MUDr. Dana Maňasková


Vyhledávání na medicinman.cz
 

Hlen plicní

Abhesives/Lubricants

Surfactant

  • Can reduce sputum adhesivity and increase the efficiency of energy transfer from the cilia to the mucus layer
  • Decrease in the amount of bronchial surfactant
  • Abnormal sputum phospholipid composition
  • Acute and chronic airway inflammation leads to the production of secretory phospholipase A2
    • Product of arachidonic acid metabolism !!
  • Airway secretory phospholipase A2
    • Can break down surfactant phospholipids into non-surface-active lysophospholipids
    • It is a potent mucin secretagogue
    • Can produce secretory hyperresponsiveness to other inflammatory stimuli
      • Thus exacerbate airway obstruction

Sputum tenacity

  • Product of adhesivity and cohesivity
  • Greatest influence on the cough clearability of sputum
  • Decreasing tenacity with surfactant
    • Effectively increases the cough transportability of secretions
  • In patients with stable chronic bronchitis 14 days of aerosolized surfactant increased
    • In vitro sputum transportability
  • Improved FEV1 and FVC by more than 10%
    • Significantly deceased trapped thoracic gas (by the ratio of residual volume to total lung capacity)
  • Effect persisted for at least a week after treatment was completed

Ambroxol

  • Has been thought to stimulate surfactant secretion,
  • Used for many years in Europe for the management of chronic bronchitis
  • Results of clinical studies of ambroxol are conflicted
  • Decreasing the viscosity of a mucus plug
    • Might actually reduce sputum cough clearability
  • Is possible to “unstick” secretions from the underlying ciliated epithelium, which would make airflowdependent clearance more efficient.

Active Chloride Secretion

  • CAMP agonists do stimulate
    • Net Cl- (Ohrui et al., 1995)
    • Fluid (Smith et al., 1994) secretion
  • Activation of CFTR and/or calcium-activated anion channels
    • By luminal adenosine and nucleotides
    • Down regulation of Na+ absorption
  • Outwardly rectifying Cl- channels (ORCC) (Schwiebert et al., 1995) and
  • Ca2+-activated Cl- channels (CaCC) (Wei et al., 1999).

Expectorants

  • Medications that improve the ability to expectorate purulent secretions
  • Increase airway water or the volume of airway secretions
    • Secretagogues that are meant to increase the hydration of luminal secretions
      • Hypertonic saline
      • Mannitol
  • Abhesives
    • Decrease the adhesivity of secretions and thus unstick them
      • Surfactants
  • Expectorants do not alter ciliary beat frequency or mucociliary clearance
  • Oral expectorants
    • Acting on the gastric mucosa to stimulate the vagus nerve
      • Probably inaccurate
  • Most commonly used expectorants are simple hydration
    • Bland aerosol
    • Oral hydration
    • Iodide-containing compounds such as
      • Super-saturated potassium iodide
      • Iodinated glycerol
    • Glyceryl guaiacolate (guaifenesin)
    • Ion-channel modifiers
      • P2Y2 purinergic agonists

Dehydration

  • Might increase the tenacity of secretions by increasing adhesivity
  • The more secretions adhere to the epithelium, the more difficult they are to cough up

Moderate hydration

  • In patients with chronic bronchitis
    • Does not significantly affect sputum volume or ease of expectoration
  • Systemic over-hydration
    • Can lead to mucosal edema and impaired mucociliary clearance

Iodide-containing agents

  • Super-saturated potassium iodide [commonly known as SSKI])
  • Generally considered to be expectorants
    • Thought to stimulate the secretion of airway fluid

Iodopropylidene glycerol

  • May briefly increase tracheobronchial clearance
    • As measured with radiolabeled aerosol in patients with chronic bronchitis
  • Double-blinded crossover study in subjects with stable chronic bronchitis
    • Iodopropylidene glycerol did not significantly change
      • Pulmonary function
      • Gas trapping,
      • Sputum properties
<2>Guaifenesin
  • Considered an expectorant rather than a mucolytic
  • Can be ciliotoxic when applied directly to the respiratory epithelium
  • May stimulate the cholinergic pathway
    • Increase mucus secretion from the airway submucosal glands
  • Not clinically effective in randomized controlled trials

