Inflammatory Response & Key Mediators

Inflammatory Response Pathophysiology

• Inflammation begins with mast cell degranulation, activation of three plasma protein systems, and macrophage activation
• Plasma protein systems include complement, clotting, and kinin systems
• Interdependent systems release numerous cytokines
• The inflammatory response consists of interdependent vascular and cellular components
• Vascular response: Vasodilation (erythema/warmth) and increased capillary permeability (edema)
• Cellular response: Cellular infiltration, phagocytosis (pus formation), and thrombosis (prevent bleeding); nerve ending stimulation causes pain

Key Mediators of Inflammation

• The key mediators are histamine, platelet-activating factor, prostaglandins, leukotrienes, chemotactants, growth factors, TNF alpha, interleukins, and interferons

Sequence of Inflammatory Events

• Tissue injury or pathogen invasion leads to PAMPs or DAMPs binding to PRRs on mast cells, macrophages, and dendritic cells
• This binding activates NF-kB and the release of cytokines, initiating vascular and cellular responses
• Leukocytes infiltrate, and phagocytosis removes offending agents
• Complement, clotting & kinin systems activated:
  • Complement to opsonization and pathogen lysis
  • Clotting to blood clot formation
  • Kinin to bradykinin production, increasing vascular permeability and causing pain
• Chronic inflammation occurs if the acute response remains unresolved

Skin Infection: Causative Organisms

• Bacterial: Coagulase-positive Staphylococcus aureus and beta-hemolytic streptococci are common
• Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) is a significant cause
• Viral: Herpes Simplex Virus type 1 (HSV-1) and type 2 (HSV-2)
• Fungal: Candida albicans (yeast) and dermatophytes like Tinea rubrum

Cellulitis: Pathophysiology and Characteristics

• Cellulitis is an infection of the dermis and subcutaneous tissue
• Streptococcus pyogenes or Staphylococcus aureus usually causes it
• Presents as an erythematous, warm, edematous, painful area without distinct borders

Erysipelas: Pathophysiology and Characteristics

• Erysipelas is a superficial skin infection, caused by beta-hemolytic streptococci
• Presents as firm, red spots enlarging and coalescing into a clearly circumscribed, bright red, hot lesion with a raised border
• Systemic symptoms often precede skin lesions

Impetigo: Pathophysiology and Characteristics

• Impetigo is a superficial skin infection caused by coagulase-positive S. aureus or alpha-hemolytic streptococci
• Impetigo is more common in children

Staphylococcal Scalded-Skin Syndrome (SSSS): Pathophysiology and Characteristics

• SSSS is caused by exfoliative toxin-producing Staphylococcus aureus
• Desquamation and wrinkling of the skin occurs

Herpes Simplex Virus (HSV): Pathophysiology and Characteristics

• HSV-1 causes cold sores and infects other areas
• HSV-2 typically causes genital lesions
• Characterized by vesicular lesions

Candidiasis: Pathophysiology and Characteristics

• Candidiasis is a yeast infection caused by C. albicans
• Affects skin and mucous membranes

Tinea Infections: Pathophysiology and Characteristics

• Tinea infections, like Tinea capitis, are fungal infections
• Characterized by scaly, itchy lesions

Transmission of Skin Infections

• Bacterial infections occur through local invasion of pathogens from wounds, ulcers, or skin structures
• HSV is transmitted by direct contact with infected lesions
  • HSV-1 orally, HSV-2 sexually
• Fungal infections are transmitted by direct contact with infected lesions or indirect contact with contaminated items

Risk Factors for Skin Infections

• Bacterial infections: Diabetes mellitus, edema, peripheral vascular disease, skin trauma, insect bites, and immunosuppression
• HSV-2: Sexual contact
• Candidiasis: Moist environments and immunocompromise; inappropriate use of topical corticosteroids worsens fungal infections

Atherosclerosis Pathophysiology

• Atherosclerosis is an inflammatory disease starting with injury to endothelial cells lining artery walls
• Progresses from endothelial injury/dysfunction, to fatty streak, to fibrotic plaque, and to a complicated lesion
• Key steps: Inflammation, macrophage adherence, inflammatory mediator release, LDL oxidation, and foam cell formation
• Plaque rupture can lead to clot formation, instability, vasoconstriction, obstructing the lumen

