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Does asking about trauma history create participant distress? If so, how does it compare with reactions to other personal questions? Do participants consider trauma questions important compared to other personal questions? Using 2 undergraduate samples (Ns = 240 and 277), the authors compared participants' reactions to trauma questions with their reactions to other possibly invasive questions through a self-report survey. Trauma questions caused relatively minimal distress and were perceived as having greater importance and greater cost-benefit ratings compared to other kinds of psychological research in an undergraduate human subjects pool population. These findings suggest that at least some kinds of trauma research appear to pose minimal risk when compared to other minimal risk research topics, and that participants recognize the importance of research about trauma. [ABSTRACT FROM AUTHOR]

The pathogenesis of end-stage, chronic lung disease is thought to be characterized by an initial inflammatory response followed by fibroproliferation and deposition of extracellular matrix. Many of these chronic lung disorders share a variety of common properties, including an unknown etiology, undefined mechanisms of initiation and maintenance, and progressive fibrosis. Unfortunately, efficacious therapeutic options are not readily available for the treatment of many chronic lung diseases, which may reflect the limited scientific and mechanistic understanding of these disorders. However, recent studies have shown that cytokine networks are likely operative in dictating the progression of these diseases, as these mediators can influence fibroblast activation, proliferation, and collagen deposition during the maintenance of chronic fibrotic lung disease. Accumulating data support the concept that the specific cytokine phenotype may provide a fundamental mechanism for the regulation or continuation of the fibrotic process. For example, interferon-gamma appears to suppresses fibroblast activities, such as proliferation and collagen production, while interleukin (IL)-4 and IL-13 can augment fibroblast growth and collagen production. Interestingly, these mediators are prototypic cytokines that functionally define either a type-1 or a type-2 immune response. Thus, experimental models of cell-mediated lung inflammation, which are characterized by either a type-1 or a type-2 response, will be useful in delineating the mechanisms that either maintain or resolve chronic lung inflammation and accompanying fibrosis. [ABSTRACT FROM AUTHOR]

Abstract Airway hyper-reactivity is a characteristic feature of many inflammatory lung diseases and is defined as an exaggerated degree of airway narrowing. Chemokines and their receptors are involved in several pathological processes that are believed to contribute to airway hyper-responsiveness, including recruitment and activation of inflammatory cells, collagen deposition and airway wall remodeling. These proteins are therefore thought to represent important therapeutic targets in the treatment of airway hyper-responsiveness. This review highlights the processes thought to be involved in airway hyper-responsiveness in allergic asthma, and the role of chemokines in these processes. Overall, the application of chemokines to the prevention or treatment of airway hyper-reactivity has tremendous potential.

Spaceflight induces molecular, cellular and physiological shifts in astronauts and poses myriad biomedical challenges to the human body, which are becoming increasingly relevant as more humans venture into space 1-6 . Yet current frameworks for aerospace medicine are nascent and lag far behind advancements in precision medicine on Earth, underscoring the need for rapid development of space medicine databases, tools and protocols. Here we present the Space Omics and Medical Atlas (SOMA), an integrated data and sample repository for clinical, cellular and multi-omic research profiles from a diverse range of missions, including the NASA Twins Study 7 , JAXA CFE study 8,9 , SpaceX Inspiration4 crew 10-12 , Axiom and Polaris. The SOMA resource represents a more than tenfold increase in publicly available human space omics data, with matched samples available from the Cornell Aerospace Medicine Biobank. The Atlas includes extensive molecular and physiological profiles encompassing genomics, epigenomics, transcriptomics, proteomics, metabolomics and microbiome datasets, which reveal some consistent features across missions, including cytokine shifts, telomere elongation and gene expression changes, as well as mission-specific molecular responses and links to orthologous, tissue-specific mouse datasets. Leveraging the datasets, tools and resources in SOMA can help to accelerate precision aerospace medicine, bringing needed health monitoring, risk mitigation and countermeasure data for upcoming lunar, Mars and exploration-class missions., (© 2024. The Author(s).)