H+ secretion

  • Slightly acidic pH of ASL
  • Three different proton transport pathways
  • 1) vacuolar H+-ATPase
  • H+ secretion pathway blocked by bafilomycin A1
    • Blocked acidification of the ASL in intact distal bronchi of the pig
      • Proton pump’s involvement in the H+ secretion (Inglis et al., 2003).
  • 2) H+/K+-ATPase colonic type
  • Acidification was blocked by colonic type H+/K+-ATPase inhibitor Sch28080 (Coakley et al., 2003)
  • 3) Zn2+ sensitive H+ channel
  • PH-stat to study of primary cultures of human tracheal epithelium (Fischer et al., 2002)
  • 4) proton channel was identified to be HVCN1 (Iovannisci et al., 2010)
  • 5) basolateral membrane protein NHE1
    • Could regulate the apical voltage-gated H+ channel activity
    • By a pathway that involves intracellular acidification (Fischer and Widdicombe, 2006). [25]

Hypothiocyanite (OSCN-)

  • Synthesized from SCN- by lactoperoxidases in the airway epithelia
  • OSCN- is known to be part of an important innate defense system against microbes in the airways
    • Induces airway inflammation in airway epithelia

LPS

  • LPS can also activate NF-kappaB via the TLR4/MyD88 pathway
    • YS-01 almost completely suppressing LPS-induced ALI remains unknown
    • Pendrin-mediated OSCN- dominantly activates the NF-kappaB cascade in an LPS-induced ALI model.
  • www.thno.org/v10p9913.htm

Mucokinetic Agents

  • Increases mucociliary clearance, generally by acting on the cilia
  • Tricyclic nucleotides,

Agonist bronchodilators

  • Methylxanthine bronchodilators
  • Increase ciliary beat frequency
  • Only a minimal effect on mucociliary clearance
  • Most of these agents are also mucus secretagogues
    • May paradoxically increase the burden of airway secretions

Bronchodilator medications

  • Can also increase airway collapse in patients with bronchomalacia
    • Relax airway smooth muscle
  • Recommended to those who have improvement in expiratory airflow following their use
    • Increased expiratory airflow can enhance the effectiveness of cough
  • Considered cough clearance promoters.

Mucolytics

  • Change the biophysical properties of secretions
  • By degrading the mucin polymers, DNA, fibrin, or F-actin in airway secretions
    • Generally decreasing viscosity
  • This will not necessarily improve secretion clearance
    • Sputum that is more viscous but less sticky tends to clear better with cough
  • May seem counterintuitive at first

NF-kappaB

    • Crucial transcription factor for inflammatory responses in airways
    • Its inhibition attenuates ALI in vivo
  • www.thno.org/v10p9913.htm

Snížená funkce NIS - možná

  • Ve štítnici, v.s. možná i v plicích - v.s. impakt málo I v buněce na trnasport I via CFTR

Estradiol

  • Downregulates the expression of NIS and iodide uptake

Zánět obecně

  • TNF and interleukins inhibit iodide uptake and NIS expression
  • Insulin like growth factor 1 (IGF-1)
    • Downregulating the expression of NIS
  • Transforming Growth Factor-beta
    • Downregulate iodide transport by several mechanisms in different species
      • Inhibition of mRNA expression of TSHR, TPO, NIS, the Na, K-ATPase and thyroglobulin

Mutations in the NIS gene

Blokáda

  • Selenocyanate (SeCN-),
  • Thiocyanate (SCN-),
    • Thiocyanate is a less potent inhibitor of NIS-mediated iodide transport than perchlorate.
  • Chlorate (ClO3-),
  • Nitrate (NO3-)
  • Pertechnetate (TcO4)
  • Perrhenate (ReO4-)
  • Perchlorate (ClO4-)
    • Competitive NIS inhibitor
  • ijpeonline.biomedcentral.com/articles/10.1186/1687-9856-2014-8