Atherosclerosis: Risk Factors

• Common: Smoking, hypertension, diabetes, increased LDL, decreased HDL, and autoimmunity
• "Nontraditional": Increased serum markers for inflammation (e.g., hs-CRP), troponin I, adipokines, infection, and air pollution

Atherosclerosis: Characteristics

• Atherosclerosis can lead to vascular remodeling (hyaline sclerosis)
• Atherosclerosis can lead to myocardial ischemia, myocardial infarction, sudden death (in coronary arteries), stroke, dementia (in cerebral arteries), and peripheral artery disease

Hypertension: Pathophysiology

• Hypertension involves multiple mechanisms including SNS, RAAS, and natriuretic peptide changes
• Inflammation, endothelial dysfunction, obesity-related hormones, and insulin resistance also play roles
• Increased vascular volume from decreased renal salt excretion contributes
• Genetic and environmental factors interact to cause neurohumoral dysfunction and promote inflammation

Hypertension: Risk Factors

• Hypertension can derive from numerous genetic vulnerabilities combined with environmental risks
• Obesity, adipokines, insulin resistance, and dysfunction of the SNS and RAAS are also risk factors

Hypertension: Characteristics

• Hypertension can lead to blood vessel sclerosis and damage to the retina, kidney, heart, and brain
• Complications include left ventricular hypertrophy, myocardial ischemia, heart failure, accelerated atherosclerosis, renal disease (nephrosclerosis), stroke, and hypertensive crisis

Heart Failure: Pathophysiology

• Inflammation, sustained hypertension, myocardial ischemia, and infection can lead to heart failure
• Sustained hypertension (increased workload) can lead to left ventricular hypertrophy and heart failure
• Myocardial ischemia/infarction (atherosclerosis) can also cause heart failure
• Infections (viral myocarditis) may lead to cardiomyopathy and heart failure

Asthma: Pathophysiology

• Asthma is a chronic inflammatory disease with bronchial hyperreactivity and reversible airflow obstruction
• Airway epithelial exposure to antigen in sensitized individuals initiates type I hypersensitivity
• Both early and late asthmatic responses occur due to dendritic cells, Th2 lymphocytes, B lymphocytes, mast cells, neutrophils, eosinophils, basophils

Asthma: Causative Organisms and Triggers

• Asthma is primarily an inflammatory and hypersensitivity reaction. However, viral infections can trigger or exacerbate asthma
• Other triggers: Allergens, inhaled irritants, obesity, acetaminophen, and GERD
• Airway dysbiosis links to allergen sensitization and asthma development

Asthma: Risk Factors

• Genetic predisposition, allergen exposure, viral infections, exposure to irritants, obesity, and possibly microbiome dysbiosis

Asthma: Characteristics

• Reversible airflow obstruction, bronchial hyperreactivity, and airway inflammation
• Presents with dyspnea, wheezing, and coughing

Chronic Obstructive Pulmonary Disease (COPD): Pathophysiology

• COPD is related to chronic irritant exposure (e.g.,) smoking which recruits neutrophils, macrophages, and lymphocytes to the lungs
• Results in lung damage from inflammation, oxidative stress, extracellular matrix proteolysis, and cell death
• Frequent infectious exacerbations and lung senescence contribute to disease progression
• Airway obstruction and loss of surface area occurs

Chronic Obstructive Pulmonary Disease (COPD): Causative Organisms and Exacerbations

• While the primary cause is chronic inflammation due to irritants, bacterial and viral infections are common causes of exacerbations

Chronic Obstructive Pulmonary Disease (COPD): Risk Factors

• Cigarette smoking is the primary risk factor
• Air pollution, occupational exposure, and genetic predisposition are other risk factors

Chronic Obstructive Pulmonary Disease (COPD): Characteristics

• Airway obstruction, air trapping, loss of surface area for gas exchange, frequent exacerbations, dyspnea, cough, hypoxemia and hypercapnia

