can occur in conjunction with an influx of neutrophils (necropurulent) or hemorrhage (necrohemorrhagic). The combination of necrosis and bacterial putrefaction is called gangrene Dark brown areas represent areas of pulmonary necrosis due to bacterial pneumonia – this is a gangrenous pneumonia. The usual cause is aspiration, something that should have stayed in the GI tract got inhaled into the lung Morphologic Diagnosis of Inflammation Serous exudate • This is a very mild form of inflammation and may indicate a minor injury, or it may be the start of something more serious. (In general, SEROUS is NOT SERIOUS!). Serous fluid is what accumulates inside a blister. Also, it is the clear yellow material that comes out of a minor skin wound. • The most common places to find serous exudate is on the skin surface ("hot spot" in flea allergy dermatitis) or in a body cavity, or in your nose! • In general serous exudates results when inflammatory mediators create endothelial gaps large enough for fluid and some protein to leak out. More severe capillary damage would result in either fibrin or red blood cells being mixed within the fluid. By definition there are few leukocytes in this exudate. This horse had abdominal surgery and died two days later of another cause. Because of the manipulation of the intestines at surgery, there was an outpouring of serous fluid into the abdomen, resulting in a "serous peritonitis." This is from a postmortem on a cat. There is excess yellow fluid in the abdomen - this is a serous peritonitis. This cat had feline infectious peritonitis. In this case, knowing the disease, it can be safely stated that this mild serous peritonitis was a harbinger of worse things to come. Fibrinous exudate • In serous exudation, just very small molecules of protein get out of the blood stream and into the tissue. With fibrinous exudation, the vascular insult is more severe, and larger holes develop, allowing fibrinogen to get out into the tissue as well. When fibrinogen reaches tissue, it turns into fibrin. Fibrinous exudation is always an indication of an more severe insult. • Don't confuse the adjective fibrinous (means fibrin in the exudate) with fibrous (is not a modifier of an exudate and means composed of fibrous connective tissue). • In the earliest stages, fibrin just appears as a light meshwork, which may have a granular appearance grossly. The lung is from a sheep in the early stages of infection with Pasteurella multocida, the pleura is responding with an outpouring of fibrin, which forms strands on the surface of the lung. These strands can be peeled off readily, in contrast to a chronic process where the fibrin becomes organized by fibrous connective tissue and becomes tough and is considerably more adherent. This is from a cat with feline infectious peritonitis. Note the granular appearance to the serosa of the intestinal loops - this is due to bits of fibrin. Also, there is a layer of fibrin over the liver. In some places, there is a distinctly strandlike appearance. This poor tortoise had an acute stomatitis. Dissection of the oral cavity reveals a layering of fibrin over various parts of the oral cavity. Fibrin is eosinophilic and strandlike microscopically. Often there are neutrophils associated with it because it is a powerful chemoattractant for these cells. When neutrophils become prominent, we get some pus mixed in with the fibrin, and the inflammation is referred to as fibrinopurulent. When necrosis is extensive, the fibrin can be pretty thick. Often it is adherent to the mucosal surface, as in the intestine of this pig infected with Salmonella Diphtheritic membrane! This term implies that the tissue underneath the fibrin is necrotic resulting in tightly adhered fibrin. Here is another example, from a tortoise with a gastrointestinal tract infection. Sometimes there is so much fibrin all at once that it forms a cast inside the lumen. The tissues on the left consist of intestine and gall bladder from a cow with salmonellosis. Each cavity has a big tubular cast of fibrin (fibrinous cast). • In many cases, the fibrin gets resorbed without causing any problems. However, fibrin is a good stimulus for fibrosis to begin. So, if the fibrin stays around for too long, especially on serosal surfaces, fibroblasts migrate in and start to make collagen. • If the fibrin exists between two serosal surfaces, such as between gut and gut or between pleura and pleura, then the fibrosis can result in permanent adhesions which impair motility. • It