paul ehrlich described mast cells for the first time more than 100 years ago , through their characteristic metachromatic staining with aniline dyes .
he noticed that these cells had abundant and dense granules ; he assumed that the granules were caused by excessive feeding .
these cells were abundant in areas near tumors , so ehrlich postulated that they played a role in the protection against cancer . since then , many functions were proposed for mast cells in the regulation of organism homeostasis , but experimental evidence to support these assumptions was lacking .
the discovery of mice with a diminished number of mast cells , and their reconstitution with bone marrow - derived mast cells , provided a tool to test these hypotheses and to extend our knowledge about the functions of mast cells in the body .
mast cells derive from hematopoietic precursors that are released from the bone marrow into the bloodstream and are recruited to connective tissues , where they complete their differentiation .
mast cells can live for months in the tissues , where they proliferate in response to different signals .
the tissues that usually contain abundant mast cells are those that interact with the external environment ( the skin and the gastrointestinal , urogenital and respiratory tracts ) , where mast cells are located near lymphatics and blood vessels , or close to nerve terminals or smooth muscle cells .
the morphology of mast cells depends on their anatomical location , ranging from rounded - shaped to elongated forms , when they are associated with blood vessels .
their size ranges from 5 to 20 m and their cytoplasm contains abundant granules , with approximately 1,000 granules per cell .
mast cell granules contain several chemical mediators , including histamine , proteoglycans , cytokines like tnf- and il-4 , and neutral proteases like tryptase , chymase , carboxypeptidase and cathepsin g. granule composition is not identical in all mast cells : human mast cells that reside in the skin have all the aforementioned neutral proteases , while epithelial lung mast cells have significant amounts of tryptase , but lack chymase , carboxypeptidase and cathepsin g. accordingly , human mast cells are classified as either mct ( skin ) or mt ( lung ) .
in addition to these pre - formed mediators that are stored in granules , mast cells are efficient producers of lipid - derived mediators , such as platelet - activating factor ( paf ) and the arachidonic acid - derived prostaglandins , thromboxanes and leukotrienes .
mast cells are also efficient producers of many soluble protein mediators , such as cytokines , chemokines and antimicrobial peptides [ 6 , 7 ] .
activation of mast cells induces the release of one group of these mediators or of all of them , depending on the triggering signal .
however , not all the mediators are released at the same time : chemical mediators from the granules are secreted in seconds after stimulation , while lipid - derived mediators are produced minutes after activation and protein soluble mediators are detected hours after the initial trigger .
mast cells produce abundant histamine , and since the discovery that histamine is a crucial element for the development of type i hypersensitivity , the relevance of mast cells for the initiation of allergic reactions was underscored . by far ,
the most studied mast cell - activating signal is the cross - linking of fcri by ige and allergen , an event that leads to mast cell degranulation and to the release of several chemical mediators that cause the immediate inflammatory response characteristic of type i hypersensitivity . as a consequence ,
much of our knowledge of mast cell biology is biased towards their participation in this pathological process .
type i hypersensitivity , or allergic inflammation , is an acute inflammation produced in sensitized individuals when they are exposed to the corresponding allergen .
sensitization occurs when dendritic cells capture an allergen in the airways , migrate to the regional lymph nodes and activate nave t cells . in the presence of il-4 ( derived from mast cells , eosinophils or innate lymphoid cells ) ,
these cytokines promote class - switch recombination in b cells , which then produce allergen - specific ige .
ige binds to fcri on mast cells , which are then primed for activation upon re - exposure to the allergen . during this subsequent exposure , the allergen cross - links fcri - bound ige , which leads to mast cell activation and degranulation .
the mediators derived from activated mast cells cause bronchoconstriction , vasodilation , increased vascular permeability , mucus production and recruitment of eosinophils and neutrophils .
repetitive or persistent exposure to the allergen leads to a chronic allergic inflammation , which causes tissue injury and remodeling ; this last process includes the severe narrowing of the airway lumen observed in asthmatic patients .
however , mast cells are conserved in different groups of vertebrates , and from an evolutionary point of view , it makes no sense that humans should have conserved a cell population that causes a harmful and even deadly response if it conferred no evolutionary advantage .
so , in the last years , the study of mast cells has been redirected to investigate their participation in processes such as innate immune response to pathogens , regulation of inflammation , wound healing and regulation of tumoral growth . in this review ,
we focus on the mechanisms used by mast cells in the lung to keep the proper function of this vital organ .
mast cells have a vast collection of cell membrane receptors that allow them to sense the external environment . a set of these receptors are pattern recognition receptors ( prr ) that recognize pathogen associated molecular patterns ( pamp ) .
these receptors are crucial for the initiation of the innate immune response , and they are classified in five groups : toll - like receptors ( tlr ) , nod - like receptors ( nlr ) , c - type lectin receptor ( clr ) , rig - i - like receptor ( rir ) and scavenger receptors .
mast cells express at least one receptor of each group , allowing them to recognize a multitude of microorganisms , including viruses , bacteria , protozoa , fungi and multicellular parasites [ 13 - 23 ] ( fig .
