Editing Pepsin (section)

== In laryngopharyngeal reflux ==
{{main|Laryngopharyngeal reflux}}

Pepsin is one of the primary causes of mucosal damage during [[laryngopharyngeal reflux]].<ref name="pmid4884956">{{cite journal | vauthors = Goldberg HI, Dodds WJ, Gee S, Montgomery C, Zboralske FF | title = Role of acid and pepsin in acute experimental esophagitis | journal = Gastroenterology | volume = 56 | issue = 2 | pages = 223–30 | date = February 1969 | pmid = 4884956 | doi = 10.1016/S0016-5085(69)80121-6 | doi-access = free }}</ref><ref name="pmid6808683">{{cite journal | vauthors = Lillemoe KD, Johnson LF, Harmon JW | title = Role of the components of the gastroduodenal contents in experimental acid esophagitis | journal = Surgery | volume = 92 | issue = 2 | pages = 276–84 | date = August 1982 | pmid = 6808683 }}</ref> Pepsin remains in the larynx (pH 6.8) following a gastric reflux event.<ref name="pmid15564833"/><ref name="pmid16466100"/> While enzymatically inactive in this environment, pepsin would remain stable and could be reactivated upon subsequent acid reflux events.<ref name="pmid17417109"/> Exposure of laryngeal mucosa to enzymatically active pepsin, but not irreversibly inactivated pepsin or acid, results in reduced expression of protective proteins and thereby increases laryngeal susceptibility to damage.<ref name="pmid17417109"/><ref name="pmid15564833"/><ref name="pmid16466100"/>

