16.3 — Inflammation and Repair

Inflammation is the body's response to injury, and it is responsible for both the healing of a cut and the destruction of a joint in rheumatoid arthritis. The same process, deployed appropriately or inappropriately.

Chapter 13.4 covered the immunology. This chapter covers it as a general pathological process — what determines whether tissue is restored or scarred, why some inflammation never resolves, and what it means when a disease is described as inflammatory.

Acute inflammation, in outline

The five signs and their mechanisms are in Chapter 13.4. The pathological summary:

Vascular changes — dilation, increased permeability, and slowing of flow.

Cellular events — neutrophils rolling, adhering, migrating and phagocytosing.

Chemical mediators — histamine, prostaglandins, complement fragments, cytokines and chemokines.

And the four possible outcomes are the useful part, because each corresponds to a clinical situation.

Complete resolution. The damaging agent is removed, the exudate is drained, the inflammatory cells die by apoptosis, and the tissue returns exactly to normal.

This requires two things: minimal tissue destruction, and a tissue capable of regeneration. A mild sunburn, a viral chest infection, a small clean cut.

Healing by fibrosis. Where destruction was substantial or the tissue cannot regenerate. Scar replaces function.

Abscess formation. Where pus is walled off. Requires drainage — antibiotics penetrate a collection poorly (Chapter 14.4).

Progression to chronic inflammation. Where the agent persists.

Why some inflammation never resolves

Three reasons, and identifying which one applies determines the treatment.

Persistent infection. Organisms that resist destruction — mycobacteria, some fungi, some parasites. The immune system cannot clear them, so it contains them.

Persistent exposure. Silica, asbestos, tobacco smoke. The agent is not alive and cannot be killed, and it is not degradable.

Autoimmunity. The antigen is the person, so it is never removed.

And this is why rheumatoid arthritis, Crohn's disease and psoriasis are lifelong: there is no stimulus to eliminate. The treatment is therefore suppression rather than cure, and it must be continuous.

Chronic inflammation

Different cells: macrophages, lymphocytes and plasma cells rather than neutrophils.

And destruction and repair occur simultaneously, which is what makes chronic inflammation so damaging. Tissue is being destroyed while scar is being laid down, so function is progressively lost.

Fibrosis is the end result — the replacement of functional tissue by collagen, in whatever organ.

Liver cirrhosis. Pulmonary fibrosis. Chronic kidney disease. Cardiac fibrosis after infarction. Adhesions after abdominal surgery or infection.

Different organs, one process.

Granulomas

A specific structure with a specific meaning: the immune system has encountered something it cannot destroy and has walled it off.

Macrophages transform into large flat "epithelioid" cells, fuse into multinucleated giant cells, and are surrounded by lymphocytes and fibroblasts.

And the list of causes is short enough to be useful:

Infections — tuberculosis (with caseous necrosis at the centre, Chapter 16.2), leprosy, fungal infections, cat scratch disease.

Foreign material — suture, talc, silica, beryllium.

Unknown cause — sarcoidosis, Crohn's disease.

So finding a granuloma on a biopsy narrows the diagnosis to a handful of possibilities immediately, which is why the pathology report says so.

Repair: regeneration or scar

Which one you get depends almost entirely on the tissue.

Tissues are classified by their capacity to divide.

Labile — dividing continuously. Skin, gut lining, bone marrow, urinary tract. Regenerate completely.

Stable — normally quiescent, capable of dividing when needed. Liver, kidney tubules, pancreas, endothelium, fibroblasts, smooth muscle. Regenerate if the supporting framework is intact.

Permanent — cannot divide. Cardiac muscle, skeletal muscle to a limited extent, and neurons. Always heal by scar.

And that classification explains the outcome of most injuries.

A superficial skin wound regenerates completely — labile tissue.

A liver damaged by a single insult regenerates completely (Chapter 9.4) — stable tissue with an intact framework. A liver damaged repeatedly over years becomes cirrhotic, because the framework itself is destroyed.

A heart attack leaves a permanent scar (Chapter 4.7) — permanent tissue, no regeneration, and this is why heart failure follows.

A cut peripheral nerve regrows; a cut spinal cord does not (Chapter 11.1).

The framework matters as much as the cells. If the basement membrane and supporting architecture survive, regeneration is orderly. If they are destroyed, even a labile tissue heals with scar — which is why a deep burn scars and a superficial one does not (Chapter 23.7).

The steps of repair

Angiogenesis — new capillaries sprouting, driven by hypoxia and growth factors.

And this is a drug target in two directions. Blocking it starves tumours and treats wet macular degeneration (Chapter 11.11). Promoting it is the goal in chronic wounds and ischaemic limbs, and has proved much harder.