1 ) . the first evidence that mast cells are crucial elements of the immune response to pathogens came from a study of the infection of the rat gastrointestinal tract with multicellular parasites .
there are few studies that investigate if mast cells play a role in the containment of parasitic diseases in the lungs .
one of the firs studies that established a role for mast cells in fungal infections in vivo reported that , in a mouse model of infection with sporothrix schenckii , mast cell depletion decreased the severity of cutaneous lesions .
whether mast cells in the lungs plays a role in fungal infections needs to be evaluated , but in vitro experiments suggest that they do have a role , because they are activated by aspergillus fumigates .
identified for the first time that mast cells are essential for the early containment of bacterial infections in the lungs ; klebsiella pneumonie , a gram - negative bacteria that causes community - acquired pneumonia , was among the bacteria tested in this study .
the authors observed that the lung bacterial load was higher in mice deficient in mast cells , compared with wild - type mice , and this correlated with a defective recruitment of neutrophils to the lung .
these results indicated that mast cells did not have a direct antimicrobial activity , but they induced inflammation through tnf- , which allowed the recruitment of neutrophils .
mast cells also participate in the immune response to mycoplasma pneumoniae , a bacteria that is among the smallest free - living organisms and lacks a classical bacterial cell wall .
airway infection of mice deficient in mast cells induced faster weight loss , more severe pneumonia , higher mortality and increased bacterial burden in the lungs , compared with wild - type mice .
this work showed that mast cells play an important role in innate immune response against bacteria that infect lungs .
tularemia is a life - threatening disease caused by francisella tularensis , a gram - negative coccobacillus that can be spread through aerosols .
intranasal infection of wild - type mice with f. tularensis induces an increased accumulation of mast cells in the lungs .
accordingly , mast cell - deficient mice showed impaired bacterial control and a significant decrease in il-4 production .
in fact , mast cells confer protection by inhibiting bacterial entry and replication in macrophages , thus showing a different mechanism by which mast cells confer protection against bacterial infection in the lungs .
it is caused by mycobacterium tuberculosis ( mtb ) , a bacteria that has a cell wall unique among bacteria , and that infects and usually persists in the lungs .
studies with humans have shown an increase of mast cells in the lymph nodes of patients with tuberculous lymphadenitis . in vitro studies demonstrated that mtb activates mast cells , inducing degranulation , production of il-6 and tnf- and even bacterial internalization through lipid rafts [ 36 , 37 ] . moreover , in vivo experiments have suggested a role of mast cells in the containment of mtb infection . in one of the first studies , mice received c48/80 , a compound that induces mast cell degranulation , before infection with mtb .
these mice showed an altered production of cytokines and chemokines , which induced a decrease in lung inflammation and an increase in mtb load , compared with untreated mice .
a second study used tlr-2 knockout mice , which are highly susceptible to mtb infection .
when these mice received mast cells that express tlr-2 before infection with mtb , they had an improved inflammatory response , with myeloid cell recruitment and granuloma formation that correlated with increased protection against the bacilli .
these studies reinforce the notion of mast cells as crucial players of the lung innate immune response against bacterial pathogens .
cytomegalovirus is a beta - herpes virus that causes interstitial pneumonia in immunocompromised patients and is a serious problem in patients with an organ transplant .
infection of mast cell - deficient mice with cytomegalovirus is followed by high viral replication and delayed virus clearance from the lungs , compared with wild - type mice .
interestingly , this phenomenon was associated with a defective production of the chemokine ccl5 ( also known as rantes ) and a decreased recruitment of cd8 + t cells into the infected lungs , providing evidence that mast cells can recognize viral infection and induce the recruitment of essential effector cells to the site of infection in the lung .
influenza is a frequent infectious disease of the human respiratory tract , which is caused by a group of viruses from the orthomyxoviridae family ; the most common of these viruses is influenza a. these viruses have attracted attention because they are associated with pandemics that have severely affected human health , like the  spanish flu of 1918 .