Acute Respiratory Distress Syndrome (ARDS): Pathophysiology

• ARDS is triggered by acute lung inflammation and diffuse alveolocapillary injury after direct/severe systemic inflammation

• Damage to pulmonary capillary endothelial/alveolar epithelial cells activates neutrophils, macrophages, and platelets to release inflammatory markers

• Increased capillary membrane permeability occurs and the leakage of fluid, protein, and blood cells to the interstitium and alveoli (pulmonary edema)

• Surfactant production decreases, leading to atelectasis

Acute Respiratory Distress Syndrome (ARDS): Causative Organisms and Risk Factors

• Predisposing factors include sepsis, pneumonia, trauma, burns and aspiration
• COVID-19 can lead to ARDS from a hyperinflammatory state

Acute Respiratory Distress Syndrome (ARDS): Characteristics

• Acute onset of bilateral chest infiltrates on radiograph
• Persistent hypoxemia despite supplemental oxygen
• Lung compliance decreases

Idiopathic Pulmonary Fibrosis (IPF): Pathophysiology

• IPF is a multifactorial disease involving epithelial damage along with innate adaptive immune responses
• Release of inflammatory cytokines and growth factors result in scarred & honeycombed lung parenchyma, oxidative stress, interstitial alveolar and fibrotic tissue fibrin deposition

Idiopathic Pulmonary Fibrosis (IPF): Causative Organisms and Risk Factors

• Exact cause is unknown, but epithelial damage and abnormal immune responses are implicated
• Genetic and environmental factors may play a role

Idiopathic Pulmonary Fibrosis (IPF): Characteristics

• Presents with progressive scarring of lung tissue leading to dyspnea, cough and reduced lung function

Hepatitis: Pathophysiology

• Hepatitis is liver inflammation resulting in hepatic cell necrosis, scarring (chronic), and Kupffer cell hyperplasia
• Cellular injury is promoted by cell-mediated immune mechanisms, inflammatory mediator release, and persistent inflammation
• Viral infection damages hepatocytes and obstructs bile canaliculi, leading to cholestasis and jaundice

Hepatitis: Causative Organisms

• Hepatitis viruses (A, B, C, D, and E).

Hepatitis: Transmission

• Hepatitis A is transmitted via the fecal-oral route
• Hepatitis E is mainly transmitted through the fecal-oral route, often through contaminated water
• Hepatitis B, C, and D are usually transmitted through bloodborne or sexual contact

Hepatitis: Risk Factors

• Vary depending on the type of hepatitis
• Includes exposure to contaminated food/water, sharing needles, unprotected sex, and mother-to-child transmission

Ulcerative Colitis (UC): Pathophysiology

• UC is a chronic inflammatory disease that begins with inflammation at the base of the crypt of Lieberkühn in the large intestine, starting in the rectum
• Lesions are limited to the mucosal epithelium and not transmural
• Increased mucosal permeability occurs from decreased mucin secretion, increased passage of pathogens and antigens, and stimulation of gut immune system, pro-inflammatory cytokine production

Ulcerative Colitis (UC): Causative Organisms and Risk Factors

• The exact cause is unknown, but a dysregulated immune response is involved in to the gut microbiota and genetic susceptibility

Ulcerative Colitis (UC): Characteristics

• Presents with inflammation, ulceration of the colonic mucosa, diarrhea (often bloody), abdominal pain, and urgency

Urinary Tract Obstructions: Pathophysiology

• Obstruction of urine flow (kidney stones, tumors, enlarged prostate etc.) leads to increased pressure within the urinary tract
• Distention of structures (ureter, renal pelvis) occurs following increased pressure
• Prolonged obstruction can impair blood flow, leading to ischemia and renal tissue damage
• Stasis of urine from obstruction increases the risk of UTIs

Urinary Tract Obstructions: Causative Organisms and Risk Factors

• Obstructions themselves are not organism-based, but increase the risk of UTIs
• Common uropathogens include E. coli, S. saprophyticus, Klebsiella, Proteus, and Pseudomonas
• Risk factors for obstruction include kidney stones, enlarged prostate, tumors, congenital abnormalities, and conditions causing strictures