Background: The Inspiration4 (I4) mission, the first all-civilian orbital flight mission, investigated the physiological effects of short-duration spaceflight through a multi-omic approach. Despite advances, there remains much to learn about human adaptation to spaceflight's unique challenges, including microgravity, immune system perturbations, and radiation exposure., Methods: To provide a detailed genetics analysis of the mission, we collected dried blood spots pre-, during, and post-flight for DNA extraction. Telomere length was measured by quantitative PCR, while whole genome and cfDNA sequencing provided insight into genomic stability and immune adaptations. A robust bioinformatic pipeline was used for data analysis, including variant calling to assess mutational burden., Result: Telomere elongation occurred during spaceflight and shortened after return to Earth. Cell-free DNA analysis revealed increased immune cell signatures post-flight. No significant clonal hematopoiesis of indeterminate potential (CHIP) or whole-genome instability was observed. The long-term gene expression changes across immune cells suggested cellular adaptations to the space environment persisting months post-flight., Conclusion: Our findings provide valuable insights into the physiological consequences of short-duration spaceflight, with telomere dynamics and immune cell gene expression adapting to spaceflight and persisting after return to Earth. CHIP sequencing data will serve as a reference point for studying the early development of CHIP in astronauts, an understudied phenomenon as previous studies have focused on career astronauts. This study will serve as a reference point for future commercial and non-commercial spaceflight, low Earth orbit (LEO) missions, and deep-space exploration., Competing Interests: Christopher E. Mason is a co-Founder of Cosmica Biosciences. Braden Tierney is compensated for consulting with Seed Health and Enzymetrics Biosciences on microbiome study design and holds an ownership stake in the former. Kelly Bolton receives research funding from Servier and Bristol Myers Squibb and serves on the medical advisory board of GoodCell. Kelly Blease, Juan Moreno, Andrew Boddicker, Junhua Zhao, Bryan Lajoie, Andrew Altomare, Semyon Kruglyak, and Shawn Levy are employees of and have a financial interest in Element Biosciences. Irina Matei is a Co-Principal Investigator for research projects funded by Atossa Therapeutics. Caleb M. Schmidt, Julian C. Schmidt, and Michael A. Schmidt hold shares in Sovaris Holdings, LLC. Min Yu is the founder and president of CanTraCer Biosciences Inc. Authors not listed here do not have competing interests. Besides, as an Editorial Board Member of Precision Clinical Medicine, the corresponding author Christopher E. Mason was blinded from reviewing and making decision on this manuscript., (© The Author(s) 2024. Published by Oxford University Press on behalf of the West China School of Medicine & West China Hospital of Sichuan University.)

Low-pass sequencing with genotype imputation has been adopted as a cost-effective method for genotyping. The most widely used method of short-read sequencing uses sequencing by synthesis (SBS). Here we perform a study of a novel sequencing technology-avidity sequencing. In this short note, we compare the performance of imputation from low-pass libraries sequenced on an Element AVITI system (which utilizes avidity sequencing) to those sequenced on an Illumina NovaSeq 6000 (which utilizes SBS) with an SP flow cell for the same set of biological samples across a range of genetic ancestries. We observed dramatically lower optical duplication rates in the data deriving from the AVITI system compared to the NovaSeq 6000, resulting in higher effective coverage given a fixed number of sequenced bases, and comparable imputation accuracy performance between sequencing chemistries across ancestries. This study demonstrates that avidity sequencing is a viable alternative to the standard SBS chemistries for applications involving low-pass sequencing plus imputation., Competing Interests: Conflicts of interest JHL, KF, and JKP were all employees of Gencove Inc., a private company that develops and markets software for the analysis of low-pass sequencing data, at the time of the experiment. KB, JZ, and SK were all employees of Element Biosciences, a private company that develops and markets sequencing instruments., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Genetics Society of America.)

The study of psychopathy has largely centered on samples of incarcerated offenders with a focus on primary psychopathy traits. Less is known, however, about how experiences of childhood betrayal trauma and dissociation influence the development of these traits in non-institutionalized individuals. In the present study, we utilized structural equation modeling to investigate the relationships among childhood betrayal trauma, adult dissociation, and adult psychopathy traits and callous affect traits in a community sample (N = 746). Childhood betrayal trauma was associated with psychopathy and callous affect traits, and mediated by dissociative experiences. These results are consistent with theory and prior empirical findings associating childhood betrayal trauma with dissociation, psychopathy, and callous affect traits. The results will help influence the design of future studies that can further inform the developmental course of psychopathy.