interestingly , studies with this strain have reported alterations in lung architecture , which are caused by an excessive inflammatory response promoted by an uncontrolled production of inflammatory cytokines and chemokines , also known as  cytokine storm . in a mouse model of infection with a pathogenic strain of h5n1 virus ,
lung lesions were reduced if mice were treated with ketotifen , a well - known mast cell degranulation inhibitor .
moreover , mice survival was dramatically increased if mice received a combined treatment of ketotifen and oseltamivir , an antiviral drug .
these results suggest that mast cell activation correlated with pathology development during h5n1 infection , and that inhibition of mast cell activation improved host health .
recently showed that the pathology associated with influenza a virus infection is significantly decreased in mast cell - deficient mice , compared with wild - type mice .
this event is associated with a lower production of the inflammatory cytokine tnf- and the chemokines ccl2 , ccl3 , ccl4 , cxcl2 and cxcl10 in the lungs , suggesting a critical role of mast cells during the induction of the  cytokine storm .
the studies in mice described above show that mast cells play a pro - inflammatory role against bacterial and viral infections , with both beneficial and detrimental effects . on the one hand , mast cells are critical for the innate immune response because they recruit effector cells that are fundamental for the containment of the pathogens during the early stages of infection ; this event has been observed in other organs besides the lungs . on the other hand , excessive mast cell activation by pathogens
can lead to damage and loss of lung function , as evinced by influenza studies .
this excessive mast cell activation has also been observed in calves with paroxystic respiratory distress syndrome caused by bovine respiratory syncitial virus .
recent evidence indicates that mast cells also play a predominant role in the development of pathology during dengue virus infection .
st john a , et al . observed a direct correlation between the serum levels of chymase and the severity of dengue disease in humans ; interestingly , treatment of mice with drugs that block mast cell degranulation or with an antibody that blocks leukotriene receptors improved the vasculopathy associated with dengue virus infection .
these studies point to mast cells as a new therapeutic target to limit the damage provoked by excessive inflammation during infectious diseases , such as influenza and dengue .
in contrast with their classical pro - inflammatory function , it has been reported that mast cells can produce significant amounts of anti - inflammatory cytokines , like il-10 . mast cell - produced il-10 plays a crucial role in limiting the sterile inflammation provoked by allergic contact dermatitis or uv radiation . moreover , mast cell - produced il-10 is essential for the induction of immune suppression by uv exposure [ 49 , 50 ] .
recently demonstrated that mast cells produce il-10 during in vivo bladder infection with uropathogenic escherichia coli , and this event was necessary to maintain the tolerance that allowed bacterial persistence .
this study demonstrated that microorganisms can tune mast cells into a pro - inflammatory or an anti - inflammatory program in order to subvert the immune response .
choi et al , recently showed that salmonella typhimurium injects a potent phosphatase ( sptp ) into the cytosol of mast cells ; sptp interferes with mast cell activation , even with a very strong signal ( fcri cross - linking ) .
this strategy is also exploited by yersinia pestis , which uses a phosphatase ( yoph ) with high homology to sptp to dampen mast cell activation .
pathogenic bacteria are not the only ones that effectively suppress mast cell activation , symbiotic bacteria have established a delicate balance with the immune response in order to colonize and survive in different anatomical locations of the host . breakdown of such balance usually results in the development of different pathologies .
so , it is not surprising that bacteria that usually colonize the gastrointestinal tract can regulate mast cell activation .
one of the first evidences of this strategy came from a study in which murine mast cells were stimulated with non - pathogenic e. coli from human gut .
unexpectedly , mast cells did not degranulate , even after incubation with a high bacterial load , which contrast with the swift degranulation in response to pathogenic e. coli .
furthermore , mast cells incubated with non - pathogenic e. coli lost the ability to degranulate in response to strong activators , such as a23187 and fcri cross - linking .
a similar phenomenon is also observed with lactobacillus and bifidobacterium , other probiotic and symbiotic bacteria that reside in the human gut [ 56 , 57 ] .
these results are of great interest in view of the association that exists between the use of probiotics and the prevention and treatment of several atopic diseases .
however , how this prevention and treatment are achieved is still a matter of discussion , and several mechanisms have been proposed to explain this phenomenon .
recent evidence derived from a mouse model of allergic inflammation points out that probiotics have the ability to decrease the effector phase in allergic diseases , even in the presence of specific ige antibodies .
this effect is related to the inhibition of mast cell activation through the alteration of the signaling pathways triggered by fcri .
the probiotics bifidobacterium breve and lactobacillus rhamnosus have been proposed as treatments for atopic diseases because of their potent effect in suppressing mucosal mast cell degranulation during chronic asthma .