Na+-K+-ATPases

  • Alveolar edema clearance requires active sodium transport that is mediated by Na+-K+-ATPases
  • Normal conditions, this pump is therefore required for maintenance of a dry alveolar space.
  • Downregulation of alveolar Na+-K+-ATPase promotes pulmonary edema in models of lung injury
    • Therefore activation of dopaminergic or adrenergic receptors that increase Na+-K+-ATPase activity
      • Provides a therapeutic potential for increasing fluid clearance from the alveolar space
  • The obvious importance of this pump is clearly reflected in its ability to resolve alveolar edema under pathological conditions
  • journals.physiology.org/doi/full/10.1152/ajplung.00285.2017

Pendrin

  • Strongly implicated in inflammation
  • T helper type 2 (Th2) and airway epithelial cells
    • Produce proinflammatory cytokines such as IL-4/ IL-13
      • Dramatically upregulate pendrin mRNA and protein expression
  • Calu-3 and primary nasal cells were treated for 48h with IL-4
    • IL-4 failed to increase pendrin expression or HCO3- secretion in Calu-3 cells
    • Dramatically elevated pendrin levels in human primary nasal cells
      • Associated with increased transport of fluid and HCO3-.
  • Responses to IL-4 in nasal cells were attenuated by
    • Si-RNA that specifically targets pendrin
    • Almost abolished by a CFTR inhibitor
  • Increases in HCO3- and fluid secretion induced by IL-4 in primary nasal cells
    • Are dependent on both pendrin and CFTR [26]
  • Knockdown of Pendrin (PDS, SLC26A4) has little effect on bicarbonate secretion by the human airway serous cell line Calu-3 [26]
  • SLC 26 polypeptides operate as multifunctional
  • Electroneutral or electrogenic anion exchangers and anion channels
    • Cl-,
    • HCO3-,
    • Sulfate,
    • oxalate,
    • I-, [26]
    • Formate (Alper and Sharma, 2013; Chernova et al., 2005; Ohana et al., 2011; Ohana et al., 2009)

Mutations in SCL26 genes

  • Multiple congenital human diseases
  • Chondrodysplasia syndromes (Jackson et al., 2012);
  • Recessive congenital chloride-losing diarrhea (CLD) (Hoglund et al., 1996)
  • Autosomal recessive non-syndromic deafness DFNB4
  • Pendred syndrome (Coyle et al., 1996; Sheffield et al., 1996). [26]

Lokalizace

  • Electroneutral anion exchanger predominantly expressed in the
    • Inner ear,
    • Thyroid gland
    • Kidney (Lacroix et al., 2001; Royaux et al., 2000; Royaux et al., 2001; Scott et al., 1999)
    • Mammary gland (Rillema and Hill, 2003)
    • Testis (Lacroix et al., 2001)
    • Placenta (Bidart et al., 2000)
    • Endometrium (Suzuki et al., 2002)
    • Liver (Alesutan et al., 2011).
    • Stria vascularis of the cochlea and in the endolymphatic duct and sac
      • As a Cl-/HCO3- exchanger
      • Loss or reduction in the function of pendrin results in
        • Pendred syndrome, OMIM#274600)
        • Non-syndromic enlarged vestibular aqueduct (ns-EVA) hearing loss (Dossena et al., 2011) [26]
    • Apical membrane of thyroid cells (Royaux et al., 2000)
      • Cl-/I- exchanger (Yoshida et al., 2004; Yoshida et al., 2002)
        • Regulating the chloride transport from the cytoplasm to the colloid space (Kopp and Bizhanova, 2011) [26]
    • Kidney apical surface of type B intercalated cells and non-A, non-B intercalated cells of the cortical collecting ducts connecting tubules of the nephron (Royaux et al., 2001)
      • Type B intercalated cells from pendrin knockout mice lack apical chloride-bicarbonate exchange
        • Primary bicarbonate extruding pathway (Royaux et al., 2001) [26]
    • Airway
      • Increases in pendrin mRNA expression - mucus overproduction models of asthma and chronic obstructive pulmonary disease (COPD) [26]

