Duvelisib attenuates bleomycin-induced pulmonary fibrosis via inhibiting the PI3K/Akt/mTOR signalling pathway

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease that seriously threatens the health of patients. The pathogenesis of IPF is still unclear, and there is a lack of effective therapeutic drugs. Myofibroblasts are the main effector cells of IPF, leading to excessive deposition of extracellular matrix (ECM) and promoting the progression of fibrosis. Inhibiting the excessive activation and relieving autophagy blockage of myofibroblasts is the key to treat IPF. PI3K/Akt/mTOR pathway plays a key regulatory role in promoting fibroblast activation and autophagy inhibition in lung fibrosis. Duvelisib is a PI3K inhibitor that can simultaneously inhibit the activities of PI3K-δ and PI3K-γ, and is mainly used for the treatment of relapsed/refractory chronic lymphocytic leukaemia (CLL) and small lymphocytic lymphoma tumour (SLL). In this study, we aimed to examine the effects of Duvelisib on pulmonary fibrosis. We used a mouse model of bleomycin-induced pulmonary fibrosis to evaluate the effects of Duvelisib on pulmonary fibrosis in vivo and further explored the potential pharmacological mechanisms of Duvelisib in lung fibroblasts in vitro. The in vivo experiments showed that Duvelisib significantly alleviated bleomycin-induced collagen deposition and improved pulmonary function. In vitro and in vivo pharmacological experiments showed that Duvelisib dose-dependently suppressed lung fibroblast activation and improved autophagy inhibition by inhibiting the phosphorylation of PI3K, Akt and mTOR. Our results indicate that Duvelisib can alleviate the severity of pulmonary fibrosis and provide potential drugs for the treatment of pulmonary fibrosis.     

VASOMOTOR RESPONSES OF ISOLATED PERIPHERAL BLOOD VESSELS FROM BOWHEAD WHALES: THERMOREGULATORY IMPLICATIONS

Temperature regulation in bowhead whales, Balaena mysticetus , is supported by the characteristic cetacean peripheral circulation, especially notable in the tail flukes. Blood vessels serving this function consist of countercurrent heat exchangers (network of veins surrounding a central artery) favoring heat conservation and an alternate routing via arteriovenous anastomoses (AVAs) providing for heat dissipation. We tested the vasomotor responses of isolated segments of countercurrent arteries and AVAs from the bowhead tail flukes to norepinephrine (NOR), the sympathetic adrenergic neurotransmitter. Isometric tension developed during exposure to a micromolar concentration of NOR was consistently higher in AVAs than in arteries. Accordingly, the AVAs are subject to sympathetic vasoconstriction, and this activation directs blood flow to countercurrent heat exchangers and results in heat conservation. In contrast, AVA relaxation by reduced sympathetic activation favors increased blood flow through AVAs and consequent peripheral heat loss.     

A comparative study of the effects of iloprost and PGE1 on pulmonary arterial pressure and edema formation in the isolated perfused rat lung model

Isolated lungs from male Wistar rats (250–350 g) were perfused at a constant flow rate (10 ml/min, non -recirculating) with Krebs-Ringerbicarbonate buffer containing 4.5 % bovine serum albumin, and were ventilated at a positive pressure (60 breaths/min). Pulmonary arterial pressure and lung weight (as a measure of edema formation) were recorded continuously. After an equilibration period of 20 minutes the various test compounds were added to the perfusion fluid and experimental recording was continued for another 60 minutes.The effects of the stable PGI₂-mimetic, iloprost, of PGE₁, and of the biologically active PGE₁-metabolite, 13,14-dihydro-PGE,, were evaluated in this model (n=6). Iloprost showed slight, but not significant vasodilation; however, lung weight remained unchanged. PGE₁ and 13,14-dihydro-PGE₁ also caused slight vasodilation, but in contrast to iloprost these compounds induced distinct pulmonary edema. The lung weight gain was discernible at concentrations of 2.8 × 10^-6 mol/1 (significant at 2.8 × 10^-5 mol/l; p 0.05) and was accompanied by increases in the wet-weight to dry-weight ratios. These findings were duplicated in a second set of experiments (n = 6) from which the same results were obtained.The results indicate that at high concentrations PGE, (and 13,14-dihydro-PGE₁), but not iloprost, can induce pulmonary edema in rats probably by increasing the permeability of the pulmonary vasculature.     

