In IPF the senescent phenotype seems to mainly affect the epithelial precursors of alveolar tissue (type-II pneumocytes), thus preventing a correct epithelial renewal at anatomical sites where mechanical stress and alveolar damage are expected to be maximal (lower/peripheral lung zones) [
56,
79]. Pneumocyte loss is followed, in this pathogenic scheme of IPF, by attempted tissue regeneration and exaggerated release of molecular signals (Wnt and Notch) triggering fibroblast proliferation and migration. Several human and experimental studies have confirmed that the Wnt-pathway is abnormally activated in IPF, and this notion is included in recent pathogenic models for IPF [
17,
56,
80‐
82]. The relevance of abnormal Wnt-signalling activation in IPF is confirmed by the up-modulation of various Wnt-pathway molecular targets observed in IPF (MMP7, cyclin-D1 and others) [
80], as well as by the demonstration that experimental fibrosis can be attenuated by the Wnt/β-catenin pathway blockade [
83]. Accordingly, perturbation of the Wnt-pathway is directly related to abnormal myofibroblast activation and epithelial-mesenchymal transition [
84], and mesenchymal precursor cells can further amplify the fibrotic process by triggering the Wnt-pathway [
85]. Myofibroblasts are key elements in IPF and their differentiation can be also triggered by loss of telomerase activity [
86]. Concurrently, Notch-signalling is crucial for myofibroblast differentiation and alveologenesis, and can also contribute to the differentiation of airway basal precursor cells [
87].
But how can senescent pneumocytes abnormally trigger these pathways in IPF? Signals provided by the milieu of damaged alveolar cells can trigger a variety of reparative mechanisms, including the recruitment and stimulation of endogenous and exogenous progenitors [
88], and it is possible to expect a severe derangement of this process in senescent alveoli. In several systems it has been demonstrated that cell senescence can trigger a "senescence-associated secretory phenotype", that is able to stimulate the production of proliferative and profibrotic mediators, including growth factors, cytokines, chemokines, and metalloproteinases [
89], acting on neighbouring epithelial and mesenchymal cells thus perturbing their physiological crosstalk as previously proposed [
16,
17]. In line with this assumption, both Wnt- and Notch pathways have been shown to be activated by cell senescence, and epithelial mesenchymal transition and mobilization of beta-catenin are among the features characterising the senescence-related hyper-secretive phenotype [
88‐
95]. In senescent alveoli mesenchymal and epithelial precursors could be the target of this deranged cascade of stimulatory signals, with eventual myofibroblast activation and bronchiolar remodelling. Senescent myofibroblasts in turn could be also stimulated to acquire a secretive phenotype, and this effect is likely to occur at short distance from damaged areas, thus contributing to produce the patchy distortion of pulmonary tissue characterising the "usual interstitial pneumonia" (UIP) pattern. Recently, we demonstrated that fibroblast foci are mainly located within micro-honeycombing lesions in IPF, at sites where basal cell airway precursors abnormally show over-expression of molecules involved in cell-motility (laminin-5 γ-2-chain and heath shock protein 27), and molecules that can be directly related to cellular senescence including p21
waf1 and p53 [
96,
97]. Small airways and alveolar epithelia are characterised by quite different renewal strategies at the molecular level, and telomere dysfunction and cellular senescence could be expected to act differently in these two compartments. Bronchiolar progenitors, located in the basal layer [
98], express high levels of ΔN-p63+, a potent anti-apoptotic mediator that can interfere with the p53/p21 pathway and may potentially contrast cell senescence in basal cells [
96,
99]. Bronchiolar abnormal proliferation and honeycomb changes are common in IPF and can be considered as consequence of divergent behaviours in proximal and distal lung compartments [
15,
56,
99]. In our view, exaggerated autocrine and paracrine activation of the Wnt- and Notch-pathways can in part explain honeycomb cyst formation, since proliferation and differentiation of basal cell precursors in small airways depend on the correct expression of these signalling pathways [
98]. Further contribute to the aberrant bronchiolar proliferation and honeycomb cyst formation in IPF is likely provided by abnormalities affecting the production of airway mucins, as recently demonstrated [
70,
100]. Interestingly, disordered mucin production with increased MUC5B forms is also observed in the airway of COPD patients [
101].