Regulace

  • Interleukin-17A (IL-17A)- important for host defense against inhaled bacteria
    • Raises pendrin expression and Cl-/ HCO3- exchange activity in human bronchial epithelial cells (Adams et al., 2014)
  • The Th2 pro-inflammatory cytokines IL-4/IL-13
    • Also dramatically induce pendrin mRNA expression in human airway primary cells (Nakagami et al., 2008; Nofziger et al., 2011; Pedemonte et al., 2007)
      • Via a STAT6-mediated pathway (Nofziger et al., 2011) [26]
    • Primary nasal samples, Pendrin expression was not affected by IL-4 treatment. [26]
  • Airway surface liquid pH was increased by IL-4 stimulation, even without stimulating CFTR using forskolin-cAMP [26]
  • Over-expression of Pendrin in mouse lung using a Sendai viral vector also induced rapid mucus overproduction (Nakao et al., 2008).
  • HCO3- secretion may link the overexpression of pendrin to mucus hyperplasia and metaplasia. [26]
  • Pendrin carries Cl-, HCO3- , thiocyanate (SCN-)
    • In presence of hydrogen peroxide (H2O2)
      • It can be transformed to the antimicrobial hypothiocyanite (OSCN-) by lactoperoxidase (LPO) (Conner et al., 2007). [26]
  • Over-expression of Pendrin in Fisher rat thyroid (FRT) cells confers cAMP-independent SCN- transport [26]
  • Pendrin mediates most Cl-/HCO3- exchange at apical membrane of Calu-3 cells during cAMP stimulation (Garnett et al.,2011)
  • Unable to confirm those results using our fluid secretion and pH stat assays and could not find evidence for a direct role of PDS in secretion.
    • Negative result is in agreement with findings from Kim et. al. who used intracellular pH and membrane potential measurements (Kim et al., 2014). [26]
  • Relatively low expression of pendrin in Calu-3 cells makes it unlikely to contribute significantly to HCO3-
  • Elevated pendrin expression has been demonstrated in bronchial epithelial cells following exposure to the pro-inflammatory cytokines
    • IL-4, IL-13, and IL-17A [(Adams et al., 2014; Di Valentin et al., 2009; Galietta et al., 2002; Merves et al., 2003; Nakagami et al., 2008; Nakao et al., 2008; Nofziger et al., 2011; Woodruff et al., 2007) ]
  • Almost abolished by a CFTR inhibitor, suggesting that increases in HCO3- and fluid secretion depend on both pendrin and CFTR. [26]
  • Pendrin, has been detected in the apical membrane of airway epithelial cells
  • NIS, CFTR, Ca2+-activated Cl- channels, and pendrin
    • Implicated in the secretion of SCN-
    • Involved in both SCN- and I- secretion in the airways [26]
  • Pendred syndrome
    • Deafness and goiter
  • Expressed at the apical membrane of the follicular epithelium in thyroid, acting as a transporter of iodide
  • In cochlea
  • Disruption of the Slc26a4 (Pds) gene causes
    • Auditory dysfunction due to dysplasia of the cochlea
  • SLC26A4 gene as an IL-13-inducible gene
    • Pendrin is highly expressed at the apical membrane of bronchial epithelial cells (BECs) in animal models of bronchial asthma and COPD
  • Pendrin encoded by the SLC26A4 (PDS) gene as
  • Responsible for airway mucus production
  • Asthma and COPD mouse models, pendrin was up-regulated at the apical side of airway epithelial cells
    • With mucus overproduction [26]
  • Sendai virus vector, rapidly induced mucus overproduction in the lumens of the lungs together with neutrophilic infiltration in mice
  • IL-13, a Th2-type cytokine
    • Central mediator in the pathogenesis of bronchial asthma
    • Inducing mucus production in bronchial epithelial cells [26]

Niflumic acid

  • A broad inhibitor of anion transport
  • Suppresses the development of asthma in mice
  • IL-13 induce expression of gob-5 (mCLCA3) [26]



Pendrin (SLC26A4)

  • Cl-/SCN- exchange activity of pendrin

IL-4

  • Upregulates the Cl-/SCN- exchange activity of pendrin
  • Increases OSCN- production
    • Results in NF-kappaB activation
    • Induces airway inflammation in a murine allergic asthma model

