Restoration of the normal Clara cell phenotype after chronic allergic inflammation

Abstract

Bronchiolar Clara cells play a critical role in lung homoeostasis. The main goal of this study was to evaluate the effects of chronic allergy on these cells and the efficacy of budesonide (BUD) and montelukast (MK) in restoring their typical phenotypes after ovalbumin-induced chronic allergy in mice. Chronic allergy induced extensive bronchiolar Alcian blue-periodic acid-Schiff (AB/PAS)-positive metaplasia. In addition, cells accumulated numerous big electron-lucent granules negative for Clara cell main secretory protein (CC16), and consequently, CC16 was significantly reduced in bronchoalveolar lavage. A concomitant reduction in SP-D and CYP2E1 content was observed. The phenotypic changes induced by allergy were pharmacologically reversed by both treatments; MK was more efficient than BUD in doing so. MK decreased AB/PAS reactivity to control levels whereas they remained persistently elevated after BUD. Moreover, most non-ciliated cells recovered their normal morphology after MK, whereas for BUD normal cells coexisted with 'transitional' cells that contained remnant mucous granules and stained strongly for CC16 and SP-D. Glucocorticoids were also less able to reduce inflammatory infiltration and maintained higher percentage of neutrophils, which may have contributed to prolonged mucin expression. These results show that chronic allergy-induced mucous metaplasia of Clara cells affects their defensive mechanisms. However, anti-inflammatory treatments were able to re-establish the normal phenotype of Clara cell, with MK being more efficient at restoring a normal profile than BUD. This study highlights the role of epithelial cells in lung injuries and their contribution to anti-inflammatory therapies.

Protective phenotypes of club cells and alveolar macrophages are favored as part of endotoxin-mediated prevention of asthma

“…Previous findings of our group revealed an alteration of the CC defensive mechanisms, including the CCSP and SP-D content, along with the mucus metaplasia establishment. 18,19 In this study, LPS exposition prior to allergen challenge resulted in a meaningful reduction in the mucus hypersecretion, which correlated with decreased EGFR expression. Indeed, CC achieved a better preservation of their typical phenotype, including CCSP and SP-D content together with the increase in TLR4 and TNFa expression.…”

“…19 Briefly, after being blocked, the sections were Diaminobenzidine (DAB, Sigma-Aldrich), which was used as a chromogen substrate, and the bronchioles (900-1700 mm diameter) were analyzed and photomicrographs  400 were taken.…”

“…[15][16][17] Related to this, our previous findings indicated that CC mucous metaplasia leads to a marked decrease in CCSP and SP-D secretion. 18,19 In common with epithelial cells, AM are also plastic cells involved in the first line of defense against inhaled agents, which are endowed with a high phagocytic and microbicidal potential and a lower expression of MHC class II molecules. 4,20 Th2 inflammation induces a wound-healing phenotype, named alternatively activated macrophages (AAM), which amplifies asthma remodeling.…”

Fibrosis and Damage Markers in Occupational Interstitial Lung Diseases

“…According to the literature, when exposed to toxic factors, low levels of CC16 in the serum may be caused by a decrease in the number of Clara cells, changes in the permeability of the alveolar epithelium, and potentially by reduced expression of CC16 in airway epithelium. 5,6 In the PC group, the serum concentration of alveolomucin (40.89±3.49 U/mL, p<0.001 versus ETA, EAA), KL-6 (429.60±145.10 U/mL, p<0.002 versus EAA, p<0.005 versus ETA) and CC16 (7.541±0.87 ng/mL, p<0.02 versus EAA, p<0.005 versus ETA) was significantly lower than active occupational alveolitis. In remission, KL-6 and CC16 levels were not different from PC.…”

Clara cell protein 16 release from the nasal mucosa in allergic rhinitis, chronic rhinosinusitis, and exposure to air pollutants

“…In patients with PAR, nasal fluid CC16 positively correlated with nasal nitric oxide (NO) levels, and the two negatively correlated with mast cell counts in the nasal mucosal lining, which points to the protective role of both CC16 and NO, as they inhibit cell chemotaxis in chronically inflamed nasal mucosa (12). In an experimental investigation, Roth et al (13) demonstrated that long-term exposure to perennial allergens caused most Clara cells to transform into large secretory goblet cells, which resulted in lower CC16 and higher mucus production in the bronchoalveolar mucosa. Studies with patients with PAR and CRSwNP demonstrated similar inhibition of CC16 nasal mucosa production by eosinophil inflammation (11,14).…”