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Biomedical subjects

Sanjiv Sur

Publications and source records attributed to Sanjiv Sur.

14 recordsLinked to original sources
PubMed2006

Subpollen particles: carriers of allergenic proteins and oxidases.

BACKGROUND: Pollen is known to induce allergic asthma in atopic individuals, although only a few inhaled pollen grains penetrate into the lower respiratory tract. OBJECTIVE: We sought to provide evidence that subpollen particles (SPPs) of respirable size, possessing both antigenic and redox properties, are released from weed pollen grains and to test their role in allergic airway inflammation. METHODS: The release of SPPs was analyzed by means of microscopic imaging and flow cytometry. The redox properties of SPPs and the SPP-mediated oxidative effect on epithelial cells were determined by using redox-sensitive probes and specific inhibitors. Western blotting and amino acid sequence analysis were used to examine the protein components of the SPP. The allergenic properties of the SPP were determined in a murine model of experimental asthma. RESULTS: Ragweed pollen grains released 0.5 to 4.5 microm of SPPs on hydration. These contained Amb a 1, along with other allergenic proteins of ragweed pollen, and possessed nicotinamide adenine dinucleotide (reduced) or nicotinamide adenine dinucleotide phosphate (reduced) [NAD(P)H] oxidase activity. The SPPs significantly increased the levels of reactive oxygen species (ROS) in cultured cells and induced allergic airway inflammation in the experimental animals. Pretreatment of the SPPs with NAD(P)H oxidase inhibitors attenuated their capacity to increase ROS levels in the airway epithelial cells and subsequent airway inflammation. CONCLUSIONS: The allergenic potency of SPPs released from ragweed pollen grains is mediated in tandem by ROS generated by intrinsic NAD(P)H oxidases and antigenic proteins. CLINICAL IMPLICATIONS: Severe clinical symptoms associated with seasonal asthma might be explained by immune responses to inhaled SPPs carrying allergenic proteins and ROS-producing NAD(P)H oxidases.

Allergens↗
PubMed2006

Lactoferrin decreases pollen antigen-induced allergic airway inflammation in a murine model of asthma.

Pollen grains contain reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidases and in contact with mucosal surfaces generate superoxide anion (O2*-). In the presence of iron, O2*- may be converted to more reactive oxygen radicals, such as to H2O2 and/or *OH, which may augment antigen-induced airway inflammation. The aim of the study was to examine the impact of lactoferrin (LF), an iron-binding protein, on ragweed (Ambrosia artemisiifolia) pollen extract (RWE)-induced cellular oxidative stress levels in cultured bronchial epithelial cells and accumulation of inflammatory and mucin-producing cells in airways in a mouse model of allergic airway inflammation. Results show that LF lowered RWE-induced increase in cellular reactive oxygen species (ROS) levels in bronchial epithelial cells. Most importantly, LF significantly decreased accumulation of eosinophils into airways and subepithelium of intranasally challenged, sensitized mice. LF also prevented development of mucin-producing cells. Amb a 1, the major allergenic ragweed pollen antigen lacking NADPH oxidase activity, induced low-grade airway inflammation. When administered along with glucose oxidase (G-ox), a superoxide-generating enzyme, Amb a 1 induced robust airway inflammation, which was significantly lowered by LF. Surprisingly, LF decreased also inflammation caused by Amb a 1 alone. Iron-saturated hololactoferrin had only a marginal effect on RWE-induced cellular ROS levels and RWE- or Amb a 1 plus G-ox-induced inflammation. We postulate that free iron in the airways chemically reduces O2*- to more reactive species which augment antigen-induced inflammation in a mouse model of asthma. Our results suggest the utility of LF in human allergic inflammatory disorders.

Allergens↗
PubMed2005

Effect of pollen-mediated oxidative stress on immediate hypersensitivity reactions and late-phase inflammation in allergic conjunctivitis.

