Pathophysiology

Today a vast number of medications are available or under study for the treatment of allergic rhinitis. This chapter will focus on the pathophysiology of allergic rhinitis and the pharmacological rationale behind current and emerging therapies. 

Allergic rhinitis is a type I hypersensitivity disease, and its pathogenesis occurs in three stages (1) sensitization, (2) reexposure or provocation resulting in the acute (early phase) allergic reaction, and (3) the late phase reaction and chronic inflammation. The pathogenesis of allergic rhinitis involves many different cell types, inflammatory mediators, cytokines, chemokines, and adhesion molecules. 

The early phase response in allergic rhinitis is characterized by sneezing, nasal itching, nasal congestion, and rhinorrhea. Sneezing and pruritus are initiated pri- 

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Experiments have shown that nasal challenge with ragweed pollen results in increased levels of not only histamine, but also leukotriene C4 (LTC4), LTD4, 

In the conditions discussed above (diabetic ketoacidosis, lactic acidosis, uremia, and ingestion of salicylate, ethylene glycol, or methanol) metabolic acidosis is associated with an increased anion gap. In the face of excess metabolic acids, bicarbonate is depleted in the process of buffering excess hydrogen ions. Provided that the renal functions is normal, the kidney attempts to compensate by secreting an acid urine and retaining bicarbonate. 

Acidification of urine is affected in renal tubular acidosis. This condition may be due to an inborn error of metabolism or to an acquired tubular lesion. The defect may be related either to the secretion of hydrogen ions or to the diffusion of hydrogen ions into the blood as a result of increased permeability of the distal tubule cell wall to secreted hydrogen ions. Because renal tubular acidosis is primarily a defect in hydrogen ion secretion, the formation of ammonia by tubule cells is not affected. 

Renal tubular acidosis can be classified into two main types, type I and type II, which are hereditary (11). Renal tubular acidosis can also result from accumulation of waste products, including a variety of metabolic acids in uremia. Another type of renal tubular acidosis, type IV, is due to hyporeninemic hypoaldostero-nism. Hypoaldosteronism appears to be secondary to the inability of the kidney to 

In type II renal tubular acidosis there is a defect in the secretion of hydrogen ions by the proximal tubule. Because the proximal tubule is the major site of bicarbonate reabsorption (4000 mEq of bicarbonate per day as compared to 70 mEq in the distal tubule), the defect in secretion of hydrogen ions in this condition leads to the flooding of the distal tubule with bicarbonate. The capacity of hydrogen ions secreted by the distal tubule to buffer this massive efflux of bicarbonate is soon overwhelmed and, as a result, large quantities of bicarbonate are excreted in the urine. Much more bicarbonate needs to be administered in this condition to correct the acidosis than is necessary in type I renal tubular acidosis. In general, in renal tubular acidosis the impairment in hydrogen ion secretion leads to excretion of potassium ions in urine. 

Metabolic acidosis can also result from loss of bicarbonate, such as in severe diarrhea, especially in infants or due to the depletion of bicarbonate when urine is delivered to the colon after transplantation of ureters into the colon. The administration of carbonic anhydrase inhibitors such as acetazolamide results in excretion of bicarbonate in urine and retention of hydrogen ions, leading to metabolic acidosis. Because of impaired hydrogen ion secretion potassium is 

Acne vulgaris typically begins around puberty and early adolescence it tends to present earlier in females, usually at about 12 or 13 years, than in males, 14 or 15 years, due to later onset of puberty in males. Acne has been estimated to affect 95-100% of 16- to 17-year-old boys and 83-85% of 16- to 17-year-old girls. Acne settles in the vast majority by 23-25 years of age, persisting for longer in some 7% of individuals 1% of males and 5% of females exhibit acne lesions at 40 years of age. There is a small group of individuals who develop late-onset acne, beyond the age of 25 years. 