YS-01

  • Blokátor pendrinu
    • NaSCN application also induced lung injury even in pendrin null mice
    • LPS-induced ALI had not developed
  • www.thno.org/v10p9913.htm
  • Electroneutral anion exchanger
  • Transporting iodide, bicarbonate, hydroxide, thiocyanate, and formate for chloride
  • 780-amino-acid-long highly hydrophobic glycoprotein
  • Three putative extracellular glycosylation sites
  • 14 membrane-spanning alpha-helices forming the N-terminal transmembrane domain (TMD)
    • Connected to a C-terminal cytosolic sulfate transporter anti-sigma factor antagonist (STAS) domain
  • Identification in 1997
  • www.mdpi.com/1422-0067/20/3/731/htm

Pendred syndrome

  • Autosomal recessive
  • Sensorineural hearing loss
  • Enlarged thyroid

Lokalizace

  • Highly expressed in
    • Epithelial cells of the inner ear
    • Thyroid gland
    • Kidney
  • Baseline levels of pendrin were also shown in other tissues
    • Airway
    • Mammary gland
    • Testis
    • Placenta
    • Endometrium
    • Liver
    • Esophageal epithelia
  • www.mdpi.com/1422-0067/20/3/731/htm

Funkce

  • Pendrin mediates Cl-/HCO3- exchange
    • Control the acid–base balance of the endolymph

In the thyroid gland

  • Fundamental for iodide efflux into the follicular lumen
    • By exchanging Cl- for I-

Kidney

  • Contributes to
    • Acid–base balance
    • Regulation of blood pressure
      • Cortical collecting duct
      • By secreting HCO3- into the tubular lumen in exchange of Cl-
  • www.mdpi.com/1422-0067/20/3/731/htm


An upregulation of pendrin expression

  • Correlation with specific diseases such as asthma, chronic obstructive pulmonary disease (COPD), and eosinophilic esophagitis (EE)
  • Predominantly mediated by interleukin (IL)-4, IL-13 and IL-17
  • www.mdpi.com/1422-0067/20/3/731/htm


Airway surface SCN-

  • Transported by pendrin
  • Is an essential component for LPS- induced airway inflammation

Sekretagoga

  • Agents that increase transport across ion channels
    • (CFTR) chloride
    • calcium-dependent chloride channel,
    • Increase water transport across the airway aquaporin water channels
  • May increase the hydration of the periciliary fluid and thus aid expectoration
  • Chloride conductance through the Ca2-dependent chloride channels is preserved in the CF airway

The tricyclic nucleotides, Uridine triphosphate and adenosine triphosphate

  • Regulate ion transport through P2Y2 purinergic receptors

Uridine triphosphate aerosol

  • Alone or in combination with amiloride
  • Increases transepithelial potential difference and the clearance of inhaled radioaerosol

P2Y2 purinergic receptor agonists

Hyperosmolar saline inhalation

  • Used to obtain specimens for the diagnosis of pneumonia
  • Long-term use of inhaled hyperosmolar saline improves pulmonary function in patients with CF
  • Unpleasant taste and induces coughing, which may limit its acceptance

Powdered mannitol

  • Improves quality of life and pulmonary function non-CF bronchiectasis
  • Significantly improves the surface adhesivity and cough clearability
  • Inhaled mannitol is beneficial in non-CF bronchiectasis

Dornase alfa

  • In the therapy of CF lung disease

Sodium bicarbonate (2%)

  • Base that has occasionally been used for direct tracheal irrigation or as an aerosol
  • Increasing the local bronchial pH
    • Weakens the bonds between the side chains of the mucus molecule
      • Decreases mucus viscosity and elasticity.
  • Bronchial irritation may occur with a bronchial pH of greater than 8.0
  • Sodium bicarbonate has not been clinically demonstrated to improve airway mucus clearance.
  • There is little to recommend its use.


