Scott A Boitano
Associate Research Scientist, Respiratory Sciences
Professor, BIO5 Institute
Professor, Cellular and Molecular Medicine
Professor, Physiological Sciences - GIDP
Professor, Physiology
Primary Department
Department Affiliations
(520) 626-2105
Research Interest
Dr. Scott Boitano Ph.D., is a Professor of Physiology, Cellular and Molecular Medicine, the BIO5 Institute and Associate Research Scientist of the Arizona Respiratory Center. Dr. Boitano received a B.S. in Plant Biology from University of California; Berkeley and a Ph.D. in Genetics & Cell Biology from Washington State University. Dr. Boitano’s primary research interest is in cell respiration. This encompasses the analysis and observation of cell physiology, cell-cell communications and cell-pathogen interactions. Dr. Boitano’s research pertains to the upper airway epithelium is an active cellular layer with ciliary movement to clear materials, the ability to secrete inflammatory effectors, and a biological barrier function that helps protect against pathogenic microorganisms, foreign insults and injury. Although much is known concerning the microbial genetics and microbial signaling of infection by Bordetella, relatively little is known about host cell pathology after exposure to Bordetella. Individuals have a primary tissue culture system that serves as an in vitro model of airway cell signaling and communication, and a battery of B. bronchiseptica strains, some of which are mutant in key factors shown to inhibit their ability to establish infection in animal models. His research goal is to define specific pathogen factors that alter host cell physiology to initiate or overcome host cell defense. The Boitano lab also analyzes the layers of the alveoli of the distal mammalian lung. Minimal information is known about this subject and Dr. Boitano believes that this model system for alveolar intercellular communication could expedite the formulating and testing of new medical treatments for dysfunctional alveolar cell physiology that underlies specific airway conditions following disease, insult and injury in the lung.


Flynn, A. N., Tillu, D. V., Asiedu, M. N., Hoffman, J., Vagner, J., Price, T. J., & Boitano, S. (2011). The protease-activated receptor-2-specific agonists 2-aminothiazol-4-yl-LIGRL-NH2 and 6-aminonicotinyl-LIGRL-NH2 stimulate multiple signaling pathways to induce physiological responses in vitro and in vivo. The Journal of biological chemistry, 286(21), 19076-88.

Protease-activated receptor-2 (PAR(2)) is one of four protease-activated G-protein-coupled receptors. PAR(2) is expressed on multiple cell types where it contributes to cellular responses to endogenous and exogenous proteases. Proteolytic cleavage of PAR(2) reveals a tethered ligand that activates PAR(2) and two major downstream signaling pathways: mitogen-activated protein kinase (MAPK) and intracellular Ca(2+) signaling. Peptides or peptidomimetics can mimic binding of the tethered ligand to stimulate signaling without the nonspecific effects of proteases. The most commonly used peptide activators of PAR(2) (e.g. SLIGRL-NH(2) and SLIGKV-NH(2)) lack potency at the receptor. However, although the potency of 2-furoyl-LIGRLO-NH(2) (2-f-LIGRLO-NH(2)) underscores the use of peptidomimetic PAR(2) ligands as a mechanism to enhance pharmacological action at PAR(2), 2-f-LIGRLO-NH(2) has not been thoroughly evaluated. We evaluated the known agonist 2-f-LIGRLO-NH(2) and two recently described pentapeptidomimetic PAR(2)-specific agonists, 2-aminothiazol-4-yl-LIGRL-NH(2) (2-at-LIGRL-NH(2)) and 6-aminonicotinyl-LIGRL-NH(2) (6-an-LIGRL-NH(2)). All peptidomimetic agonists stimulated PAR(2)-dependent in vitro physiological responses, MAPK signaling, and Ca(2+) signaling with an overall rank order of potency of 2-f-LIGRLO-NH(2) ≈ 2-at-LIGRL-NH(2) > 6-an-LIGRL-NH(2) ≫ SLIGRL-NH(2). Because PAR(2) plays a major role in pathological pain conditions and to test potency of the peptidomimetic agonists in vivo, we evaluated these agonists in models relevant to nociception. All three agonists activated Ca(2+) signaling in nociceptors in vitro, and both 2-at-LIGRL-NH(2) and 2-f-LIGRLO-NH(2) stimulated PAR(2)-dependent thermal hyperalgesia in vivo. We have characterized three high potency ligands that can be used to explore the physiological role of PAR(2) in a variety of systems and pathologies.

Yeee, M. C., Nichols, H. L., Polley, D., Pal, K., Lee, K., Daines, M. O., Boitano, S. A., Hollenberg, M. D., & DeFea, K. A. (2017). Protease-activated receptor 2-induced signaling through β-arrestin-2 mediates Alternaria serine protease-induced airway inflammation. PLoS One, In Revision.