Fibroblast migration and proliferation.

Collagen deposition — type III initially, replaced by type I (Chapter 14.4).

Remodelling — reorganisation over months to years, mediated by enzymes that degrade collagen and their inhibitors. The balance between them determines whether a scar strengthens appropriately, contracts excessively, or breaks down.

And a scar reaches only 70 to 80 percent of original tensile strength, which is the practical fact behind post-operative restrictions.

When repair goes wrong

Too little — chronic wounds (Chapter 14.4), and non-union of fractures (Chapter 5.9).

Too much — keloid scars, hypertrophic scars, contractures.

And too much in an internal organ is fibrosis, which is the final common pathway of a very large share of chronic disease.

Adhesions deserve specific mention. Fibrous bands forming between abdominal structures after surgery or infection, and they occur after the majority of abdominal operations.

They are the commonest cause of small bowel obstruction in the developed world, they cause chronic pain and infertility, and surgery to divide them frequently causes more. It is one of the more intractable problems in surgery, and it is a direct consequence of a healing process working exactly as designed in a place where scar is unhelpful.

Systemic effects

Inflammation is not local, and the systemic response is measurable.

Fever (Chapter 13.4).

Acute phase proteins — produced by the liver in response to inflammatory cytokines.

C-reactive protein (CRP) rises within hours and falls quickly, which makes it useful for tracking. Very high levels — over 100 mg/L — suggest bacterial infection. Modest elevation is non-specific, and it should not be used alone to make decisions.

Erythrocyte sedimentation rate (ESR) rises and falls more slowly, over days to weeks, which makes it more useful in chronic conditions. It is also raised by anaemia, pregnancy and age, which limits its specificity.

Ferritin, fibrinogen and complement also rise.

And two fall — negative acute phase proteins: albumin and transferrin.

Which matters for interpretation. A low albumin in an unwell patient may reflect inflammation rather than malnutrition or liver disease, and treating it as a nutritional marker in acute illness is a common error.

Raised white cell count — neutrophils in bacterial infection, lymphocytes in viral (Chapter 7.1).

And "left shift" — immature neutrophils appearing in the blood, indicating the marrow is releasing cells faster than it can mature them.

Anaemia of chronic disease — inflammation causes the liver to produce hepcidin, which locks iron away in storage. Iron is present and unavailable.

And this is thought to be a defence, denying iron to bacteria (Chapter 13.1). The practical consequence is that giving iron does not correct it — treating the underlying inflammation does, and distinguishing it from true iron deficiency is a common diagnostic question.

Inflammation in chronic disease

The recognition that low-grade chronic inflammation contributes to conditions not traditionally considered inflammatory is one of the significant shifts of the last thirty years.

Atherosclerosis — now understood as an inflammatory disease of the arterial wall rather than passive lipid deposition (Chapter 18.1).

Type 2 diabetes and obesity — adipose tissue as an inflammatory organ (Chapter 12.7).

Some cancers — chronic inflammation as a driver, most clearly in hepatitis and liver cancer, H. pylori and gastric cancer, and inflammatory bowel disease and colorectal cancer (Chapter 19.1).

Neurodegeneration — microglial activation.

And the strongest evidence that this is causal rather than associated comes from trials. The CANTOS trial gave an anti-inflammatory antibody to people after a heart attack and reduced cardiovascular events without changing cholesterol at all — which established inflammation as a treatable contributor rather than a marker.

Colchicine, an ancient and cheap anti-inflammatory (Chapter 1.5), has since shown benefit in coronary disease.

Where the evidence is much weaker is the enormous popular literature about "chronic inflammation" as a general explanation for unwellness, and the diets and supplements sold on that basis. The mechanistic and trial evidence supports specific interventions in specific diseases, and it does not support the general framing.

Anti-inflammatory treatment

NSAIDs — Chapter 13.4.

Steroids — Chapter 12.4.

Disease-modifying drugs — methotrexate, sulfasalazine, and the biologics (Chapter 13.6).

And the encouraging summary belongs here. Targeted biologics have transformed rheumatoid arthritis, psoriasis, inflammatory bowel disease and severe asthma within a single professional generation. Conditions that reliably caused deformity, disability and repeated hospital admission are now, for a large proportion of patients, controlled to the point of remission.

The trade-off is infection risk and cost, and both are real. But the direction of travel — from broad immunosuppression to blocking one specific molecule — means each new agent is more precise than the last.

What the next page fixes

Understanding disease processes is not the same as identifying which one a particular person has. Chapter 16.4 covers diagnosis — how a doctor actually reaches one, why the history matters more than the examination and the tests combined, and why a test result means something different depending on who is being tested.