Sodium Absorption

  • Major active ion transport process in the human airways (Blouquit-Laye and Chinet, 2007; Knowles et al., 1984; Widdicombe et al., 2005)
  • Epithelial sodium channels (ENaCs) in the apical membrane
    • Sodium entry down its net electrochemical gradient
  • Intracellular sodium then exchanges for extracellular potassium
    • Stoichiometry of 3:2 through the basolateral sodium pump (Na+-K+-ATPase)
  • Potassium ions are recycled through basolateral K+ channels

ENaC Activity Regulation

  • Heterotrimer
    • Subunits alpha, beta, gamma, delta
  • Closely related to the ASL volume
    • Active when the volume is high
    • Inhibited when the volume approaches its normal value (Boucher, 2004).

ENaC is regulated by

  • Second messengers
  • Phosphoinositides
  • Proteolytic enzymes
  • Epidermal growth factor receptor (Tong and Stockand, 2005)
  • Epinephrine (Planes et al., 2005)
  • Respiratory viruses (Kunzelmann et al., 2000; Kunzelmann et al., 2007).

Inactivated

  • Agonists that raise cyclic adenosine monophosphate (cAMP) in airway epithelial cells
  • A decrease in the amount of intracellular phosphatidylinositol 4,5-bisphosphate (PIP2)
    • Which binds to the ENaC alpha subunit in the apical membrane
    • Helps prevent ENaC channels from running down (Ma et al., 2002)
    • Lowers the activity of ENaC (Davis and Lazarowski, 2008)
  • Soluble protein SPLUNC1
    • Can apparently bind to ENaC and prevent its activation by proteolysis (Garcia-Caballero et al., 2009)
  • Amiloride
    • Sodium absorption is inhibited by the ENaC blocker

Stimulated

  • CAMP stimulates ENaC in cystic fibrosis (CF) airways that lack functional CFTR (Boucher et al., 1986; Knowles et -al., 1983a; Knowles et al., 1983b)
    • CFTR alters the sensitivity of ENaC to cAMP (Stutts et al., 1995; Stutts et al., 1997)
  • Cleavage of the extracellular domain of alpha and gamma subunits
    • By intracellular furin-type protease in the trans-Golgi network (Hughey et al., 2004)
    • By extracellular serine proteases (Gaillard et al., 2010) - important role in the airway.
      • Channel-activating protease 1 (CAP1;prostasin) (Vallet et al., 1997)
      • CAP2
      • CAP3 (matriptase or epithin)
      • Human neutrophil elastase (Caldwell et al., 2005)
      • Trypsin (Gaillard et al., 2010; Vallet et al., 1997)

|Sputum

  • A secondary polymer network is composed of
    • Neutrophil-derived DNA
    • Cell-wall-associated filamentous actin (F-actin)
    • Responsible for many of the abnormal properties of purulent secretions

YS-01

  • YS-01 inhibited LPS-induced NF-kappaB activation
    • Subsequent cytokine production in a murine ALI model and alveolar epithelia
  • Pendrin inhibitor YS-01
    • Blocking the transepithelial transport of SCN-
      • Inhibiting OSCN- generation
        • Inh. NF-kappaB activation
          • Suppression of proinflammatory cytokine production
  • Pendrin inhibitors attenuated OVA-induced allergic airway inflammation
    • By inhibiting the pendrin/OSCN-/NF-kappaB cascade
  • www.thno.org/v10p9913.htm

Amiloride



Classic mucolytics

  • Depolymerize the mucin glycoprotein oligomers by hydrolyzing the disulfide bonds
  • By free thiol (sulfhydryl) groups, which hydrolyze disulfide bonds attached to cysteine residues of the protein core

N-acetyl L-cysteine (NAC)