Acne can present in the neonate, with an incidence that may be around 20%, considering the presence of only a few comedones. Infantile or juvenile acne (acne infantum) typically appears between the age of 3 and 18 months. Males are affected far more than females in a ratio of 4 1. The lesions usually occur on the face and in about 1 in 20 patients on the trunk. Acne infantum seems to be predictive of severer acne in the adolescent period. 

The pilosebaceous follicles are the target sites for acne. The pathophysiology of acne centers on interplay of follicular hyperkeratinization, increased sebum production, action of Propi-onibacterium acnes (P. acnes) within the follicle, and production of inflammation (Table 11.1). 

The earliest morphological change in the sebaceous follicle is an abnormal follicular epithelial differentiation, which results in ductal hypercornification. Cornified cells in the upper section of the follicular canal become abnormally adherent. Comedones represent the retention of hyperproliferating ductal keratinoc-ytes in the duct. Several factors have been implicated in the induction of hyperproliferation sebaceous lipid composition, androgens, local cytokine production (IL-i, EGF) and bacteria (P. acnes). 

acnes is an anaerobic diphteroid that populates the androgen-stimulated sebaceous follicles and is a normal constituent of the cutaneous microflora even if acne is not infectious, the commensal P. acnes acts in acne pathogenesis. Three pieces of evidence support the role of P. acnes in acne 1) higher counts of P. acnes in individuals with acne than in those without acne 2) correlation between the reduction of P. acnes counts and the clinical improvement of the disease and 3) correlation between development of acne and presence of antibiotic-resistant P. acnes organisms. P. acnes products mediate the formation of comedones and contribute to their rupture, leading to extrusion of 

Inflammation involves a series of cellular changes that facilitate phagocytosis and the killing of microorganisms or the digestion of cell debris. This is followed by proliferation of connective tissue cells and repair. Both of these events require the complex control of various cell types at a local level. There is increasing evidence that, while many different molecules mediate effects such as vascular permeability and chemotaxis, cytokines control many of the cellular processes of inflammation. 

The local processes of inflammation are facilitated by systemic metabolic changes that mobilize energy as glucose, fatty acids, and amino acids. Fever potentiates several enzymatic reactions in inflammatory and tissue cells that. 

The systemic responses that accompany trauma and inflammation are known as the acute phase response (D16). The present evidence supports the idea that this is an adaptive response conditioning the milieu interieur so that inflammation and healing may progress optimally. A complex array of hormones and cytokines induces and controls the components of this response and it is rapidly becoming clear that these and the nervous system are closely integrated. 

Acute phase proteins are a family of approximately 30 plasma proteins produced in increased amounts by the liver in inflammation. They may all have roles to play in inflammation or the healing process that follows (Table 3). The rate of increase in their plasma concentration and the incremental changes that occur following inflammation vary considerably among them and reflect their induction by different cytokines and their molecular size, volume of distribution, and rate of catabolism both in the circulation and at the site of inflammation. Inflammation complicated by other processes such as intravascular coagulation may thus induce a different pattern of acute phase protein elevation, although in simple acute inflammation it is very stereotyped for a particular species of animal. 

Since the liver was discovered to be the major site of acute phase protein synthesis, a vast amount of experimental work has been directed toward elucidation of the chemical messengers involved in synthesis and regulation. Although several cytokines have been implicated, the complexity of the acute phase response is only just becoming apparent and it is likely that synergistic interaction takes place not only between cytokines, but also between cytokines, hormones, and other molecules. 

Stasis is, by definition, a diminution in the normal rate of bile flow, which appears to be necessary for the removal of potential gallstone nidi. This flow is initially determined primarily by bile salt secretion from the hepatocyte, but secretion by ductular cells and reabsorption of fluid and electrolytes by biliary tract epithelium are also important factors. In species with gallbladders, flow in this organ also depends on its filhng passively and then emptying by muscular contraction. In all cases, flow can be diminished by mechanical obstruction, and most of the early work with stasis mentioned 

Atheroselerosis literally means hardening of the arteries. This is eaused by smooth musele proliferation within the intimal layer. These smooth musele eells 

Cardiac risk factors cannot predict how disease will progress, and as these important chemical changes occur at an asymptomatic phase, there is a need to delineate underlying chemical structure at this early stage, thus allowing optimal planning of treatment. At present the majority of patients present after a clinical vascular event, such as a myocardial infarction (MI, heart attack ) or cerebrovascular accident (CVA, stroke ). At this stage, permanent morbidity 

To be able to enumerate the compounds present in the atherosclerotic plaque, with quantities present, would provide the ability to intervene early in those patients at high risk of plaque rupture and prevent clinical vascular events and their attendant morbidity and mortality. 