BACKGROUND: Allergic eye diseases are complex inflammatory conditions of the conjunctiva that are becoming increasingly prevalent and present an increasing economic burden because of direct and indirect health expenditures. OBJECTIVE: We sought to identify factors that may synergize with antigen-induced allergic inflammation and lead to allergic conjunctivitis. We used a murine model of allergic conjunctivitis to test the effect of oxidative stress generated by pollen oxidases using nicotinamide adenine dinucleotide (reduced) or nicotinamide adenine dinucleotide phosphate (reduced) (NAD[P]H) as an electron donor present in pollen grains. METHODS: Reactive oxygen species (ROS) generation by hydrated Ambrosia artemisiifolia pollen (short ragweed pollen; RWP) grains was determined by using 2'-7'-dihydro-dichlorofluorescein diacetate, nitroblue tetrazolium reduction, and Amplex Red assay. The RWP-induced changes in intracellular ROS levels were examined in A549 cells, human primary bronchial epithelial cells, and murine conjunctiva. RESULTS: Ragweed pollen grains contain NAD(P)H oxidase activity, which is diphenyleneiodonium-sensitive and quinacrine-sensitive and sodium azide-resistant. These NAD(P)H oxidases generate a superoxide anion that can be converted to H2O2 by pollen grain-associated superoxide dismutase. These diffusible oxygen radicals from pollen grains increase intracellular ROS levels in cultured epithelial cells and murine conjunctiva. Similar phenomena were observed in sensitized and naive mice, indicating that the RWP-induced oxidative stress in conjunctival epithelium is independent of adaptive immunity. Inactivation of NAD(P)H oxidase activity in RWP decreases the immediate-type hypersensitivity and inflammatory cell infiltration into the conjunctiva. CONCLUSION: Our data suggest that ROS generated by NAD(P)H oxidases in pollen grains intensify immediate allergic reactions and recruitment of inflammatory cells in murine conjunctiva.

Animals↗
PubMed2005

ROS generated by pollen NADPH oxidase provide a signal that augments antigen-induced allergic airway inflammation.

Pollen exposure induces allergic airway inflammation in sensitized subjects. The role of antigenic pollen proteins in the induction of allergic airway inflammation is well characterized, but the contribution of other constituents in pollen grains to this process is unknown. Here we show that pollen grains and their extracts contain intrinsic NADPH oxidases. The pollen NADPH oxidases rapidly increased the levels of ROS in lung epithelium as well as the amount of oxidized glutathione (GSSG) and 4-hydroxynonenal (4-HNE) in airway-lining fluid. These oxidases, as well as products of oxidative stress (such as GSSG and 4-HNE) generated by these enzymes, induced neutrophil recruitment to the airways independent of the adaptive immune response. Removal of pollen NADPH oxidase activity from the challenge material reduced antigen-induced allergic airway inflammation, the number of mucin-containing cells in airway epithelium, and antigen-specific IgE levels in sensitized mice. Furthermore, challenge with Amb a 1, the major antigen in ragweed pollen extract that does not possess NADPH oxidase activity, induced low-grade allergic airway inflammation. Addition of GSSG or 4-HNE to Amb a 1 challenge material boosted allergic airway inflammation. We propose that oxidative stress generated by pollen NADPH oxidases (signal 1) augments allergic airway inflammation induced by pollen antigen (signal 2).

Aldehydes↗
PubMed2004

Unc119, a novel activator of Lck/Fyn, is essential for T cell activation.

The first step in T cell receptor for antigen (TCR) signaling is the activation of the receptor-bound Src kinases, Lck and Fyn. The exact mechanism of this process is unknown. Here, we report that the novel Src homology (SH) 3/SH2 ligand-Uncoordinated 119 (Unc119) associates with CD3 and CD4, and activates Lck and Fyn. Unc119 overexpression increases Lck/Fyn activity in T cells. In Unc119-deficient T cells, Lck/Fyn activity is dramatically reduced with concomitant decrease in interleukin 2 production and cellular proliferation. Reconstitution of cells with Unc119 reverses the signaling and functional outcome. Thus, Unc119 is a receptor-associated activator of Src-type kinases. It provides a novel mechanism of signal generation in the TCR complex.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Immunomodulation: the future of allergy and asthma treatment.

