growth factor pathway proteins are significantly suppressed

in eosinophilic CRSwNP(422). Elevated TRPV1 levels in comorbid

asthma and allergy may have a function in CRSwNP (259). Substance
P was released from the sensory neurons and human/
murine nasal epithelial cells within 15 minutes of local TLR7 stimulation (
423), highlighting a novel role for sensory neuropeptides

as acute and local mediators of pathogen-driven inflammation,

rapidly priming innate immune defences in the airway. Neurotrophin-
3, a neurotrophic factor, was associated with CRSwNP
compared to controls(424). Neuronal dysfunction has been proposed
as an endotype for chronic rhinitis, but it is also likely that
these mechanistic pathways play a role in CRS as well (425).
5.2.2.4. Conclusions and future needs
A wide array of exogenous agents are inhaled through the nose
and interact with the sinonasal mucosa, a process that begins
at birth with rapid colonization by viruses, bacteria and fungi.
In healthy individuals, the mucosa serves as a relative barrier
limiting and regulating environmental interaction with the host
immune system, a process that is likely beneficial to the host in
a number of ways including development of tolerance, generation
of important metabolites and competitive inhibition of
pathogens(136). In healthy patients, when the barrier is breached,
a specific, self-limited physiologic immune response is generated,
characterized by a cellular and cytokine repertoire targeting
the pathogen(s). Although the in vivo response is much more
complex, at the basic level Type 1 immunity targets viruses,
Type 2 parasites and Type 3 extracellular bacteria and fungi,
resolving with elimination of the pathogens and restoration of
barrier integrity. In cases of CRS, the current working hypothesis
is that barrier penetration, possibly by an alternate mechanism,
results in a chronic inflammatory response that still utilizes the
Type 1, 2 or 3 pathways alone, or in combinations. CRS immune
responses are: a) dynamic and heterogeneous, likely exhibiting
plasticity; b) not self-limiting (remaining active for months to
years); c) not clearly matched to the inciting agents; and d) often
associated with various types of tissue remodeling, presumably
linked to the pattern of inflammation. There is no evidence at
this point for a specific dominant pathogen and, based on the
limited evidence currently available, the immunologic response
is polyclonal, targeting antigens derived from multiple organisms,
including nasal bacteria(168, 172). In some severe, recurrent
CRS cases, self antigens are also targeted but the development
of autoimmunity is mostly viewed as a phenomenon secondary
to the chronic process(367).
Many questions remained unanswered including the mechanism
for initiation of CRS, but presumably this results from a
combination of environmental stressors, genetic su