Diller describes three main phases associated with phosgene induced lung injury as the initial reflex syndrome, the clinical latent phase and the clinical oedema phase.  

Immediate onset symptoms following phosgene exposure result from the irritant effeets on mucous membranes and may trigger protective reflexes. As with the odour, the severity of irritant symptoms is related to vapour concentration and not dose. Therefore, low concentrations of phosgene for longer exposure periods may produce pulmonary oedema without irritation of the upper respiratory tract (Table 4.1). Diller and Zante quote a concentration of 3 ppm (12 mg m ) as having an irritant effect on the nose, throat and bronchi.  

However, as phosgene is relatively hydrophobic with low solubility in aqueous environments, it may not readily diffuse through the mucus and 

The potential inability of the chemosensory system to detect phosgene may compound the damage inflicted to the respiratory system. Additionally, hydrophobic chemicals such as phosgene may not readily interaet with aqueous compounds in the airway fluids, whose function it is to sequester and neutralise reactive chemicals.  

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Labeit et al., 1997] Labeit, S., Kolmerer, B., and Linke, W. The giant protein titin emerging roles in physiology and pathophysiology. Circulation Research. 80 (1997) 290-294... 

The PGs, PGI2 and TXA2 collectively exhibit a wide variety of biochemical and pharmacological activities and are iavolved ia both physiological and pathophysiological processes. However, the iadividual compounds show different overall activity profiles sometimes ia opposiag directions. Excellent reviews are available (59—64). A survey of some of the more important biological actions of the prostanoids foUow. 

Embury, S.H. The clinical pathophysiology of sickle-cell disease. Annu. Rev. Med. 37 361-376, 1986. 

Emerging evidence suggests that dysfunction of the ubiquitin-proteasome system may be part of the pathophysiology of sporadic Parkinson s disease, especially... 

Moore DJ, West AB, Dawson VL et al (2005) Molecular pathophysiology of Parkinson s disease. Annu Rev Neurosci 28 57-87... 

Atherogenesis is the process that leads to changes in the arterial blood vessels, including deposition of cholesterol (atherosclerosis). It is the pathophysiological process behind the vast majority of heart attacks. 

Tfelt-Hansen J, Brown EM (2005) The calcium-sensing receptor in normal physiology and pathophysiology a review. Crit Rev Clin Lab Sci 42(1 ) 3 5-70... 

Chemokines have been shown to be associated with a number of autoinflammatory diseases including multiple sclerosis, rheumatoid arthritis, atherosclerosis, dermatitis, and organ transplant rejection. Evidence, reviewed below, is mounting that chemokines may play a major role in the pathophysiology of these diseases and thus chemokine receptor antagonists could prove to be useful therapeutics in treating these and other proinflammatory diseases. 

MT-associated proteins (MAPs) are attached to MTs in vivo and play a role in their nucleation, growth, shrinkage, stabilization and motion. Of the MAPs, the tau family proteins have received special attention as they are involved in the pathophysiology of Alzheimer s disease. 

Okusa MD, Ellison DH (2000) Physiology and pathophysiology of diuretic actions. In Seldin DW, Giebisch G (eds) The kidney. Physiology and pathophysiology. Lippincott Williams Wilkins, Philadelphia, p. 2877-2922... 

Palmer LG, Garty H (2000) Epithelial Na Channels. In Seldin DW, Giebisch G, (eds.) The Kidney physiology and pathophysiology, 3rdedn, vol 1. Lippincot Williams Wilkins Philadelphia, pp 251—276... 

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