Nociceptin/Orphanin Fq in inflammation and remodeling of the small airways in experimental model of airway hyperresponsiveness

Abstract

It is widely recognized that airway inflammation and remodeling play a key role not only in the central airway but also small airway pathology during asthma. Nociceptin/Orphanin FQ (N/OFQ), an endogenous peptide, and its receptor N/OFQ peptide (NOP) are involved in airway hyperresponsiveness (AHR). We studied a murine model of AHR in order to understand the role of N/OFQ in the inflammation and remodeling of the small airways. Balb/c mice were sensitized to ovalbumin (OVA). At days 0 and 7 (pre-OVA sensitization) or from day 21 to 23 (post-OVA sensitization), the mice were treated intraperitoneally with N/OFQ or saline solution. After the last OVA challenge, all OVA-sensitized mice were aerosol-challenged with 1% OVA in PBS for 48 h, and then euthanized. Small airway compliance (sC_aw ) was measured and lung samples were collected for histological and molecular evaluations such as perimeter and diameter of small airway, total wall area, airway smooth muscle (ASM) thickness and number of alveolar attachments. Both pre- and post-OVA sensitization N/OFQ treatments induced: (1) increases in sC_aw ; (2) reduction of the bronchial wall thickness; (3) attenuation of the hyperplastic phase of airway smooth muscle mass; and (4) protection against loss of alveolar attachments compared with saline solution treatments. These results suggest that N/OFQ protects against inflammation, and mechanical damage and remodeling of small airways caused by OVA sensitization, suggesting a new potential therapeutic target for asthma.

Keywords: Airway remodeling; Asthma; N/OFQ; Small airways.

Figure 1

Experimental protocols. Pre‐OVA sensitization (A) and post‐OVA sensitization (B) treatments with N/OFQ.

Figure 2

Measurements of airway compliance. Mice treated with N/OFQ show an increase in airway compliance compared to untreated OVA‐sensitized group. Data in naive, OVA alone, N/OFQ alone, pre‐ and post‐ OVA sensitization N/OFQ‐treated groups are represented mean ± SEM. * P < 0.001 versus OVA; ^# P < 0.001 versus naïve.

Figure 3

Measurements of perimeter (A) and diameter (B) of the small airways. N/OFQ treatments do not alter significantly the perimeter and diameter of the small airways. Data in naive, OVA alone, N/OFQ alone, pre‐ and post‐ OVA sensitization N/OFQ‐treated groups are represented as mean ± SEM.

Figure 4

Measurements of wall thickness of the small airways. Both pre‐ and post‐OVA sensitization N/OFQ treatments significantly reduced the total wall area of the small airways compared to OVA‐sensitized mice not treated with N/OFQ. Data in naive, OVA alone, N/OFQ alone, pre‐ and post‐ OVA sensitization N/OFQ‐treated groups are represented as mean ± SEM. *P < 0.001.

Figure 5

Measurements of airway smooth muscle mass (ASM). In (A naïve, B OVA alone, C N/OFQ alone, D OVA+N/OFQ pre, E OVA+N/OFQ post) representative pictures of Trichrome‐stained lung sections in the 5 experimental groups are shown. Blu Arrows indicate bronchial wall thickening; red arrows indicate airway remodeling. (F) shows the quantification of airway smooth muscle mass (ASM) in the five experimental groups. N/OFQ treatment attenuated the increase of airway smooth muscle mass observed in OVA‐sensitized mice not treated with N/OFQ. Data in naive, OVA alone, N/OFQ alone, pre‐ and post‐ OVA sensitization N/OFQ‐treated groups are represented as mean ± SEM. *P < 0.001.

Figure 6

Quantification of alveolar attachments in the five experimental groups. Both pre‐ and post‐OVA sensitization N/OFQ treatments significantly restored alveolar attachments. Data in naive, OVA alone, N/OFQ alone, pre‐ and post‐ OVA sensitization N/OFQ‐treated groups are represented as mean ± SEM. *P < 0.001.