The pathogenesis of cystic fibrosis

Section 1: Imagine that you had to give a talk on the pathogenesis of Cystic Fibrosis.

Produce a short but comprehensive sum-up of the talk. Make non travel into therapy etc.

Pathogenesis of Cystic Fibrosis ( CF ) :

Cystic Fibrosis, an familial disease ( autosomal recessive ) normally involves break of the exocrine map of the pancreas but besides affects enteric secretory organs, bilious tree, bronchial secretory organs and perspiration secretory organs. Happening in both males and females every bit causes break of their generative capablenesss.A mutant in the cistron ( 7q31.2 ) encoding the cystic fibrosis transmembrane conductance regulator ( CFTR ) protein consequences in the disease happening. Of the 1500 identified CFTR mutants, the category II mutants affecting the absence of a Phenylalanine at place 508 ( Phe508del ) histories for the most common type of functional change that consequences in bulk instances of Cystic Fibrosis.

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CFTR mutants can be grouped as in table 1 ( Ratjen, 2009 ) .The fact that CFTR disfunction leads to the phenotypic disease can be explained by merely narrating the hypotheses concluded from assorted researches.High salt Hypothesis: When the functional CFTR is absent, the keeping of the Na and chloride is enormously increased and this consequences in increased concentration of chloride in the periciliary bed ( Zabner et al. , 1998 ) . Such event leads to the functional break of of import innate antibiotic molecules such as human & A ; szlig ; -defensin 1, therefore allowing the relentless happening of bacteriums that are usually cleared from the air passage surface liquid ( Goldman et al. , 1997 ) .Low-volume Hypothesis: Another hypothesis affecting the CFTR disfunction reveals that surplus of Na and H2O resorption consequences in the desiccation of the periciliary liquid bed and abolishes the mucous secretion conveyance. Such a failure causes a monolithic decrease of the lubricating bed between the epithelial tissue and the mucous secretion, therefore suppressing the normal ciliary map of cough clearance.

Plaque formation occurs and seaports bacteriums peculiarly the Pseudomonas aeruginosa ( hypoxic niche ) that initiates the Cystic fibrosis air passage infection ( Matsui et al. , 1998 ) . The airway surface liquid volume ordinance is dependent on ATP, a individual extracellular signaling system and a dysregulation increases susceptibleness to disease doing pathogens ( Boucher, 2007 ) .

As a consequence of the happening of the above, a loss of chloride outflow therefore prevents the epithelial tissue from modulating the air passage surface liquid volume to normal degrees.Dysregulation of the Host inflammatory response: This is considered as the most basic defect in the cystic fibrosis. The abolition of cAMP-stimulated anion conveyance due to non functional CFTR in the apical membranes of epithelial cells consequences in the bacterial accretion in mucous secretion. These bacteriums release Flagellin that triggers the Toll-like receptor 5 and the NF- { kappa } B signaling pathway, therefore ensuing in a hyperinflammatory response affecting the release of proinflammatory cytokines that recruit neutrophils to the septic parts and harm CF lung tissue. Chloride, hydrogen carbonate and glutathione inadequacies affect the air passage surface liquid. Loss of apical CFTR consequences in the hyperpolarization of the membrane potencies taking to increase in the cytosolic and intracellular Ca degrees and the NF- { kappa } B signaling ( Machen, 2006 ) . An instability is observed between the proinflammatory molecules ( interleukin 8, interleukin 6, tumour mortification factor a and arachidonic acid metabolites ) and the anti inflammatory substances ( interleukin 10, lipoxin, docosahexaenoic acid ) .Platelet hyper-reactivity and neutrophil programmed cell death abnormalcies have besides been reported in association with CF ( Reviewed in O’Sullivan and Freedman, 2009 ) .

Sensitivity to infection: A comparative survey of the interaction of the P. aeruginosa in normal hosts and CF patients postulates this hypothesis. In normal hosts the bacteriums binds to the functional CFTR and initiates an immune response where as in CF patients the P.

aeruginosa and Staphylococcus aureus attach to the air passage epithelial tissue doing no CFTR mediated immune response. Such activity is associated with an addition in asialo-GM1 in apical cell membranes that facilitate the bacterial fond regard and show decreased self restricting response ( Reviewed in O’Sullivan and Freedman, 2009 ) .Drumhead: Though most facets of the CF pathophysiology have been clarified, yet many challenging facts still need to be considered.

Therefore sum uping the cascade of pathophysiology of CF, the stairss include the CFTR cistron being faulty, , that consequences in faulty ion conveyance and depletion of airway surface liquids. This causes a faulty mucociliary clearance and the clogging mucose consequences in infection and redness, therefore explicating the pathogenesis of Cystic Fibrosis ( Reviewed in Ratjen, 2009 ) .


  1. Boucher, RC.

    ( 2007 ) Airway surface desiccation in cystic fibrosis: pathogenesis and therapy. Annual Review of Medicine, 58, pp. 157-70.

  2. Reappraisal on the pathogenesis of cystic fibrosis with elaborate accounts related to disease.

  3. Goldman, MJ.

    , Anderson, GM. , Stolzenberg, ED. , Kari, UP. , Zasloff, M.

    , Wilson, JM. ( 1997 ) Human beta-defensin-1 is a salt-sensitive antibiotic in lung that is inactivated in cystic fibrosis. Cell, 88, pp. 553-60.

  4. The original beginning of information on high salt hypothesis explicating the consequence of innate antibiotic molecules.

  5. Machen, TE. ( 2006 ) Innate immune response in CF airway epithelia: hyperinflammatory? Am J Physiol Cell Physiology, 291, pp.


  6. Clear accounts in relation to the dysregulation of host inflammatory responses.

  7. Matsui, H. , Grubb, BR. , Tarran R.

    , Randell SH. , Gatzy, JT. , Davis, CW. and Boucher, RC.

    ( 1998 ) Evidence for periciliary liquid bed depletion, non unnatural ion composing, in the pathogenesis of cystic fibrosis air passages disease. Cell, 95, pp. 1005-15.

  8. Detailed description on low volume hypothesis explains the consequence of low periciliary liquid bed.

  9. O’Sullivan, BP. and Freedman, SD. ( 2009 ) Cystic fibrosis. Lancet, 373 pp. 1891-904.
  10. Latest reappraisal covering with the hypotheses for pathogenesis and besides explanative about the original documents related to the assorted hypotheses.

  11. Ratjen FA.

    ( 2009 ) Cystic Fibrosis: Pathogenesis and Future Treatment Strategies. Respiratory Care, 54 ( 5 ) , pp. 595- 602.

  12. Latest reappraisal on the pathogenesis of Cystic fibrosis explicating the effects in lungs and besides the familial facets involved in dysregulatory activities during the disease.

  13. Zabner, J. , Smith, JJ. , Karp, PH.

    , Widdicombe, JH. , Welsh, MJ. , ( 1998 ) Loss of CFTR chloride channels alters salt soaking up by cystic fibrosis airway epithelia in vitro. Mol Cell, 2, pp.