In conclusion, we have provided functional in vitro evidence that EP2/EP4 are potential therapeutical targets having a role in the Z-VAD-FMK regulation of MC degranulation that may prevent EIB in asthma by nullifying the hyperosmolar-induced degranulation of airway mast cells. Upon generation of a DNA damage, cells activate a cascade of events known as DNA damage response to coordinate the DNA repair and the transient arrest of cell-cycle progression until DNA damage has been removed in full. If the DNA damage remains unrepaired, cells enter in a permanent state known as cellular senescence, associated with a persistently active DDR. DDR activation has been observed upon different senescence inducing stimuli; these include genotoxic agents, telomere shortening or dysfunction and oncogene activation. Cellular senescence has been causally linked with organismal aging and DDR activation has been demonstrated in vivo in tissues of aging mammals including primates and in human skin naevi, which are composed of oncogene-induced senescent melanocytes. DDR activity is causally involved both in the establishment and in the maintenance of cellular senescence triggered by different stimuli, as demonstrated by the loss of senescence traits upon experimental inactivation of DDR pathways. However, it has also been reported that while early in the senescence process DDR can be readily detected in the majority of the cells, after prolonged establishment of cellular senescence, detection of markers of DDR activation is reduced. This has led some investigators to conclude that markers of an activated DDR are detectable only in “senescing” cultures of human fibroblasts and that they are then lost when cultures are “fully senescent”. Therefore, it is still controversial whether cellular senescence establishment and maintenance is intrinsically and causally associated with persistent DDR activation or, instead, it is established by an initial burst of DDR signaling whose continuous activity might not be necessary for the maintenance of a senescent state. In order to address this important question, we performed long-term analyses of DDR activation in different types of human fibroblast cell strains having different characteristics and undergoing cellular senescence by different mechanisms. These investigations allowed us to conclude that DDR signaling is indeed maintained even for years in stable cultures of senescent cells. However, when culture conditions do not allow the longterm survival of senescent cells, DDR signaling is apparently diminished, but this is in fact due to the progressive loss of cell viability that may bias against the survival of the most damaged cells. Therefore, we conclude that DDR is persistently active even months after entry into cellular senescence. Cellular senescence can be a very stable condition and anecdotic evidence indicates that senescent cells can be maintained in culture for years. To extend our observations, we searched for and gained access to two independent batches of human skin fibroblasts, named cen2 and cen3, which had undergone telomere-initiated replicative senescence three years before our analysis and have been kept in culture under standard tissue culture conditions since then. As expected, virtually all cells stained strongly positive for senescence-associated betagalactosidase activity, a marker of cellular senescence and a prolonged pulse of BrdU revealed only 6–11 BrdU-positive nuclei among 15000 plated cen2 or cen3 cells, indicating that less than 0.08% of cells were still proliferating.