Asthma is an inflammatory disease of the airways that may result from exposure to allergens or other environmental irritants, resulting in bronchoconstriction, wheezing, and shortness of breath. The structural changes of the airways associated with asthma, broadly referred to as airway remodeling, is a pathological feature of chronic asthma that contributes to the clinical manifestations of the disease. Airway remodeling in asthma constitutes cellular and extracellular matrix changes in the large and small airways, epithelial cell apoptosis, airway smooth muscle cell proliferation, and fibroblast activation. These pathological changes in the airway are orchestrated by crosstalk of different cell types within the airway wall and submucosa. Environmental exposures to dust, chemicals, and cigarette smoke can initiate the cascade of pro-inflammatory responses that trigger airway remodeling through paracrine signaling and mechanostimulatory cues that drive airway remodeling. In this review, we explore three integrated and dynamic processes in airway remodeling: (1) initiation by epithelial cells; (2) amplification by immune cells; and (3) mesenchymal effector functions. Furthermore, we explore the role of inflammaging in the dysregulated and persistent inflammatory response that perpetuates airway remodeling in elderly asthmatics.

Asthma is a chronic inflammatory disease process involving the conductive airways of the human lung. The dysregulated inflammatory response in this disease process may involve multiple cell-cell interactions mediated by signaling molecules, including lipid mediators. Extracellular vesicles (EVs) are lipid membrane particles that are now recognized as critical mediators of cell-cell communication. Here, we compared the lipid composition and presence of specific lipid mediators in airway EVs purified from the bronchoalveolar lavage (BAL) fluid of healthy controls and asthmatic subjects with and without second-hand smoke (SHS) exposure. Airway exosome concentrations were increased in asthmatics, and correlated with blood eosinophilia and serum IgE levels. Frequencies of HLA-DR+ and CD54+ exosomes were also significantly higher in asthmatics. Lipidomics analysis revealed that phosphatidylglycerol, ceramide-phosphates, and ceramides were significantly reduced in exosomes from asthmatics compared to the non-exposed control groups. Sphingomyelin 34:1 was more abundant in exosomes of SHS-exposed asthmatics compared to healthy controls. Our results suggest that chronic airway inflammation may be driven by alterations in the composition of lipid mediators within airway EVs of human subjects with asthma.

The tyrosine kinase Pyk2 is vital for integrating receptor-mediated signals controlling adhesion and motility in neuronal, epithelial, and hematopoietic cell types. In T cells, the stimulation of the TCR and costimulatory, chemokine, cytokine, and integrin receptors leads to the phosphorylation of Pyk2 and the induction of its catalytic activity. However, our understanding of the mechanism of the TCR-induced, site-specific phosphorylation of this kinase is incomplete and contradictory. To address this issue, the role of individual signaling pathways in the phosphorylation of Pyk2 tyrosines 402 and 580 upon TCR activation was assessed in human T cells. In contrast to other receptor systems, the TCR-induced phosphorylation of Pyk2 tyrosines 402 and 580 was dependent on the Src family kinases, Fyn or Lck. Interestingly, the TCR-mediated phosphorylation of Pyk2 tyrosines 402 and 580 did not require Ca(2+) influx, ZAP-70 activation, actin cytoskeleton rearrangement, or PI3K function. These observations are different than other receptor systems, which require the induction of one or more of these pathways. Together, these data have defined more fully the mechanism for the TCR-induced phosphorylation of specific sites on Pyk2, suggesting that the TCR has a distinct pathway for the activation of Pyk2 compared with other receptor systems.

Summary T cell immunoglobulin mucin-1 (Tim-1) is a transmembrane protein postulated to be a key regulator of Th2-type immune responses. This hypothesis is based in part upon genetic studies associating Tim-1 polymorphisms in mice with a bias toward airway hyperresponsiveness and the development of Th2-type CD4+ T cells. Tim-1 is expressed by Th2 CD4+ T cells on which it has been proposed to function as a co-stimulatory molecule. Tim-1 is also expressed by B cells, macrophages, and dendritic cells, but its role in responses by these cell types has not been firmly established. We generated Tim-1 deficient mice to determine the role of Tim-1 in a murine model of allergic airway disease that depends on the development and function of Th2 effector cells and results in the generation of AHR. We found antigen-driven recruitment of inflammatory cells into airways is increased in Tim-1 deficient mice relative to wild-type mice. In addition, we observed increased antigen-specific cytokine production by splenocytes from antigen-sensitized Tim-1 deficient mice relative to those from controls. These data support the conclusion that Tim-1 functions in pathways that suppress recruitment of inflammatory cells into the airways and the generation or activity of CD4+ T cells.

The gene encoding T cell immunoglobulin and mucin domain-1 (TIM-1) is linked to atopy and asthma susceptibility in mice and humans. TIM-1 is a transmembrane protein expressed on activated lymphocytes and appears to have a role as a co-stimulatory receptor in T cells. The protein has not been shown to have enzymatic activity but contains a site within its cytoplasmic tail predicted to be a target for tyrosine kinases. Here, we show that Tim-1 can associate with the kinase Fyn, a member of the Src family of tyrosine kinases. This association does not require Fyn’s kinase activity and is independent of the phosphorylation of a conserved tyrosine present within the cytoplasmic tail of Tim-1. Fyn is necessary for phosphorylation of this tyrosine in Tim-1 and the phosphorylation of Tim-1 varies with the levels of Fyn present in cells. These data suggest a role for Fyn in the signaling downstream of Tim-1.