Pepsin may also cause mucosal damage during weakly acidic or non-acid gastric reflux. Weak or non-acid reflux is correlated with reflux symptoms and mucosal injury.<ref name="pmid15531244">{{cite journal | vauthors = Tamhankar AP, Peters JH, Portale G, Hsieh CC, Hagen JA, Bremner CG, DeMeester TR | title = Omeprazole does not reduce gastroesophageal reflux: new insights using multichannel intraluminal impedance technology | journal = Journal of Gastrointestinal Surgery | volume = 8 | issue = 7 | pages = 890–7; discussion 897–8 | date = November 2004 | pmid = 15531244 | doi = 10.1016/j.gassur.2004.08.001 | s2cid = 6574429 }}</ref><ref name="pmid15180717">{{cite journal | vauthors = Kawamura O, Aslam M, Rittmann T, Hofmann C, Shaker R | title = Physical and pH properties of gastroesophagopharyngeal refluxate: a 24-hour simultaneous ambulatory impedance and pH monitoring study | journal = The American Journal of Gastroenterology | volume = 99 | issue = 6 | pages = 1000–10 | date = June 2004 | doi = 10.1111/j.1572-0241.2004.30349.x | pmid = 15180717 | s2cid = 8530885 }}</ref><ref>{{cite journal | vauthors = Oelschlager BK, Quiroga E, Isch JA, Cuenca-Abente F | title = Gastroesophageal and pharyngeal reflux detection using impedance and 24-hour pH monitoring in asymptomatic subjects: defining the normal environment | journal = Journal of Gastrointestinal Surgery | volume = 10 | issue = 1 | pages = 54–62 | date = January 2006 | pmid = 16368491 | doi = 10.1016/j.gassur.2005.09.005 | s2cid = 41176354 }}</ref><ref name="pmid16556669">{{cite journal | vauthors = Mainie I, Tutuian R, Shay S, Vela M, Zhang X, Sifrim D, Castell DO | title = Acid and non-acid reflux in patients with persistent symptoms despite acid suppressive therapy: a multicentre study using combined ambulatory impedance-pH monitoring | journal = Gut | volume = 55 | issue = 10 | pages = 1398–402 | date = October 2006 | pmid = 16556669 | pmc = 1856433 | doi = 10.1136/gut.2005.087668 }}</ref> Under non-acid conditions (neutral pH), pepsin is internalized by cells of the upper airways such as the larynx and hypopharynx by a process known as [[receptor-mediated endocytosis]].<ref name="pmid18217514">{{cite journal | vauthors = Johnston N, Wells CW, Blumin JH, Toohill RJ, Merati AL | title = Receptor-mediated uptake of pepsin by laryngeal epithelial cells | journal = The Annals of Otology, Rhinology, and Laryngology | volume = 116 | issue = 12 | pages = 934–8 | date = December 2007 | pmid = 18217514 | doi = 10.1177/000348940711601211 | s2cid = 32026624 }}</ref> The receptor by which pepsin is endocytosed is currently unknown. Upon cellular uptake, pepsin is stored in intracellular vesicles of low pH at which its enzymatic activity would be restored. Pepsin is retained within the cell for up to 24 hours.<ref name="pmid20860281">{{cite journal | vauthors = Johnston N, Wells CW, Samuels TL, Blumin JH | title = Rationale for targeting pepsin in the treatment of reflux disease | journal = The Annals of Otology, Rhinology, and Laryngology | volume = 119 | issue = 8 | pages = 547–58 | date = August 2010 | pmid = 20860281 | doi = 10.1177/000348941011900808 | s2cid = 44531943 }}</ref> Such exposure to pepsin at neutral pH and endocyctosis of pepsin causes changes in gene expression associated with inflammation, which underlies signs and symptoms of reflux,<ref name="pmid19861190">{{cite journal | vauthors = Samuels TL, Johnston N | title = Pepsin as a causal agent of inflammation during nonacidic reflux | journal =  	Otolaryngology–Head and Neck Surgery | volume = 141 | issue = 5 | pages = 559–63 | date = November 2009 | pmid = 19861190 | doi = 10.1016/j.otohns.2009.08.022 | s2cid = 23855277 }}</ref> and tumor progression.<ref name="pmid11229684">{{cite journal | vauthors = Balkwill F, Mantovani A | title = Inflammation and cancer: back to Virchow? | journal = Lancet | volume = 357 | issue = 9255 | pages = 539–45 | date = February 2001 | pmid = 11229684 | doi = 10.1016/S0140-6736(00)04046-0 | s2cid = 1730949 }}</ref> This and other research<ref name="pmid10722017">{{cite journal | vauthors = Adams J, Heintz P, Gross N, Andersen P, Everts E, Wax M, Cohen J | title = Acid/pepsin promotion of carcinogenesis in the hamster cheek pouch | journal = Archives of Otolaryngology–Head & Neck Surgery | volume = 126 | issue = 3 | pages = 405–9 | date = March 2000 | pmid = 10722017 | doi = 10.1001/archotol.126.3.405 | doi-access =  }}</ref> implicates pepsin in carcinogenesis attributed to gastric reflux.

Pepsin in airway specimens is considered to be a sensitive and specific marker for laryngopharyngeal reflux.<ref name="pmid16094128">{{cite journal | vauthors = Knight J, Lively MO, Johnston N, Dettmar PW, Koufman JA | title = Sensitive pepsin immunoassay for detection of laryngopharyngeal reflux | journal = The Laryngoscope | volume = 115 | issue = 8 | pages = 1473–8 | date = August 2005 | pmid = 16094128 | doi = 10.1097/01.mlg.0000172043.51871.d9 | s2cid = 2196018 }}</ref><ref name="pmid20392035">{{cite journal | vauthors = Samuels TL, Johnston N | title = Pepsin as a marker of extraesophageal reflux | journal = The Annals of Otology, Rhinology, and Laryngology | volume = 119 | issue = 3 | pages = 203–8 | date = March 2010 | pmid = 20392035 | doi = 10.1177/000348941011900310 | s2cid = 29266257 }}</ref> Research to develop new pepsin-targeted therapeutic and diagnostic tools for gastric reflux is ongoing. A rapid non-invasive pepsin diagnostic called Peptest is now available which determines the presence of pepsin in saliva samples.<ref>{{cite journal | vauthors = Bardhan KD, Strugala V, Dettmar PW | title = Reflux revisited: advancing the role of pepsin | journal = International Journal of Otolaryngology | volume = 2012 | pages = 646901 | year = 2012 | pmid = 22242022 | pmc = 3216344 | doi = 10.1155/2012/646901 | doi-access = free }}</ref>