PURPOSE OF REVIEW: As the prevalence of asthma and allergic disease increases around the world, it is clear that more effective therapies and disease-modifying agents are needed. Treatment for allergic disease is evolving with an increase in understanding of the etiology. RECENT FINDINGS: The first immunomodulatory treatment was recently approved for use in the United States when the Food and Drug Administration approved the use of a humanized monoclonal anti-IgE antibody in patients with allergic asthma. Another strategy that has proved effective in a murine model is the downregulation of the whole immune system by targeting adhesion molecules, which has been evaluated in a recent human trial. Other strategies for the treatment of allergic diseases concentrate on refocusing the immune system away from an allergic-type response. These include the use of targeted therapies towards specific cytokines, cytokine receptors or chemokine receptors, and the use of specific bacterial DNA sequences (unmethylated cytosine-guanine dinucleotides). Finally, attention is being focused on possible therapies that may tilt the immune response to a non-allergic response by interfering with signaling molecule pathways. SUMMARY: Immunomodulation will play a key role in future therapies for allergic disease. These treatment modalities may not only treat allergic disease, but also be beneficial in reducing the morbidity and mortality for which it is responsible.

Animals↗
PubMed2003

Interleukin-12: potential role in asthma therapy.

Asthma is an inflammatory disease of the airways leading to significant morbidity and mortality. With advances in the understanding of the molecular and cellular mechanisms involved in the asthmatic response, researchers have identified specific mediators that may be targeted to control the inflammatory state of asthma. The Th2 hypothesis proposes that the inflammation in asthma arises from an imbalance between the two CD4+ T lymphocyte subsets, T helper (Th) type 1 and Th2. Th2 cells release many cytokines that have been shown to regulate the inflammatory response, while the Th1 cytokines counteract this response. The Th1 cytokine, interleukin (IL)-12, has been a target of intense study because it mediates the Th1 response and offers a means of modifying the asthmatic inflammatory response. Numerous murine studies have shown that this cytokine can potently inhibit allergic airway inflammation in asthma. Inhalation of IL-12 has been shown to increase its efficacy in inhibiting allergic inflammation in murine models while decreasing adverse effects seen with systemic administration of this cytokine. However, an initial study of inhaled IL-12 in humans with asthma was terminated because of adverse effects. The use of systemically administered IL-12 in patients with asthma has been limited due to cytokine toxicity. Another treatment option that has the potential of inducing a Th1 cytokine response is the use of IL-12 linked to polyethylene glycol (PEG) moieties. This mode of administration is likely to enhance cytokine delivery to the target organ, while decreasing its toxicity. IL-12 gene therapy has also been examined as a means of suppressing airway hyperreactivity in murine asthma, but its potential in human asthma has not been explored. Several recent studies have investigated the role of CpG DNA motifs as endogenous inducers of IL-12 with encouraging results in both mice and humans. These studies may result in novel Th1- inducing CpG-based immunotherapies for asthma.

Adjuvants, Immunologic↗
PubMed2002

Safe administration of a humanized murine antibody after anaphylaxis to a chimeric murine antibody.