Early data suggested that CC-115, a clinical molecule, already known to inhibit the mammalian target of rapamycin kinase (TORK) and DNA-dependent protein kinase (DNA-PK) may have additional targets beyond TORK and DNA-PK. Therefore, we aimed to identify such target(s) and investigate a potential therapeutic applicability. Functional profiling of 141 cancer cell lines revealed inhibition of kinase suppressor of morphogenesis in genitalia 1 (SMG1), a key regulator of the RNA degradation mechanism nonsense-mediated mRNA decay (NMD), as an additional target of CC-115. CC-115 treatment showed a dose-dependent increase of SMG1-mediated NMD transcripts. A subset of cell lines, including multiple myeloma (MM) cell lines sensitive to the endoplasmic reticulum stress-inducing compound thapsigargin, were highly susceptible to SMG1 inhibition. CC-115 caused the induction of UPR transcripts and cell death by mitochondrial apoptosis, requiring the presence of BAX/BAK and caspase activity. Superior antitumor activity of CC-115 over TORK inhibitors in primary human MM cells and three xenograft mouse models appeared to be via inhibition of SMG1. Our data support further development of SMG1 inhibitors as possible therapeutics in MM., (© 2022 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

As a result of emerging biological data suggesting that within the c-Jun N-terminal kinase (JNK) family, JNK1 and not JNK2 or JNK3 may be primarily responsible for fibrosis pathology, we sought to identify JNK inhibitors with an increased JNK1 bias relative to our previous clinical compound tanzisertib (CC-930). This manuscript reports the synthesis and structure-activity relationship (SAR) studies for a novel series of JNK inhibitors demonstrating an increased JNK1 bias. SAR optimization on a series of 2,4-dialkylamino-pyrimidine-5-carboxamides resulted in the identification of compounds possessing low nanomolar JNK inhibitory potency, overall kinome selectivity, and the ability to inhibit cellular phosphorylation of the direct JNK substrate c-Jun. Optimization of physicochemical properties in this series resulted in compounds that demonstrated excellent systemic exposure following oral dosing, enabling in vivo efficacy studies and the selection of a candidate for clinical development, CC-90001 , which is currently in clinical trials (Phase II) in patients with idiopathic pulmonary fibrosis (NCT03142191).

The PKC-θ isoform of protein kinase C is selectively expressed in T lymphocytes and plays an important role in the T cell antigen receptor (TCR)-triggered activation of mature T cells, T cell proliferation, and the subsequent release of cytokines such as interleukin-2 (IL-2). Herein, we report the synthesis and structure-activity relationship (SAR) of a novel series of PKC-θ inhibitors. Through a combination of structure-guided design and exploratory SAR, suitable replacements for the basic C4 amine of the original lead ( 3 ) were identified. Property-guided design enabled the identification of appropriately substituted C2 groups to afford potent analogs with metabolic stability and permeability to support in vivo testing. With exquisite general kinase selectivity, cellular inhibition of T cell activation as assessed by IL-2 expression, a favorable safety profile, and demonstrated in vivo efficacy in models of acute and chronic T cell activation with oral dosing, CC-90005 ( 57 ) was selected for clinical development.

The Wnt/β-catenin signaling pathway has been implicated in human proliferative diseases such as cancer and fibrosis. The functions of β-catenin and several other components of this pathway have been investigated in fibrosis. However, the potential role of R-spondin proteins (RSPOs), enhancers of the Wnt/β-catenin signaling, has not been described. A specific interventional strategy targeting this pathway for fibrosis remains to be defined. We developed monoclonal antibodies against members of the RSPO family (RSPO1, 2, and 3) and probed their potential function in fibrosis in vivo. We demonstrated that RSPO3 plays a critical role in the development of fibrosis in multiple organs. Specifically, an anti-RSPO3 antibody, OMP-131R10, when dosed therapeutically, attenuated fibrosis in carbon tetrachloride (CCl4)-induced liver fibrosis, bleomycin-induced pulmonary and skin fibrosis models. Mechanistically, we showed that RSPO3 induces multiple pro-fibrotic chemokines and cytokines in Kupffer cells and hepatocytes. We found that the anti-fibrotic activity of OMP-131R10 is associated with its inhibition of β-catenin activation in vivo. Finally, RSPO3 was found to be highly elevated in the active lesions of fibrotic tissues in mouse models of fibrosis and in patients with idiopathic pulmonary fibrosis (IPF) and nonalcoholic steatohepatitis (NASH). Together these data provide an anti-fibrotic strategy for targeting the Wnt/β-catenin pathway through RSPO3 blockade and support that OMP-131R10 could be an important therapeutic agent for fibrosis., Competing Interests: Mingjun Zhang, Michael Haughey, Nai-Yu Wang, Kate Blease, Suzana Couto, Igor Belka, Matthew Groza, James Hartke, Brydon Bennett, Brent Benish, Paola Castigilioni, Clifton Drew, Jean Lachowicz, Leon Carayannopoulos, Kandasamy Hariharan, Ho Cho, and Weilin Xie are employees of Celgene Corporation, whose company funded this study. Ann M. Kapoun, Timothy Hoey, Jennifer Cain, and Austin Gurney are employees of Oncomed Pharmaceuticals. OMP-131R10 is an Oncomed Pharmaceuticals product. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials.

