Integrins are a large family of transmembrane heterodimeric proteins that constitute the main receptors for extracellular matrix components. Integrins were initially thought to be primarily involved in the maintenance of cell adhesion and tissue integrity. However, it is now appreciated that integrins play important roles in many other biological processes such as cell survival, proliferation, differentiation, migration, cell shape and polarity. Lung cells express numerous combinations and permutations of integrin heterodimers. The complexity and diversity of different integrin heterodimers being implicated in different lung diseases present a major challenge for drug development. Here we provide a comprehensive overview of the current knowledge of integrins from studies in cell culture to integrin knockout mouse models and provide an update of results from clinical trials for which integrins are therapeutic targets with a focus on respiratory diseases (asthma, emphysema, pneumonia, lung cancer, pulmonary fibrosis and sarcoidosis).

Increased airway smooth muscle (ASM) mass is believed to underlie the relatively fixed airway hyperresponsiveness (AHR) in asthma. Developments of therapeutic approaches to reverse airway remodeling are impeded by our lack of insight on the mechanisms behind the increase in mass of contractile ASM cells. Increased expression of laminin, an extracellular matrix protein, is associated with asthma. Our studies investigate the role of laminin-induced ASM survival signals in the development of increased ASM and AHR. Antagonizing laminin integrin binding using the laminin-selective competing peptide, YIGSR, and mimicking laminin with exogenous α2-chain laminin, we show that laminin is both necessary and sufficient to induce ASM cell survival, concomitant with the induction of ASM contractile phenotype. Using siRNA, we show that the laminin-binding integrin α7β1 mediates this process. Moreover, in laminin-211-deficient mice, allergen-induced AHR was not observed. Notably, ASM cells from asthmatic airways express a higher abundance of intracellular cell survival proteins, consistent with a role for reduced rates of cell apoptosis in development of ASM hyperplasia. Targeting the laminin-integrin α7β1 signaling pathway may offer new avenues for the development of therapies to reduce the increase in mass of contractile phenotype ASM cells that underlie AHR in asthma.

Airway hyperresponsiveness (AHR) is one of the cardinal features of asthma. Contraction of airway smooth muscle (ASM) cells that line the airway wall is thought to influence aspects of AHR, resulting in excessive narrowing or occlusion of the airway. ASM contraction is primarily controlled by agonists that bind G protein-coupled receptor (GPCR), which are expressed on ASM. Integrins also play a role in regulating ASM contraction signaling. As therapies for asthma are based on symptom relief, better understanding of the crosstalk between GPCRs and integrins holds good promise for the design of more effective therapies that target the underlying cellular and molecular mechanism that governs AHR. In this paper, we will review current knowledge about integrins and GPCRs in their regulation of ASM contraction signaling and discuss the emerging concept of crosstalk between the two and the implication of this crosstalk on the development of agents that target AHR.

Airway smooth muscle (ASM) cells exhibit plastic phenotypic behavior marked by reversible modulation and maturation between contractile and proliferative phenotypic states. Integrins are a class of transmembrane proteins that have been implicated as novel therapeutic targets for asthma treatment. We previously showed that integrin α7 is a novel marker of the contractile ASM phenotype suggesting that targeting this protein may offer new avenues to counter the increase in ASM cell mass that underlies airways hyperresponsiveness (AHR) in asthma. We now determine whether inhibition of integrin α7 expression would revert ASM cells back to a proliferative phenotype to cause an increase in ASM cell mass. This would be detrimental to asthmatic patients who already exhibit increased ASM mass in their airways. Using immunohistochemical analysis of the Melbourne Epidemiological Study of Childhood Asthma (MESCA) cohort, we show for the first time that integrin α7 expression in patients with severe asthma is increased, supporting a clinically relevant role for this protein in asthma pathophysiology. Moreover, inhibition of the laminin-integrin α7 signaling axis results in a reduction in smooth muscle-alpha actin abundance and does not revert ASM cells back to a proliferative phenotype. We determined that integrin α7-induced Kras isoform of p21 Ras acts as a point of convergence between contractile and proliferative ASM phenotypic states. Our study provides further support for targeting integrin α7 for the development of novel anti-asthma therapies.

To identify and report the effects of anesthetics on hemodynamic variables and cardio vascular system of inpatients admitted to the selected general surgery wards of a tertiary health care hospital. METHODS: A prospective observational study of 6 months was carried out on inpatients aged above 18 years who received at least one anaesthetic drug. The patients were monitored for haemodynamic-cardio complications during the peri-operative period. Parameters like blood pressure and heart rate were analysed after the administration of anaesthesia. The data retrieved from medical records, anesthesia log papers, ECG reports, 2D-Echo reports and patient interviews was transcribed into specially designed data collection forms. The causal relationship of ADRs was assessed using Naranjo's scale. RESULTS: A total of 117 patients were studied, out of which 66(56.4%) were operated under General Anesthesia (GA) and 51(43.6%) under Local Anesthesia (LA). GA included a combination of propofol, fentanyl, atracurium, midazolam and isoflurane while LA comprised of bupivacaine and buprenorphine. The dose of anaesthetics was titrated in individual patients based on their body mass index. Out of the 137 ADRs identified, haemodynamic and cardiovascular system related side effects contributed to 113 (82.5%) which mainly comprised of hypotension 66 (58.4%), bradycardia 13 (11.5%), tachycardia 11 (9.7%), hypertension 12 (10.6%), ECG changes 7 (6.2%) and arrhythmia 2 (1.8%).Hypotension was common after GA (65.1%), whilst tachycardia (63.6%) and ECG changes (57.1%) were prominent in patients administered with LA. 102(90%) ADRs were possible and 11(10%) were probable according to naranjo scale. Therapeutic interventions were required for 47 ADRs(40.1%). CONCLUSIONS: These results indicated a dominant parasympathetic effect and dose dependant myocardial depression by anaesthetics. Hence, the results can be contemplated to optimise patients safety which substantially improves therapeautic outcomes.