BACKGROUND: Basiliximab and daclizumab are potent and relatively safe immunosuppressive induction agents used in transplantation. These chimeric or humanized monoclonal antibodies, respectively, act by binding to the alpha chain of interleukin-2 receptors on activated T lymphocytes. Herein, the authors describe successful transplant induction therapy with a humanized murine antibody in a patient with a history of anaphylaxis to a chimeric murine antibody. METHODS: The authors report a 42-year-old woman who received a dose of basiliximab without adverse reaction before an anticipated renal transplant that was canceled. Two weeks later, she received a second dose of basiliximab. Within 10 min of receiving the second dose, she developed chest tightness, shortness of breath, tongue swelling, diffuse pruritic rash, and skin flushing. RESULTS: The authors hypothesized that her anaphylaxis was mediated by immunoglobulin (Ig) E antibodies to basiliximab. Consistent with this hypothesis, intradermal administration of a 1:100 dilution of basiliximab induced a 10 x 10-mm flare. The authors sought to find an alternative immunosuppressive agent for this patient. The patient elicited prick and intradermal skin testing responses to horse and rabbit polyclonal antithymocyte antibody preparations. However, she mounted neither a prick nor an intradermal response to daclizumab. The patient was administered daclizumab without any adverse effects. CONCLUSIONS: The negative skin test and safe administration of daclizumab is surprising because the similarity of these hybrid antibodies would have predicted similar IgE responsiveness and clinical outcome. The authors propose that patients who develop anaphylaxis to basiliximab or other chimeric antibodies may be candidates for treatment with a humanized antibody preparation such as daclizumab in the presence of a negative skin test to the humanized agent.

Adult↗
PubMed2002

Identification of UNC119 as a novel activator of SRC-type tyrosine kinases.

Lyn, an Src-type tyrosine kinase, is associated with the interleukin (IL)-5 receptor in eosinophils. The mechanism of its activation is unknown. Through yeast two-hybrid screening we have cloned and characterized a new signaling molecule, Unc119, that associates with IL-5Ralpha and Src family tyrosine kinases. Unc119 induces the catalytic activity of these kinases through interaction with Src homology 2 and 3 domains. IL-5 stimulation of eosinophils increases Unc119 association with Lyn and induces its catalytic activity. Lyn is important for eosinophil survival. Eosinophils that are transduced with Unc119 have increased Lyn activity and demonstrate prolonged survival in the absence of IL-5. Inhibition of Unc119 down-regulates eosinophil survival. To our knowledge Unc119 is the first receptor-associated activator of Src family tyrosine kinases.

Amino Acid Sequence↗
PubMed2002

In vivo role of p38 mitogen-activated protein kinase in mediating the anti-inflammatory effects of CpG oligodeoxynucleotide in murine asthma.

DNA containing unmethylated CpG motifs is intrinsically immunostimulatory, inducing the production of a variety of cytokines and chemokines by immune cells. The strong Th1 response triggered by CpG oligodeoxynucleotide (ODN) inhibits the development of Th2-mediated allergic asthma in mice. This work documents that CpG ODN-induced IL-12 production plays a critical role in this process, because intrapulmonary CpG ODN inhibits allergic inflammation in wild-type but not IL-12(-/-) mice. CpG ODN rapidly localized to alveolar macrophages (AM), thereby triggering the phosphorylation of p38 mitogen-activated protein kinase (MAP kinase). AM cultured with CpG but not control ODN up-regulated IL-12 p40 expression and release, and these effects were blocked by the highly specific p38 MAP kinase inhibitor SB202190. Intrapulmonary administration of this inhibitor blocked the ability of CpG ODN to produce IL-12 in the lungs and reversed the anti-inflammatory effects of CpG ODN on allergic lung inflammation. These findings indicate that IL-12 production by AM is stimulated by intrapulmonary CpG ODN administration through a p38 MAP kinase-dependent process, and IL-12 is a key cytokine that mediates CpG ODN-induced protection against allergic lung inflammation.

Adjuvants, Immunologic↗
PubMed2002

Lyn tyrosine kinase is important for IL-5-stimulated eosinophil differentiation.

