Mechanisms Midterm - Lecture 10

asthma

A multifactorial pulmonary disorder with airway hyperactivity and allergic responses causing bronchospasm.

asthma attack

An irritant (allergen, smoke) makes bronchioles constrict and airways narrow; increased mucus production narrows them further.

Narrowed airways make it difficult to move air out, which can lead to hypoxemia.

Why does asthma cause air trapping?

COPD

Chronic obstructive pulmonary disease: chronic inflammation of the larger airways with destruction of alveolar walls, producing larger sacs and less surface area for gas transfer.

gas exchange consequences of COPD

CO2 retention and hypoxemia, because of the enlarged air sacs and reduced surface area.

emphysema

Alveolar dilation (large air sacs), a component of COPD; the end stage of COPD.

causes of pulmonary hypertension

Congenital heart disease (left-to-right shunting, e.g., a ventricular septal defect increasing blood flow to the right side), COPD (lung damage impairs blood flow through the lungs), and cardiac disease.

Increased resistance from the right heart into the lungs and chronic increased blood flow raise pressure in the pulmonary artery, which lessens blood flow to the lungs and causes V/Q mismatch.

How does pulmonary hypertension develop?

cor pulmonale

Pulmonary hypertension that may become permanent (permanently increased pressure), straining the right side of the heart.

ENaC (Na+ channel that reabsorbs Na+ from fluid) is normally inhibited by CFTR secreting Cl-. With CFTR open, net reabsorption is limited and the mucus layer stays hydrated.

Normally, how do CFTR and ENaC regulate mucus hydration?

ENaC reabsorbs Na+ and Cl- comes through other channels, causing net reabsorption of Na+ and Cl- from mucus gland fluid. Mucus dehydrates and becomes gummy, cilia can't clear it, and trapped bacteria cause chronic infection.

What happens in CF when CFTR is nonfunctional?

Abnormal fluid and electrolyte transport, leading to thick, viscid mucus.

What is the general defect in CF epithelial cells?

problems in cystic fibrosis

Sinus problems and nasal polyps, salty sweat (difficulty reabsorbing Cl-), right-sided heart failure, gallstones (lack of bile secretion), and pancreatic enzyme blockage causing digestion problems and malnutrition.

Newborn screening: blood IRT (immunoreactive trypsinogen, a trypsin precursor that accumulates with pancreatic damage) followed by a genetic panel. The sweat chloride test is diagnostic.

How is CF screened and diagnosed?

CF treatment

Supportive care; digestive enzyme replacement (treats nutritional deficiencies); antibiotics (inhaled for chronic infection, IV during attacks); and allele-specific treatments that reactivate or bypass genetic abnormalities to produce some active chloride channels.

SERPINA1; autosomal recessive.

What gene is affected in alpha-1 antitrypsin deficiency and how is it inherited?

alpha-1 antitrypsin

It is made in the liver, secreted by inflammatory cells, and inhibits elastase (made by leukocytes recruited in infections). Deficiency is a protease inhibitor deficiency.

Lung (COPD) and liver (infantile liver disease).

What organs are affected in alpha-1 antitrypsin deficiency?

Pi typing

Typing of alpha-1 antitrypsin alleles. MM = normal levels; Z allele = highest risk; ZZ = most severe with low levels; SZ = some risk of lung disease; S allele lower risk; SS and MM low risk.

Supportive treatment, avoiding smoking and environmental exposures, and protein (enzyme) replacement therapy.

How is alpha-1 antitrypsin deficiency treated?

immotile cilia syndrome

Also called primary ciliary dyskinesia; an autosomal recessive disorder (at least 32 loci) of ciliary protein structures. Kartagener syndrome is the form with situs inversus.

Respiratory epithelium (microbial clearance in upper airways and sinuses), sperm flagella (immotile sperm cause infertility), and the embryonic primitive node.

Where do cilia and flagella function in the body?

Monocilia on the ventral side of the primitive node beat leftward, moving differentiation factors (Lefty, Nodal, etc.) to the left of the embryo, which stimulates "left" features and forms the L-R axis.

How do cilia determine left-right sidedness?

Sidedness is random. L-R sidedness is reversed (situs inversus) in half of people with immotile cilia syndrome.

What happens to sidedness when cilia don't function?

cilia

An axoneme with 9 microtubule doublets surrounding a central pair of microtubules (9+2), linked by radial spokes. Outer doublets have dynein arms that hydrolyze ATP for movement.

They attach to the 9+2 architecture to hold doublets in place and anchor them to the central pair via spokes. Without them cilia don't beat, so no mucus or sperm movement.

What do the ~200 accessory proteins do in cilia?

heterotaxy

A rarer finding in which only some organs are on the wrong side (vs complete situs inversus).

Kartagener/immotile cilia phenotype

Situs inversus (in about half), recurrent sinusitis, bronchitis and pneumonia (respiratory epithelium problems), and male infertility.

Supportive treatment, similar to CF (e.g., improving chronic sinusitis and bronchitis).

How is immotile cilia syndrome treated?