Targeted protein degradation via small-molecule modulation of cereblon offers vast potential for the development of new therapeutics. Cereblon-binding therapeutics carry the safety risks of thalidomide, which caused an epidemic of severe birth defects characterized by forelimb shortening or phocomelia. Here we show that thalidomide is not teratogenic in transgenic mice expressing human cereblon, indicating that binding to cereblon is not sufficient to cause birth defects. Instead, we identify SALL4 as a thalidomide-dependent cereblon neosubstrate. Human mutations in SALL4 cause Duane-radial ray, IVIC, and acro-renal-ocular syndromes with overlapping clinical presentations to thalidomide embryopathy, including phocomelia. SALL4 is degraded in rabbits but not in resistant organisms such as mice because of SALL4 sequence variations. This work expands the scope of cereblon neosubstrate activity within the formerly 'undruggable' C2H2 zinc finger family and offers a path toward safer therapeutics through an improved understanding of the molecular basis of thalidomide-induced teratogenicity.

Ischemia/reperfusion (I/R) injury is an important cause of acute and chronic renal failure. Neutrophils and macrophages, by integrin-based recruitment, play a key role in renal I/R injury. Integrin-based activation of spleen tyrosine kinase (Syk) contributes to myeloid cell adhesion to activated endothelial cells in vitro; however, whether Syk is required for myeloid cell recruitment and tubular damage in I/R injury is unknown. Therefore, we investigated the function of Syk in mouse I/R injury using two different approaches. C57Bl/6J mice underwent bilateral warm ischemia and were sacrificed after 30 minutes or 24 hours of reperfusion. Mice were treated with the Syk inhibitor CC0417, or vehicle, beginning 1 hour before surgery. Syk was expressed by infiltrating neutrophils, macrophages, and platelets in vehicle-treated I/R injury which exhibited severe renal failure and tubular damage at 24 hours. CC0417 treatment markedly reduced neutrophil, macrophage, and platelet accumulation with improved renal function and reduced tubular damage. Next, we compared mice with conditional Syk gene deletion in myeloid cells (Syk(My)) versus Syk(f/f) littermate controls in a 24-hour study. Syk(My) mice also showed a marked reduction in neutrophil and macrophage infiltration with significant protection from I/R-induced acute renal failure and tubular damage. These studies define a pathologic role for myeloid Syk signaling in renal I/R injury and identify Syk as a potential therapeutic target in this condition., (Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Aims: Spleen tyrosine kinase (Syk) is a non-receptor tyrosine kinase involved in the signalling pathways of the B cell receptor, Fcγ-receptor and some leukocyte integrins. However, Syk can also be expressed by some non-haematopoietic cell types, although whether Syk signalling in these cells contributes to the pathogenesis of kidney disease is unknown. To address this question, we examined the function of Syk in antibody-independent renal interstitial fibrosis in the unilateral ureteric obstruction (UUO) model., Main Methods: Groups of C57BL/6J mice were treated with a selective Syk inhibitor (CC0417, 30 mg/kg/bid), vehicle, or no treatment, from the time of surgery until being killed 7 days later., Key Findings: A substantial accumulation of interstitial Syk(+) cells was seen in the UUO kidney. Double staining identified Syk expression by infiltrating macrophages and by a subset of α-SMA(+) myofibroblasts. CC0417 treatment substantially reduced the Syk(+) cell population in conjunction with a reduction in both myofibroblast and macrophage accumulation. This was associated with a substantial reduction in collagen IV deposition and mRNA levels of pro-fibrotic (collagen I, collagen IV, fibronectin, α-SMA, TGF-β1 and PAI-1) and pro-inflammatory molecules (MCP-1, TNF-α and NOS2). CC0417 treatment reduced both PDGF-B mRNA levels and Ki67(+) proliferating interstitial cells in the UUO kidney. Furthermore, CC0417 inhibited PDGF-AB induced ERK activation and cell proliferation of cultured primary kidney fibroblasts., Significance: This study has identified a pathologic role for Syk in renal interstitial fibrosis. Syk inhibitors may have therapeutic potential in chronic fibrotic kidney disease., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Autoantibodies and the immunoreceptors to which they bind can contribute to the pathogenesis of autoimmune diseases such as rheumatoid arthritis (RA). Spleen Tyrosine Kinase (Syk) is a non-receptor tyrosine kinase with a central role in immunoreceptor (FcR) signaling and immune cell functionality. Syk kinase inhibitors have activity in antibody-dependent immune cell activation assays, in preclinical models of arthritis, and have progressed into clinical trials for RA and other autoimmune diseases. Here we describe the characterization of a novel triazolopyridine-based Syk kinase inhibitor, CC-509. This compound is a potent inhibitor of purified Syk enzyme, FcR-dependent and FcR-independent signaling in primary immune cells, and basophil activation in human whole blood. CC-509 is moderately selective across the kinome and against other non-kinase enzymes or receptors. Importantly, CC-509 was optimized away from and has modest activity against cellular KDR and Jak2, kinases that when inhibited in a preclinical and clinical setting may promote hypertension and neutropenia, respectively. In addition, CC-509 is orally bioavailable and displays dose-dependent efficacy in two rodent models of immune-inflammatory disease. In passive cutaneous anaphylaxis (PCA), CC-509 significantly inhibited skin edema. Moreover, CC-509 significantly reduced paw swelling and the tissue levels of pro-inflammatory cytokines RANTES and MIP-1α in the collagen-induced arthritis (CIA) model. In summary, CC-509 is a potent, moderately selective, and efficacious inhibitor of Syk that has a differentiated profile when compared to other Syk compounds that have progressed into the clinic for RA.