Urinary Tract Obstructions: Characteristics

• Varies based on location and severity
• Includes flank pain, changes in urination (frequency, urgency, output), and UTI symptoms (dysuria, fever)

Acute Kidney Injury (AKI): Pathophysiology

• AKI can result from ischemic injury, nephrotoxic exposure, obstructive processes, or sepsis
• Injured renal tissues initiate a complex inflammatory immunopathophysiological response
• Leads to microcirculatory disturbances, functional impairment, and cell death
• Activation of innate immunity components drive kidney inflammation and damage

Acute Kidney Injury (AKI): Causative Organisms and Risk Factors

• Sepsis (gram-negative bacteremia) is a major cause of AKI
• Postinfectious glomerulonephritis and endocarditis can also lead to AKI
• Risk factors include hypovolemia, reduced cardiac output, renal hypoperfusion, exposure to nephrotoxic agents, and systemic inflammation

Acute Kidney Injury (AKI): Characteristics

• Characterized by a sudden decline in kidney function
• Results in increased serum creatinine and blood urea nitrogen, oliguria, and electrolyte imbalances

Chronic Kidney Disease (CKD): Pathophysiology

• CKD is a progressive loss of nephron function due to various causes
• Proteinuria and angiotensin II activity are factors in progression of renal injury
• Chronic inflammation significantly contributes to oxidative stress in CKD. Hypoxia and oxidative stress to the development of renal fibrosis

Chronic Kidney Disease (CKD): Causative Organisms and Risk Factors

• Direct infection is less commonly a primary cause, but recurrent pyelonephritis (kidney infection) can lead to scarring and CKD
• Systemic infections like postinfectious glomerulonephritis can also contribute
• Major risk factors for CKD: Diabetes mellitus, hypertension, glomerulonephritis, polycystic kidney disease, and obstructive uropathy

Chronic Kidney Disease (CKD): Characteristics

• Presents with kidney function decline, but often with few early symptoms, and gradual loss of function
• Azotemia, uremia, fluid/electrolyte imbalances, anemia hypertension, and systemic effects eventually manifest

Diabetes Mellitus: Pathophysiology

• Characterized by hyperglycemia and glucose intolerance
• Type 1 is caused by defect/failure of beta cells in the pancreas, leading to impaired insulin production. 80-90% of cell function is lost before evident, involves an autoimmune mechanism
• Type 2 is characterized by insulin resistance and impaired insulin secretion, resulting in less glucose uptake/storage
• Gestational diabetes is diagnosed during pregnancy. Chronic hyperglycemia leads to oxidative stress and glycation

Diabetes Mellitus: Causative Organisms

• Has autoimmune basis, but not by an infecting organism
• Viral or bacterial infections may be linked to the onset of type 1 diabetes

Diabetes Mellitus: Characteristics

• Characterized by hyperglycemia and glucose intolerance
• Acute complications are hypoglycemia and diabetic ketoacidosis
• Chronic complications: Oxidative stress, microvascular diseases (retinopathy, nephropathies), macrovascular disease; diabetic retinopathy can lead to blindness

Diabetes Mellitus: Risk Factors

• Type 2 DM: Age, obesity, hypertension, physical inactivity, family history, metabolic syndrome

Diabetes Insipidus: Pathophysiology

-It is a state of hypofunction of the posterior pituitary gland- leads to insufficient ADH action or secretion that results in an inability of the kidneys to conserve water

Disorders of the Anterior and Posterior Pituitary Gland: Pathophysiology

• Disorders are broadly categorized by hyperfunction or hypofunction of the anterior and posterior pituitary glands:
  • Anterior Pituitary Hyperfunction (Hyperpituitarism) is often linked to a pituitary adenoma
  • Anterior Pituitary Hypofunction (Hypopituitarism) is often linked to damage or the presence of a tumor
  • Posterior Pituitary Hyperfunction (Syndrome of Inappropriate ADH Secretion - SIADH) presents with excessive antidiuretic hormone (ADH) secretion that results in hyponatremia

Disorders of the Anterior and Posterior Pituitary Gland: Causative Organisms and Risk Factors