as described in the previous section , mast cells play an essential role in the initiation of the innate immune response to pathogens .
in fact , all the cells that participate in type i hypersensitivity also participate in type 2 immune responses , which protect against infections with bacteria , viruses and multicellular parasites , and participate in the clearance of venoms , xenobiotics and irritants .type 2 innate lymphoid cells and th2 lymphocytes produce il-5 , which induces eosinophil activation and recruitment ; they also produce il-9 , which causes basophil and mast cell proliferation , and il-13 , which increases mucus production and causes fibrosis .
these cell populations constantly interact with each other : for example , type 2 innate lymphoid cells produce il-13 in response to mast cell - derived prostaglandin d2 , for which they have a specific receptor , crth2 .
since mast cells play a fundamental role during the early stages of type i hypersensitivity and also during the initiation of the innate immune response to pathogens , two important questions arise : 1 . is the response of mast cells to pathogens affected in an allergic environment ?
2 . can pathogens exacerbate type i hypersensitivity through mast cell activation ? in relation to the first question , there is considerable epidemiological evidence that asthma is a risk factor for viral and bacterial infections in the lungs , but what promotes this increased susceptibility to infections is poorly understood [ 63 - 67 ] .
a deficient immune response could explain this increased susceptibility ; for example , jung j et al . observed that asthmatic patients have decreased titers of specific pneumococcal antibodies when compared to not - asthmatic individuals .
other authors suggest a defective innate immune response as the cause of this increase in the susceptibility to infections .
several mechanisms of the innate immune response are altered in allergic patients , including a defective epithelial barrier , an excessive mucus production and a decreased production of cytokines .
however , this defective innate immune response apparently does not affect the potential of mast cell to combat infections , as is demonstrated in a mouse model of infection with mycoplasma pneumonie in an allergic setting . in relation to the second question ,
infectious diseases , especially those caused by bacteria and viruses , are considered important environmental elements that exacerbate atopic diseases .
several reports indicate that infections with bacteria and viruses that affect the respiratory tract induce the production of ige antibodies specific for bacterial or viral components .
infection of newborn mice with respiratory syncital virus ( rsv ) induces the production of virus - specific ige , and reinfection of these mice caused the airway symptoms classically associated with an allergic response .
moreover , in a mouse model of acute infection with influenza a virus , an enhanced susceptibility of the host to develop a severe allergic response to house dust - mite was described .
these studies suggest that the induction and the exacerbation of allergic responses by pathogens are associated with a modification of the environment that favors ige production ; however , another mechanism could be the exacerbation of mast cell responses .
as we discussed earlier , several bacterial and viral pathogens can induce mast cell activation , inducing a pro - inflammatory environment that recruits effector immune cells .
but how does a mast cell respond if it is simultaneously activated through fcri and through receptors that sense infection ?
early studies suggested that this double stimuli results in an increased activation of mast cells .
for example , mast cell lines activated through fcri and infected with rhinovirus release more histamine and produce more cytokines than mast cell lines activated with a single stimuli .
patients with allergic rhinitis that were experimentally infected with rhinovirus showed increased levels of histamine and eosinphil recruitment in bronchoalveolar lavages , compared with allergic individuals that were not infected with rhinovirus , suggesting an altered mast cell response .
several reports also associate infection with pathogenic bacteria with the development of an environment that facilitates or exacerbates the development of type i hypersensitivity .
for example , the pathogenic bacteria mycoplasma pneumoniae , streptococcus pneumoniae , haemophilus influenza and chlamydia pneumoniae induce the production of ige specific for bacterial components , suggesting that infection promotes an environment favorable for the development of allergies [ 76 - 78 ] .
however , little information exists about how these pathogenic bacteria could affect mast cell activation through fcri . as mentioned above , the only bacteria that have been analyzed in this respect are symbiotic bacteria from the gastrointestinal tract ( e. coli , lactobacillus spp and bifidobacterium spp ) , and these bacteria ameliorated fcri - mediated activation of mast cells , showing a therapeutic potential of these bacteria for allergic reactions in the gut .
however , other symbiotic bacteria that colonize a different environment , the vagina , apparently do not mimic this effect .
interestingly , new evidence has demonstrated that the human respiratory tract is home to several symbiotic bacteria , and environments that were thought to be sterile , like the bronchial tree , in fact contain about 2,000 bacterial genomes per cm .
moreover , asthmatic patients showed altered bacterial communities in their airways , when compared with healthy individuals , with an increase in haemophillus spp and a decrease in prevotella spp .
how these changes in microbiota airway affect the progress of type i hypersensitivity and how they alter mast cell function are fields that need to be clarified in the future .
