Reduced Airway Inflammation and Remodeling in Parallel with Mucin 5AC Protein Expression Decreased by S-Carboxymethylcysteine, a Mucoregulant, in the Airways of Rats Exposed to Sulfur Dioxide

Abstract

Background: Human obstructive airway diseases are histopathologically characterized by inflammatory cell infiltration, goblet cell hyperplasia, and mucus hypersecretion in airways. We prepared a rat model of airway injury by exposure of sulfur dioxide (SO₂) and then evaluated the effects of S-carboxymethylcysteine (S-CMC), a mucoregulant. Methods: Rats were exposed to SO₂ gas for 44 days and orally given S-CMC at 250 mg/kg, twice daily, from 21 to 44 days of exposure for histopathological and immunohistochemical evaluation. Results: SO₂ exposure induced inflammatory cell infiltration and mucus cell increase in rat airways. S-CMC treatment significantly decreased this inflammatory cell infiltration in proximal and peripheral airways. Morphometrically, SO₂ exposure significantly increased the number of Alcian blue (pH 2.5)- and periodic acid-Schiff (AB/PAS)-positive cells in rat airways (11.8 × 10^–2 cell/nuclear profiles per micrometer basement membrane) compared to normal rat airways (1.6 × 10^–2 cell/nuclear profiles per micrometer basement membrane). S-CMC treatment significantly decreased the number of AB/PAS-positive cells (4.4 × 10^–2 cell/nuclear profiles per micrometer basement membrane, p < 0.01 vs. SO₂-exposed rats). Immunohistochemically, SO₂ exposure increased the expression of mucin 5AC (MUC5AC) protein in the airway epithelium of rats, but S-CMC treatment inhibited the increase. Conclusions: The increased mucus cells and MUC5AC protein expression seem associated with SO₂-induced airway inflammation in rats. The fact that S-CMC suppresses airway inflammation and the increase in mucus cells and MUC5AC protein expression suggests that this mucoregulant may be advantageous in the treatment of inflammatory airway diseases with goblet cell hyperplasia.

Carbocisteine inhibits rhinovirus infection in human tracheal epithelial cells

“…Furthermore, bafilomycin A 1 , a blocker of vacuolar H + -ATPase, reduces endosome acidification [17] in airway epithelial cells and reduces production of reactive oxygen species in alveolar macrophages [30], suggesting a relationship between antioxidant effects and the reduced acidification of endosomes. Reduced production of inflammatory cytokines and ICAM-1 by carbocisteine, in the present study, also suggests anti-inflammatory effects of carbocisteine, as shown in previous studies that demonstrated reduced IL-6 concentrations in breath condensate caused by SCMC-Lys in COPD patients [10] and reduced numbers of inflammatory cells in airways in rats caused by SCMC-Lys [11] and SCMC [12]. In summary, this is the first report that a mucolytic drug, carbocisteine, inhibits infection by rhinovirus 14 and decreases the susceptibility of cultured human tracheal epithelial cells to rhinovirus 14 infection, probably through the inhibition of intercellular adhesion molecule-1 expression and endosomal acidification.…”

“…SCMC-Lys reduces the concentration of IL-6 in the breath condensate of acute COPD patients [10], suggesting anti-inflammatory effects of SCMC-Lys in COPD. SCMC-Lys [11] and Scarboxymethylcysteine (SCMC) [12] also reduce the number of inflammatory cells in airways after exposure to cigarette smoke or sulphur dioxide in rats, and inhibit neutrophil activation [13]. These findings are suggestive of anti-inflammatory effects of mucolytic drugs, including carbocysteine.…”

Cellular and Molecular Biology of Airway Mucins

“…Both viral and bacterial components directly upregulated mucin gene expression (Shimizu et al, 1996; Mata et al, 2011). Inhalation of sulfur dioxide, ozone, cigarette smoke, or acorlein upregulated Muc5ac expression, stimulated neutrophilic inflammation, and induced GCM in rat and mouse airway epithelia (Wagner et al, 2003; Sueyoshi et al, 2004; Bein and Leikauf, 2011; Nie et al, 2012). Chemical irritant-induced airway inflammation appeared to mediate the development of GCM.…”

Inhibitory effects of carbocisteine on type A seasonal influenza virus infection in human airway epithelial cells

“…antioxidant effects (39), reduction of mucin 5AC protein production (27), and improvement of airway mucociliary transport (20). Mucolytic agents are also suggested to have clinical benefits in reducing the frequency of exacerbations and improvement of quality of life in patients with chronic obstructive pulmonary disease (COPD) (40).…”