  • No data convincingly demonstrate that any classic mucolytic, including NAC, improves the ability to expectorate mucus.
  • Can decrease mucus viscosity in vitro
  • Oral acetylcysteine is rapidly inactivated
    • Does not appear in airway secretions
    • Is ineffective in vivo ???
  • Published evidence suggests that oral acetylcysteine may
    • Improve pulmonary function in selected patients with chronic suppurative lung disease
      • Including chronic obstructive pulmonary disease (COPD)
      • Clinical benefit observed is probably due to antioxidant properties
  • Daily use of acetylcysteine
    • Reduces the risk of re-hospitalization for COPD exacerbation by approximately 30%
    • Does not modify the outcomes of COPD exacerbations.
  • Well-controlled, large, long-term study of daily NAC at fairly high dose
    • Had no effect on pulmonary function, quality of life, exacerbation rate, or hospitalization
  • The regular use of aerosol NAC may be harmful in persons with CF
    • Producing unacceptable adverse effects
    • Decreased pulmonary function in some patients
      • Selectively depolymerizing the essential mucin polymer structure
      • Pathologic polymers of DNA and F-actin intact.
  • High-dose oral NAC
    • May effectively decrease the hyperinflammatory airway state characteristic of CF

Peptide Mucolytics

  • Mucin polymer network is essential for normal mucus clearance
  • Pathologic polymer gel serves no obvious purpose in airway protection
  • In stable CF there is almost no mucin in airway secretions
  • Much less mucin than DNA in the CF airway
  • Peptide mucolytics are designed specifically to depolymerize the
    • DNA polymer (dornase alfa) (Pulmozyme)
  • F-actin network (eg, gelsolin, thymosin 4)

Aerosolized dornase alfa

  • Reduces the viscosity and adhesiveness of infected sputum
  • Modestly improves FEV1 in patients with CF
  • Not uniformly effective for the treatment of CF airway disease
    • Does not seem to be related to sputum DNA content
  • May be effective in
    • Non-CF bronchiectasis
    • Primary ciliary dyskinesia.
    • Purulent sputum of chronic bronchitis
      • Does not appear to improve pulmonary function or reduce morbidity
  • Actin is the most prevalent cellular protein in the body
    • Structural integrity of cells
  • Actin polymerizes to form F-actin
  • Extracellular F-actin probably contributes to the viscoelasticity of expectorated CF sputum

Nondestructive Mucolytics

  • “loosen” this network by charge shielding.

Low-molecular-weight dextran

Heparin

Other sugars or glycoproteins


Mucus

  • Adhesive,
  • Viscoelastic gel,
  • Properties of which are largely determined by entanglements of long polymeric gel-forming mucins

MUC5AC and MUC5B

  • This layer entraps and clears bacteria
  • Inhibits bacterial growth and biofilm formation
  • Protects the airway from
    • Inhaled irritants
    • Fluid loss

In cystic fibrosis

  • There is almost no mucin (and thus no mucus) in the airway
  • Secretions consist of
    • Inflammatory-cell derived DNA
    • Filamentous actin polymers
      • Similar to pus
  • Retention of this airway pus
    • Leads to ongoing inflammation and airway damage

Mucoactive medications

  • Expectorants,
  • Mucolytics,
  • Mucokinetic drugs

Expectorants

  • Increase the volume of airway water or secretion
  • To increase the effectiveness of cough

Guaifenesin (eg, Robatussin or Mucinex)

  • no evidence that they are effective for the therapy of any form of lung disease
  • Administered in combination with a cough suppressant such as dextromethorphan
    • Risk of increased airway obstruction

Hyperosmolar saline and mannitol powder

  • Used as expectorants in cystic fibrosis

Mucolytics

  • That depolymerize mucin, such as N-acetylcysteine
  • no proven benefit
  • A risk of epithelial damage when administered via aerosol

DNA-active medications

  • Dornase alfa (Pulmozyme)
  • Potentially actin-depolymerizing drugs such as thymosin 4
  • May be of value in helping to break down airway pus

Mucokinetic agents

  • Can increase the effectiveness of cough
    • By increasing expiratory cough airflow
    • By unsticking highly adhesive secretions from the airway walls

Aerosol surfactant

  • One of the most promising of this class of medications
  • ::[Respir Care 2007;52(7):859–865. © 2007 Daedalus Enterprises]::

Literatura

[1] Mucolytics, Expectorants, and Mucokinetic Medications; Bruce K Rubin MEngr MD MBA FAARC

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Poslední aktualizace: 30. 9. 2024 1:08:20