this process develops in an orderly fashion , involving hemostasis , inflammation , cell proliferation and remodeling of the affected tissue .
alterations in the sequence , duration or intensity of any of these stages result in an impaired tissue repair that is usually reflected in the development of different pathologies .
several cell populations are involved in this process , and cells of the immune system have been implied in different steps of the process .
first , they tend to accumulate and degranulate in the wounded tissue , favoring the recruitment of effector cells , mainly neutrophils and macrophages .
the neutral proteases chymase and tryptase favor the degradation of the extracellular matrix [ 83 , 84 ] ; mast cell production of arachidonic acid - derivatives induces the production of type i collagen by fibroblasts , and mast cell production of fibroblast growth factor ( fgf ) , vascular endothelial growth factor ( vegf ) and transforming - growth factor 1 ( tgf-1 ) is considered important for fibroblast proliferation and for the formation of new blood vessels .
however , much of the knowledge about the role of mast cells during wound healing comes from studies in the skin , and little work has been performed in the lung , perhaps because of the lack of an appropriate model of lung injury , making this an interesting field that needs more research to clarify the role of mast cells in this environment .
paul ehrlich described that mast cells were abundant in areas near tumors , and assumed that these cells played an important role in the regulation of tumor growth more than 100 years ago .
since then , several reports have confirmed that mast cells usually accumulate in areas near tumors , and that this accumulation is associated with a poor prognosis in breast cancer , melanoma , hodgkin s lymphoma , oral squamous cell carcinoma , renal carcinoma , pancreatic cancer , endometrial cancer , cervical cancer , etc . in 2000 , imada et al . observed that patients with stage i non - small cell lung adenocarcinoma had an increased number of mast cells in tumor areas around blood vessels , and those patients with higher mast cells counts had a worse prognosis .
it has been suggested that tumor cells produce chemotactic mediators that attract mast cells to the tumor , but few of these chemotactic mediators have been identified .
one example is stem cell factor ( scf ) , which is produced by several tumor - derived cell lines , including a human alveolar adenocarcinoma cell line .
scf interacts with the receptor c - kit , which is expressed on mast cells , and directs their migration to the tumor .
how mast cells contribute to tumor growth is still matter of research , but three main mechanisms have been proposed : 1 ) production of tumor growth factors , 2 ) facilitation of tumor angiogenesis and 3 ) modification of the interaction between the epithelial cells and the stroma . a mast cell product that leads to the proliferation of tumor cells is histamine , which promotes the proliferation of alveolar basal carcinoma cells .
adrenomedullin - stimulated mast cells produce cytokines , such as fibroblast growth factor ( fgf ) and vascular endothelial growth factor ( vegf ) , which are associated with increased angiogenesis in vivo .
observed an increase in the number of mast cells that produce vegf in patients with lung adenocarcinoma .
in contrast with previous reports by several authors , welsh et al . reported that , in non - small cell lung adenocarcinoma , the number of mast cells in the tumor stroma had no correlation with tumor progression , while an increased number of mast cells in the tumor cell islets correlated with an improved prognosis .
these results suggested an anti - tumor role for the infiltrating mast cells , but the mechanism was not investigated , and further studies are needed to clarify this issue .
mast cells can trigger different mechanisms that contribute to the homeostasis and adequate function of the lungs .
disequilibrium in the function of mast cells can lead to pathological states , of which asthma is the most recognized .
mast cells play an essential role in type i hypersensitivity ( allergic inflammation ) and also during the early stages of the innate immune response to pathogens .
several causes , from infections to tumor growth , alter the function of mast cells ( fig .
the regulation of mast cell activation by conventional drugs or microorganisms , either pathogenic or symbiotic , opens a new window of opportunities to develop new treatments that could preserve and restore lung health .
 lungs are indispensable organs for the respiratory process , and maintaining their homeostasis is essential for human health and survival . however , 
 during the lifetime of an individual , the lungs suffer countless insults that put at risk their delicate organization and function . 
 many cells of the immune system participate to maintain this equilibrium and to keep functional lungs . among these cells , 
 mast cells have recently attracted attention because of their ability to rapidly secrete many chemical and biological mediators that modulate different processes like inflammation , angiogenesis , cell proliferation , etc . in this review , 
 we focus on recent advances in the understanding of the role that mast cells play in lung protection during infections , and of the relation of mast cell responses to type i hypersensitivity - associated pathologies . 
 furthermore , we discuss the potential role of mast cells during wound healing in the lung and its association with lung cancer , and how mast cells could be exploited as therapeutic targets in some diseases 