• SIADH can be caused by ADH-secreting tumors while hypopituitarism can be initiated by tumors. -Infections of the central nervous system with damage and tumors can affect the pituitary potentially impact pituitary function by affecting the medulla

Disorders of the Anterior and Posterior Pituitary Gland: Characteristics

• SIADH presents with excessive water reabsorption by the kidneys potentially leading to fluid overload and disturbances of electrolyte levels such as hyponatremia

Disorders of the Adrenal Cortex: Pathophysiology

• The adrenal cortex, located atop the kidney is involved in cortisol secretion and disorders focusing on cortisol include:
  • Hyperfunction (Cushing's Syndrome) is characterized by having elevated levels of circulating cortisol (Hypercortisolism) this can be either by a primary cause such as when issues are present within the adrenal cortex such as in cases of adrenocortical: adenoma, carcinoma, or hyperplasia) OR secondary due to ACTH secretion having increased levels from the area of the anterior pituitary
  • Hypofunction (Addison's Disease) can arise from autoimmune destruction of adrenal cortical cells, adrenal atrophy or destruction by a multitude of diseases, removal of adreanal glands after surgical procedures of inadequate secretion of ACTH by way of the pituitary gland

Disorders of the Adrenal Cortex: Causative Organisms

• Specific types of Organisms are not detailed in these excerpts yet still, while infections have been cataloged as possible causes for Addison's disease specific organisms are not listed from the excerpts on hand

Disorders of the Adrenal Cortex: Characteristics

• Addison's Disease presents with muscle weakness, fatigue due to hypoglycemia, weight reduction, reduced blood pressure called hypotension, and females are susceptible to losssome sex characteristics
• The clinical signs for Cushing Syndrome are not listed form the excerpts

Disorders of the Adrenal Cortex: Risk factors

 - In causes of  *Cushing Syndrome* which include: presence of carcinoma/adenoma/ hyperplasia , increased  ACTH secretion from the pituitary

• In causes of Addison's Disease which include autoimmune disorders in addition to atrophy from infections, gland removal via surgical procedures or injury and traumas as well as medications may contribute

Thyroid Disorders: Pathophysiology

• Hyperthyroidism including with Grave’s disease) with the presence of more thyroid hormone production can signal excess hormones in the body of the thyroid it is often in cases such as hypothyroidism in which Hashimoto characterized with Hashimoto's presenting as Autoimmune cause

Thyroid Disorders: Symptoms

• Tachycardia, heat intolerance and weight loss, increased appetite, weight loss diarrhea are symptoms for hyperthyroidism
• Potential thyrotoxic crisis
• Hypothyroidism presents with fatigue, cold intolerance, weakness, and constipation
• Myxedematous coma

Primary Hyperparathyroidism

• It is typically signaled that abnormal production of hormones occurs at the hormone at parathyroid known as secretion this is often by genes that produce neoplasias/adenomas by glands

Secondary Hyperparathyroidism

• Secondary effects are from complications that arise related to hypercalcemia or hypocalemia that involves high calcium and low phosphate

Mechanisms of Stress Response

• Occurs when demands override capacity
• Three Physiological Systems: HPA axis,SNS, and Immunity (HPA Axis releases cortisol which supports the release of catecholamines

Stages Stress Response

• Alarm : Body senses the stressor
• Resistance; Adaptation but "on guard" is present with Stress related symptoms
• Exhaution: Resources Depilated with Immune Compromise as the body tries to combate or protect, causes mental exacerbation.

Eating Disorders

• Eating disorders originate from Monoamine functioning as seratonin disturbances contribute to impulse control and anxious behaviors with anorexia stemming from reduce food and metabolism leading to protein deficiency.
• Up to 10x more common in women in mid/late adolescence

Schizophrenia Spectrum

• Disorders characterized by hallucinations characterized by dys organized thoughts with increased dopamine/neurotransmitters as gene expressions environmental factors interact that affects brain
  • Characterized by a lower monozygotic rate when compared/related and genetic issues or changes

Bipolar Disorders

- Characterized by depression after mania with the theory that  hormone increased as  prefontal mass  reduced, it  is N/A to organisms that affect/cause, characterized as genetic component.