Kidney allografts induce strong T-cell and antibody responses which mediate acute rejection. Spleen tyrosine kinase (Syk) is expressed by most leucocytes, except mature T cells, and is involved in intracellular signalling following activation of the Fcγ-receptor, B-cell receptor and some integrins. A role for Syk signalling has been established in antibody-dependent native kidney disease, but little is known of Syk in acute renal allograft rejection. Sprague-Dawley rats underwent bilateral nephrectomy and received an orthotopic Wistar renal allograft. Recipient rats were treated with a Syk inhibitor (CC0482417, 30 mg/kg/bid), or vehicle, from 1 h before surgery until being killed 5 days later. Vehicle-treated recipients developed severe allograft failure with marked histologic damage in association with dense leucocyte infiltration (T cells, macrophages, neutrophils and NK cells) and deposition of IgM, IgG and C3. Immunostaining identified Syk expression by many infiltrating leucocytes. CC0482417 treatment significantly improved allograft function and reduced histologic damage, although allograft injury was still clearly evident. CC0482417 failed to prevent T-cell infiltration and activation within the allograft. However, CC0482417 significantly attenuated acute tubular necrosis, infiltration of macrophages and neutrophils and thrombosis of peritubular capillaries. In conclusion, this study identifies a role for Syk in acute renal allograft rejection. Syk inhibition may be a useful addition to T-cell-based immunotherapy in renal transplantation., (© 2014 The Authors. International Journal of Experimental Pathology © 2014 International Journal of Experimental Pathology.)