is very important that you distinguish between fibrinous and fibrous. They are very different processes and it is too bad that the words sound so similar. • Often fibrinous inflammation (which is always ACUTE) will LEAD to fibrous but it does not always necessarily follow. When fibrosis does occur that is an indication that the process is CHRONIC. This is a fibrinous peritonitis from a horse. Had the animal lived, this amount of fibrin would have made a great framework for fibrosis to follow, resulting in a knot of intestines with impaired mobility. And holy mackerel, here is another horse, this one died of pleuritis. Look at all these yellow strands of fibrin, connecting the lung to the ribs. When this amount of fibrin is on the pleural surface, invariably, fibrous adhesions form between the visceral and parietal pleura. The result is impaired ability to expand the lungs and respiratory compromise. Heart from a cat. Here the pericardial sac has been opened to reveal a dense layer of fibrin all over the epicardium. The other really bad place for adhesions is on the lung. • Catarrhal exudate Catarrhal exudate consists of excess mucus. So, it is only seen in tissues that already produce mucus. We already talked about a runny nose as being serous exudate. Well, add some mucus to that and it becomes catarrhal rhinitis, as in this dog with canine distemper. • Here are some other examples: The mucosa of this bovine intestine is covered with excess mucus. There may also be some fibrin mixed in here too. Let's call it fibrinocatarrhal enteritis. The animal was affected by mucosal disease, which is caused by infection with bovine viral diarrhea virus. Purulent exudate Purulent = suppurative = pus The essential elements in purulent exudates are neutrophils. Purulent inflammation almost always signifies the presence of bacteria. This is an opened mammary gland from a cow (teat is at the left). What is the creamy tan material? Yes, it is pus The gland is packed with neutrophils. Here is another picture of purulent inflammation. This is from a dog with purulent prostatitis. The gland lumens and interglandular spaces are filled with neutrophils. Grossly, purulent exudate was oozing from the cut surface. • Purulent inflammation can have a variety of consistencies. In this example of purulent sinusitis in a cow, the pus has become thickened and dried. Often, this form of pus is referred to as "inspissated" or "caseous". Purulent exudate is often associated with fibrinous exudate. In the examples above of a riproaring pericarditis, both types of exudates are obviously present and we would call this fibrionopurulent pericarditis. On the left is the brain of a one-month-old lamb. There is a diffuse purulent meningitis. The arrows are pointing to the purulent exudate found within the sulci. • If the purulent inflammation is well-localized by fibrous tissue, it is referred to as an abscess. Here are some examples: This foal didn't have much of a chance, with two brain abscesses caused by Streptococcus equi. The fibrous wall is very thin because the CNS has little capacity to form connective tissue. Had this been in another location, for example the liver, the fibrous capsule would have been more prominent. These multiple abscesses in a sheep spleen were caused by Corynebacterium pseudotuberculosis, the agent of caseous lymphadenitis. This is a common cause of "wasting ewe syndrome." Not surprising. So many neutrophils around and nonstop production of inflammatory mediators. This is a liver from a guinea pig that was doing poorly for some time prior to death. Yersinia pseudotuberculosis was cultured from the abscesses. As you have noticed purulent exudate can have different colors. The color can be affected by a number of variables. If blood is in the mix it may be pink. If the bacteria has pigment they can change the color. Necrotic tissue can add color and the neutrophils can give the exudate a white or green appearance. Hemorrhagic inflammation is serious business. Some of the most pathogenic agents cause hemorrhagic inflammation. The holes in the blood vessels are big enough to let even the erythrocytes out. Prognosis may be guarded. This is the lung of a lamb infected with Mannheimia hemolytica. The lung is turgid and filled with fibrin and inflammatory cells. But in addition, it is diffusely reddened, indicating that there has been considerable hemorrhage as well. A good morphologic diagnosis for this lesion would be severe acute diffuse hemorrhagic pneumonia.