Secretion of unprocessed human surfactant protein B in milk of transgenic mice

Because of the apparent clinical importance of human pulmonary surfactant B (SP-B), the expression of SP-B was directed to the mammary gland of transgenic mice using previously characterized rat whey acidic protein (WAP) regulatory sequences. rWAP/SP-B mRNA was expressed specifically in the mammary gland, and ranged from 1 to 5% of the endogenous WAP mRNA levels. SP-B was detected immunologically in both tissue and milk. The transgene product had an apparent molecular weight of 40--45 kDa, corresponding to the predicted size of the SP-B proprotein. Incubation of an SP-B-enriched fraction of milk with cathepsin D in vitro produced 20--25 kDa species, consistent with cleavage of the amino terminal domain by cathepsin D. This was confirmed using antibodies specific to the carboxy-terminal domain of SP-B. However, the appearance of only the SP-B proprotein in milk suggests that cathepsin D is not involved in the in vivo processing of SP-B. The SP-B proprotein can be expressed in milk of transgenic mice without any observed effects on mammary gland morphology or lactation     

Influence of central command and ergoreceptors on the splanchnic circulation during isometric exercise

The splanchnic circulation can make a major contribution to blood flow changes. However, the role of the splanchnic circulation in the reflex adjustments to the blood pressure increase during isometric exercise is not well documented. The central command and the muscle chemoreflex are the two major mechanisms involved in the blood pressure response to isometric exercise. This study aimed to examine the behaviour of the superior mesenteric artery during isometric handgrip (IHG) at 30% maximal voluntary contraction (MVC). The pulsatility index (PI) of the blood velocity waveform of the superior mesenteric artery was taken as the study parameter. A total of ten healthy subjects [mean age, 21.1 (SEM 0.3) years] performed an IHG at 30% MVC for 90 s. At 5 s prior to the end of the exercise, muscle circulation was arrested for 90 s to study the effect of the muscle chemoreflex (post exercise arterial occlusion, PEAO). The IHG at 30% MVC caused a decrease in superior mesenteric artery PI, from 4.84 (SEM 1.57) at control level to 3.90 (SEM 1.07) (P = 0.015). The PI further decreased to 3.17 (SEM 0.70) (P = 0.01) during PEAO. Our results indicated that ergoreceptors may be involved in the superior mesenteric artery vasodilatation during isometric exercise.     

Effect of feed zone in fed-batch fermentations of Saccharomyces cerevisiae

In production-scale, fed-batch fermentations, feed is often added to a single point at the top of the fermentor, which, combined with poor mixing, results in formation of a "feed zone" rich in nutrients. Frequent exposure of the culture to high concentrations of nutrients in the feed zone for sufficient duration can produce unexpected effects on its performance. The effect of the feed zone was evaluated by conducting aerobic fed-batch fermentations of Saccharomyces cerevisiae with both complex and defined media. The broth was recirculated between a recycle loop and a bench-scale fermentor, and feed was intermittently added into the recycle loop to simulate the circulation of cells through the feed zone. Experiments were carried out for a range of residence times in the recycle loop from 0.5 to 12 min. Biomass yields from the complex-media fermentations were not affected by exposure to high nutrient levels in the recycle loop for residence times up to 12 min. Ethanol consumption was reduced by as much as 50% for residence time in the loop up to 3 min. Very long exposure of yeast cells to excess nutrient levels (12 min) gave acetic acid formation. In a defined medium, the simulated feed zone effect increased biomass yield by up to 10%, but had no effect on ethanol levels. This study indicates that the feed zone effect on biomass yield in yeast fermentation, using complex substrates, will be negligible under fully aerobic conditions.     