In this Letter we describe the optimization of an aminopurine lead (1) with modest potency and poor overall kinase selectivity which led to the identification of a series of potent, selective JNK inhibitors. Improvement in kinase selectivity was enabled by introduction of an aliphatic side chain at the C-2 position. CC-359 (2) was selected as a potential clinical candidate for diseases manifested by ischemia reperfusion injury., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

In this Letter we describe the discovery of potent, selective, and orally active aminopurine JNK inhibitors. Improving the physico-chemical properties as well as increasing the potency and selectivity of a subseries with rat plasma exposure, led to the identification of four structurally diverse inhibitors. Differentiation based on PK profiles in multiple species as well as activity in a chronic efficacy model led to the identification of 1 (CC-930) as a development candidate, which is currently in Phase II clinical trial for IPF., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Glomerular antibody deposition induces acute neutrophil-mediated glomerular injury via activation of c-Jun amino terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK). However, the link between antibody deposition and activation of JNK/p38 MAPK signalling is unclear. This study tested the postulate that spleen tyrosine kinase (Syk), which is activated via Fcγ-receptor ligation, is required for activation of JNK and p38 signalling and acute neutrophil-mediated glomerular injury. We used a Syk inhibitor (SYKi) in rat nephrotoxic serum nephritis (NTN) in which neutrophil-mediated glomerular injury is dependent upon JNK and p38 signalling. SYKi or vehicle treatment of Sprague-Dawley rats began 30 min before administration of anti-GBM serum with rats killed 3 or 24 h later. Immunostaining identified de novo glomerular Syk activation (p-Tyr 525/526) in untreated NTN, being most prominent in neutrophils. Vehicle and untreated NTN exhibited heavy proteinuria and glomerular thrombosis at 24 h with P-selectin and fibrin immunostaining within capillaries, glomerular macrophage and T cell infiltration, activation of JNK and p38 MAPK signalling, and upregulation of glomerular mRNA levels of pro-inflammatory molecules (TNF-α, NOS2, MMP-12 and CCL2). In contrast, SYKi treatment provided complete protection from proteinuria, with a profound reduction in glomerular thrombosis and immunostaining for P-selectin and fibrin, and a substantial reduction in glomerular mRNA levels of pro-inflammatory molecules. SYKi treatment also reduced the acute glomerular neutrophil influx and pro-inflammatory response at 3 h in NTN. These protective effects were associated with a significant reduction in glomerular JNK and p38 MAPK activation. In addition, activation of Syk, JNK and p38 was identified in human biopsy samples of acute crescentic glomerulonephritis. In conclusion, this study demonstrates that Syk signalling is required for JNK and p38 MAPK signalling and acute neutrophil-dependent glomerular injury in rat NTN. These findings identify Syk as a potential therapeutic target in antibody-dependent kidney disease.

In this communication, we report the discovery of 1S (apremilast), a novel potent and orally active phosphodiesterase 4 (PDE4) and tumor necrosis factor-alpha inhibitor. The optimization of previously reported 3-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-3-(3,4-dimethoxyphenyl)propionic acid PDE4 inhibitors led to this series of sulfone analogues. Evaluation of the structure-activity relationship of substitutions on the phthalimide group led to the discovery of an acetylamino analogue 1S, which is currently in clinical trials.

The effects of associative strength on rates of 7- and 11-year-old children's true and false memories were examined when category and Deese-Roediger-McDermott (DRM) lists were used to cue the same critical lure. Backward associative strength (BAS) was varied such that the category and DRM lists had the same strength (DRM=category), DRM lists had more BAS (DRM>category), or category lists had more BAS (DRM

Targeting the IL-13 pathway appears to be a viable approach to ameliorate pulmonary inflammation and remodeling. Support for this hypothesis comes from preclinical and preliminary clinical data. Diverse approaches have been used to target the IL-13 pathway, including neutralizing antibodies specific for IL-13, targeting IL-13 receptors using antibodies or chimeric proteins, and therapeutics that target the downstream signaling molecules that are activated upon binding of the IL-13 receptor to its ligand. This review summarizes the progress made in the development of therapeutics targeting the IL-13 pathway for treating diseases associated with inflammation and remodeling of the lung.

Through a regulation cascade via the site-specific phosphorylation of downstream substrates, members of kinase signaling pathways play multiple cellular regulatory roles. Because of the contribution of kinases in a diverse number of cellular processes, members of these pathways have become attractive targets for rational drug design. Members of these kinase signalling families, such as mitogen-activated kinases, tyrosine kinases (receptor and non-receptor) and ras human orthologue kinases among others have been shown to play key roles in the pathogenesis of immune, inflammatory and remodelling events that occur during asthma. This review highlights, through information that has been obtained from transgenic and knockout systems, small-molecule inhibitors and antisense technology, the role of select members of kinase families in the pathogenesis of asthma, and discusses the rationale for developing specific inhibitors of these kinases for the treatment of asthma.