Protease-Activated Receptor-2 (PAR2) is a G-protein-coupled receptor that is activated by a variety of trypsin-like serine proteases, including those found in common allergens such as Alternaria fungi, which are causative in asthma-associated morbidity and mortality worldwide. PAR2 signals through both G-protein and β-arrestin-dependent pathways and β-arrestin-2 mediates PAR2-induced leukocyte chemotaxis into the airway. Previous studies showed that an unidentified serine protease activity in Alternaria alternata can activate PAR2 to trigger an inflammatory cell pathology in murine lung. We hypothesized that a serine-protease-mediated PAR2/β-arrestin signaling axis plays a key role in Alternaria-induced lung inflammation. Here we isolate, from Alternaria extracts, the single serine protease responsible for PAR2 activation, AASP (Alternaria Alkaline Serine Protease). Both extracts and isolated AASP promote PAR2 β-arrestin-dependent signaling in cultured cells. Intranasal administration of Alternaria extract in wild-type (but not β-arrestin-2-/- or PAR2-/- mice) increases airway epithelial damage, mucin production, and recruitment of eosinophils, CD4+T-cells and macrophages and this response is abolished by administration of soybean trypsin inhibitor (SBTI). Administration of AASP alone is sufficient to induce eosinophil and lymphocyte recruitment. Our data demonstrate that a single serine protease in an aeroallergen like Alternaria alternata can activate PAR2 signaling through β-arrestin-2 to cause an inflammatory asthma phenotype. Thus, β-arrestin-biased PAR2 antagonists represent attractive therapeutic targets for treating aeroallergen-induced asthma.

Boitano, S., Sherwood, C. L., Lantz, R. C., Burgess, J. L., & Boitano, S. A. (2011). Arsenic alters ATP-dependent Ca²+ signaling in human airway epithelial cell wound response. Toxicological sciences : an official journal of the Society of Toxicology, 121(1).
BIO5 Collaborators
Scott A Boitano, Clark Lantz

Arsenic is a natural metalloid toxicant that is associated with occupational inhalation injury and contaminates drinking water worldwide. Both inhalation of arsenic and consumption of arsenic-tainted water are correlated with malignant and nonmalignant lung diseases. Despite strong links between arsenic and respiratory illness, underlying cell responses to arsenic remain unclear. We hypothesized that arsenic may elicit some of its detrimental effects on the airway through limitation of innate immune function and, specifically, through alteration of paracrine ATP (purinergic) Ca²+ signaling in the airway epithelium. We examined the effects of acute (24 h) exposure with environmentally relevant levels of arsenic (i.e.,

Field, J. A., Luna-Velasco, A., Boitano, S. A., Shadman, F., Ratner, B. D., Barnes, C., & Sierra-Alvarez, R. (2011). Cytotoxicity and physicochemical properties of hafnium oxide nanoparticles. Chemosphere, 84(10), 1401-7.

Nano-sized hafnium oxide (HfO(2)) particles are being considered for applications within the semiconductor industry. However, little is known about their cytotoxicity. The objective of this work was to assess several HfO(2) nanoparticles (NPs) samples for their acute cytotoxicity. Dynamic light scattering analysis of the samples indicated that the average particle size of the HfO(2) in aqueous dispersions was in the submicron range with a fraction of particles having nano-dimensions. The media used in the toxicity assays decreased or increased the average particle size of HfO(2) NPs due to dispersion or agglomeration. Static time-of-flight secondary ion mass spectrometry (ToF-SIMS) revealed numerous surface contaminants on the NPs. Only one HfO(2) sample caused moderate cytotoxicity to human cell lines. The inhibitory sample caused a 50% response in the Live/Dead assay with HaCaT skin cells at 2200 mg L(-1); and a 50% response in the mitochondrial toxicity test at 300 mg L(-1). A microbial inhibition assay based on methanogenic activity also revealed that another HFO(2) sample caused moderate inhibition. The difference in toxicity between samples could not be attributed to size. Instead the difference in toxicity was likely due to differences in the contaminants of the HfO(2). The ToF-SIMS analysis indicated unique signatures of Br and P in the sample toxic to human cell lines suggesting a distinct synthesis was used for that sample which may have been accompanied by inhibitory impurities. The results taken as a whole indicate that HfO(2) itself is relatively non-toxic.

Flynn, A. N., Hoffman, J., Tillu, D. V., Sherwood, C. L., Zhang, Z., Patek, R., Asiedu, M. N., Vagner, J., Price, T. J., & Boitano, S. (2013). Development of highly potent protease-activated receptor 2 agonists via synthetic lipid tethering. FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 27(4), 1498-510.

Protease-activated receptor-2 (PAR₂) is a G-protein coupled receptor (GPCR) associated with a variety of pathologies. However, the therapeutic potential of PAR₂ is limited by a lack of potent and specific ligands. Following proteolytic cleavage, PAR₂ is activated through a tethered ligand. Hence, we reasoned that lipidation of peptidomimetic ligands could promote membrane targeting and thus significantly improve potency and constructed a series of synthetic tethered ligands (STLs). STLs contained a peptidomimetic PAR₂ agonist (2-aminothiazol-4-yl-LIGRL-NH₂) bound to a palmitoyl group (Pam) via polyethylene glycol (PEG) linkers. In a high-throughput physiological assay, these STL agonists displayed EC₅₀ values as low as 1.47 nM, representing a ∼200 fold improvement over the untethered parent ligand. Similarly, these STL agonists were potent activators of signaling pathways associated with PAR₂: EC₅₀ for Ca(2+) response as low as 3.95 nM; EC₅₀ for MAPK response as low as 9.49 nM. Moreover, STLs demonstrated significant improvement in potency in vivo, evoking mechanical allodynia with an EC₅₀ of 14.4 pmol. STLs failed to elicit responses in PAR2(-/-) cells at agonist concentrations of >300-fold their EC₅₀ values. Our results demonstrate that the STL approach is a powerful tool for increasing ligand potency at PAR₂ and represent opportunities for drug development at other protease activated receptors and across GPCRs.