IL-5 plays a pivotal role in growth and differentiation of eosinophils. The signal transduction mechanism of IL-5Ralpha is largely unknown. We have demonstrated that IL-5 induces tyrosine phosphorylation of IL-5Ralpha in eosinophils. To identify IL-5Ralpha-associated tyrosine kinases, we have examined the expression of Src family tyrosine kinases in eosinophils. Among the Src family members, Lyn, Hck, Fgr, and Lck are present in eosinophils, and, among these four kinases, only Lyn is associated with the IL-5Ralpha under basal conditions. We also confirm the association of Janus kinase (Jak)2 with IL-5Ralpha. Lyn kinase phosphorylates both IL-5Ralpha and betacR in vitro. The importance of Lyn kinase for eosinophil differentiation was studied using antisense oligodeoxynucleotides. Lyn antisense oligodeoxynucleotide blocks eosinophil differentiation from stem cells in a dose-dependent manner. The Jak2 inhibitor tyrphostin AG490 also inhibits eosinophil differentiation. The importance of Lyn for eosinophil differentiation was further studied using Lyn knockout mice. The IL-5-stimulated eosinophil differentiation from bone marrow cells is significantly inhibited in Lyn(-/-) mice as compared with that in control mice. We conclude that both Lyn and Jak2 play an essential role in IL-5Ralpha signaling, leading to eosinophil differentiation. The effect of Lyn appears to be relatively specific for the eosinophilic lineage.

Animals↗
PubMed2002

CCL7 and CXCL10 orchestrate oxidative stress-induced neutrophilic lung inflammation.

Oxidative stress from ozone (O(3)) exposure augments airway neutrophil recruitment and chemokine production. We and others have shown that severe and sudden asthma is associated with airway neutrophilia, and that O(3) oxidative stress is likely to augment neutrophilic airway inflammation in severe asthma. However, very little is known about chemokines that orchestrate oxidative stress-induced neutrophilic airway inflammation in vivo. To identify these chemokines, three groups of BALB/c mice were exposed to sham air, 0.2 ppm O(3), or 0.8 ppm O(3) for 6 h. Compared with sham air, 0.8 ppm O(3), but not 0.2 ppm O(3), induced pronounced neutrophilic airway inflammation that peaked at 18 h postexposure. The 0.8 ppm O(3) up-regulated lung mRNA of CXCL1,2,3 (mouse growth-related oncogene-alpha and macrophage-inflammatory protein-2), CXCL10 (IFN-gamma-inducible protein-10), CCL3 (macrophage-inflammatory protein-1alpha), CCL7 (monocyte chemoattractant protein-3), and CCL11 (eotaxin) at 0 h postexposure, and expression of CXCL10, CCL3, and CCL7 mRNA was sustained 18 h postexposure. O(3) increased lung protein levels of CXCL10, CCL7, and CCR3 (CCL7R). The airway epithelium was identified as a source of CCL7. The role of up-regulated chemokines was determined by administering control IgG or IgG Abs against six murine chemokines before O(3) exposure. As expected, anti-mouse growth-related oncogene-alpha inhibited neutrophil recruitment. Surprisingly, Abs to CCL7 and CXCL10 also decreased neutrophil recruitment by 63 and 72%, respectively. These findings indicate that CCL7 and CXCL10, two chemokines not previously reported to orchestrate neutrophilic inflammation, play a critical role in mediating oxidative stress-induced neutrophilic airway inflammation. These observations may have relevance in induction of neutrophilia in severe asthma.

Adjuvants, Immunologic↗
PubMed2002

Asthma: future directions.

Asthma continues to be a significant health care problem, as reflected by the increasing rise in disease morbidity and mortality. Because steroids are relatively safe, clinically effective, and easy to administer, they remain the gold standard of treatment. After many decades of use, however, it is apparent that inhaled corticosteroids have failed to halt the progression of the asthma epidemic. Newer, more effective drugs are being developed to combat this disease, and the interest in developing new medications to treat allergic disease and asthma has increased exponentially. The financial burden of asthma has also been a significant motivating factor in the development of new medications. It is estimated that in 1998 the total cost of asthma on society was $11 billion [175]. This consideration has further intensified the quest to develop more effective asthma medications. Table 1 reviews the wide array of drugs currently being investigated. With the development and approval of novel asthma treatments, millions of asthma sufferers will undoubtedly have increased therapeutic options for control of their disease in the near future.

Anti-Asthmatic Agents↗