Carapace movements associated with ventilation and irrigation of the branchial chambers in the semaphore crab,Heloecius cordiformis (Decapoda: Brachyura: Ocypodidae)

Summary Carapace movements in crabs are briefly reviewed. While on land and recirculating branchial water, the Australian semaphore crab Heloecius cordiformis (Decapoda: Ocypodidae), a semi-terrestrial air-breathing mangrove crab, sequentially depresses and elevates its carapace relative to its thorax (0.5–1 mm excursion) in a regular pump-like manner. In quiescent crabs each carapace-pumping cycle lasts about 4 s; carapace depression takes 3 s and elevation 1 s. Carapace movements are brought about by pressures generated within the branchial chambers by the scaphognathites, probably in combination with carapace muscles. Carapace movements are associated with bilaterally synchronised scaphognathite activity. Unilateral scaphognathite activity was not observed. During normal forward recirculation of branchial water the scaphognathites beat at about 1.5 Hz (slow-forward pumping) and the lungs (epibranchial chambers) are not ventilated. In Heloecius, the lungs are not physically separated from the gills below by an anatomical barrier. Lung ventilation is accomplished during the following sequence of events: the carapace is lowered and the scaphognathites pump in a fast-forward mode at about 2.8 Hz. This activity preferentially pumps air out of the lungs and generates suction within the branchial chambers (4–10 cm H₂O below ambient) which draws water from external body surfaces into the hypobranchial space below and around the gills. At the end of the carapace's downward travel the scaphognathites switch from fast-forward to fastreverse beating at about 4 Hz. This pumps air into the lungs and the carapace elevates. As a result, during carapace elevation the water which had previously been drawn into the branchial chambers by fast-forward pumping activity is released and flows out between the legs and into the abdominosternal cavity. When the carapace reaches its original resting or up position the scaphognathites switch from fast-reverse to slowforward beating to re-establish water recirculation through the branchial chambers. This cycle is subsequently repeated. In stationary crabs, there are 2 carapace-pumping cycles per minute, increasing to 14 per minute in active crabs (walking). When water is absent, the lungs are preferentially ventilated by slow-reverse scaphognathite pumping activity. Carapace movements do not occur in the absence of branchial water. Carapace pumping is thought to provide a mechanism which permits the scaphognathites to ventilate the lungs in the presence of recirculating branchial water, without this water interfering with lung ventilation or being lost to the environment.Abbreviations FF, FR, SF, SR fast-forward, fast-reverse, slowforward, slow-reverse scaphognathite pumping - MEA Milne Edwards aperture     

Effect of cotton dust on lungs among female workers in cotton industry in northern Gujarat,India

Byssinosis is a disabling occupational lung disease caused by cotton dust. It is a well-known occupational respiratory disease in cotton industry workers caused by cotton dust pollution. Many studies have been documented the effects of cotton dust on pulmonary function among workers employed in cotton-spinning mills. However, little data exist on the prevalence of this disorder in female workers particularly in western part of India. The present study was conducted to analyze the effects of exposure to cotton dust on pulmonary functions among female workers. The study was designed to assess the effects of exposure to cotton dust on lung functions among female cotton industry workers. Study group comprises 50 Female workers of cotton industry and control group comprises 50 age matched females who were neither worked in cotton industry nor exposed to cotton dust. Information was collected using standardized questionnaires, physical examination and spirometric measurements. Student''s T test was used to find the difference between spirometric parameters. All the respiratory parameters (FVC, FEV1, FEV1/FVC ratio, FEF 25-75 % PEFR and MVV) were reduced in cotton industry workers as compared with control subjects (p<0.0001) and no significant difference of SpO2 between groups. Cotton dust exposure makes huge impact on respiratory parameters of the cotton industry workers. This deterioration in respiratory health deteriorates with increasing duration of exposure. The health hazards caused by cotton dust should be controlled by creating awareness among the workers & employers.