Overexpression of Substance P in pig airways increases MUC5AC through an NF‐kβ pathway

Abstract

Substance P (SP) is a tachykinin that regulates airway mucous secretion in both health and disease. Our study aimed to determine whether overexpression of SP without pre‐existing inflammation was sufficient to induce changes in mucin secretion and transport in small airways. Utilizing porcine precision‐cut lung slices, we measured the impact of AAV‐mediated overexpression of SP on airway physiology ex vivo. Immunofluorescence signal intensity for MUC5AC was significantly increased in SP‐overexpressed precision‐cut lung slices compared to GFP controls. No difference in MUC5B signal intensity between treatments was detected. SP‐overexpressed precision‐cut lung slices also exhibited decreased IL10 mRNA, an important inhibitor of mucous cell metaplasia. Overt deficits in mucociliary transport were not noted, though a trend for decreased mean transport speed was detected in methacholine‐challenged airways overexpressing SP compared to GFP controls. Pharmacologic inhibition of the NF‐kβ pathway abrogated the effects of overexpression of SP on both MUC5AC and IL10. Collectively, these data suggest that overexpression of SP in the absence of existing inflammation increases MUC5AC via activation of the NF‐kβ pathway. Thus, these data further highlight SP as a key driver of abnormal mucous secretion and underscore NF‐kβ signaling as a pathway of potential therapeutic intervention.

Nociceptor neurons promote IgE class switch in B cells

“…In turn, these neurons locally release neuropeptides that promote conventional type 2 dendritic cell–mediated allergen trafficking to the lymph nodes ( 41 ), increase T H 2 and ILC2 polarization ( 6 , 7 , 42 ), and induce mast cell degranulation ( 27 ). Substance P, one such neuropeptide, is increased in asthmatic patients’ lungs and promotes bronchial hyperresponsiveness ( 6 ), mucin imbalance ( 20 , 43 , 44 ), and coughing ( 45 ). Because these neurons detect immune complexes between IgE and allergens, and the genetic elimination of FcεR1 from TRPV1 + sensory neurons prevents the development of type 2 inflammation ( 13 , 16 , 46 , 47 ), we postulate that the neurons contribute to humoral responses.…”

Role of Sensory Nerves in Pulmonary Fibrosis

“…Substance P is synthesized in cell bodies within the dorsal root ganglia and transported in vesicles, along with CGRP and ATP, via axons to sensory nerve terminals [ 28 , 45 ]. Following its release, substance P elicits its effect by binding to neurokinin-1 receptors (NK1Rs) coupled to G-protein signaling in airways [ 46 ] and in vascular ECs [ 28 , 47 ]. Substance P does not undergo reuptake and, therefore, continues exerting its effects until undergoing enzymatic degradation [ 45 ].…”

“…CGRP itself is not an effective mediator of bronchoconstriction but can attenuate substance P-induced bronchoconstriction with a greater effect on distal (smaller) airways than proximal (larger) airways [ 76 ]. Substance P plays a key role in airway contraction [ 77 ] and mucus secretion [ 46 ]. Purinergic signaling plays a key role in pulmonary inflammation signaling through molecules such as interleukin 1α [ 42 ] and is important for mucociliary clearance [ 40 ].…”

Post COVID-19 complications and follow up biomarkers

“…Nuclear factor kappa B (NF-kB) pathways were reported to be involved in the SP overexpression in airways causing inammation and inhibition of Interlukin10 (Sponchiado et al, 2020). 107 Cytokine storms were aroused in the COVID-19 infection and contributed to airway inammation (Riffat, 2021). 108 The cytokine storm syndrome is reported in critically ill COVID-19 patients and presents with high inammatory mediators, systemic inammation and multiple organ injury or failure.…”