Cyclical inflation of the lungs depends on the elasticity of lung parenchymal tissues, a mechanical property that is largely determined by elastic fibers and collagen fibers contained therein. ...Breakdown of elastic fibers in lungs and lack of the ability to repair damaged elastic fibers causes emphysema, and excessive collagen fibrillogenesis in lung parenchyma is critical for the pathogenesis of lung fibrosis. Recent studies revealed that fibulin-3, 4, and 5, which are matricellular proteins collectively termed “short fibulins” or “elastic fibulins”, play crucial roles in the assembly of elastic fibers. Although these fibulins are closely related paralogs with very similar domain structures and sequences, they have independent molecular functions in elastogenesis, as evidenced by different phenotypes in their gene-knockout mice and in patients with mutations in these genes. More recently, emerging evidence suggests that fibulin-4 is also necessary for fibrillar collagen assembly. In this review, I focus on the roles of short fibulins and their associating molecules in the assembly of elastic fibers and collagen fibers. Human diseases caused by mutations in the genes for these molecules are also reviewed. These matricellular proteins could be novel therapeutic targets for emphysema and lung fibrosis.
•Fibulin-3, 4, and 5 play independent, crucial roles in elastic fiber assembly.•Fibulin-4 is also required for collagen fibrillogenesis.•ECM modification by short fibulins could be a new paradigm for treating lung diseases.
I evaluated the effects of long-term (about 270 d/year) and large-volume (83.3% at mean flow) reductions in stream flow on a population of Whitespotted Char Salvelinus leucomaenis . I compared a ...range of biological parameters (density, biomass, condition factor, and age composition) between populations of char in the free-flowing (above dam) and regulated (below dam) sections of a Japanese mountain stream over a 4-year period. The density and biomass of age-1 and older fish was significantly lower in the regulated section than in the free-flowing section: 32.8% reduction in density and 42.5% in biomass. The mean condition factor of age-1 and older fish was significantly lower in the regulated section. In addition, the percentage of age-2 and older fish in the total catch was significantly lower in the regulated section. Except for flow, the physical environment was similar in both the free-flowing and regulated sections. Thus, the changes I observed in the regulated section were likely caused by flow reduction. I hypothesize that a decrease in food availability associated with the reduction in flow caused the decrease in density and condition factor in the regulated section. I also speculate that an increase in density in the pools due to flow reduction resulted in increased aggression among conspecifics. In turn, this results in an increase in the emigration of individuals, particularly older and larger fish, in the regulated section. The decreases in the density, condition factor, and the number of older and larger fish following the reduction in flow probably explain the decrease in biomass in the regulated section. Received November 20, 2012; accepted July 15, 2013
Tocilizumab (TCZ), a biologic that blocks the signal transduction of interleukin-6, has been used for the treatment of various autoimmune diseases. Many of these cases are sometimes complicated by ...ulcerative colitis (UC). However, the effect of TCZ on UC is unclear. We experienced two cases with concomitant UC that were treated with TCZ, one for Takayasu arteritis (TAK) and the other for relapsing polychondritis (RP). TCZ did not improve UC in either of these cases. TCZ might have adverse effects on the intestinal tract, since interleukin-6 signaling plays an important role in intestinal epithelium maintenance. Treatment with TCZ should therefore be carefully provided in patients complicated with UC.
Sterol regulatory element-binding protein 2 (SREBP-2) transcription factor has been identified as a key protein in cholesterol metabolism through the transactivation of the LDL receptor and ...cholesterol biosynthesis genes. Here, we generated mice lacking microRNA (miR)-33, encoded by an intron of the Srebp2, and showed that miR-33 repressed the expression of ATP-binding cassette transporter A 1 (ABCA 1) protein, a key regulator of HDL synthesis by mediating cholesterol efflux from cells to apolipoprotein A (apoA)-I. In fact, peritoneal macrophages derived from miR-33—deficient mice showed a marked increase in ABCA 1 levels and higher apoA-I—dependent cholesterol efflux than those from WT mice. ABCA 1 protein levels in liver were also higher in miR-33—deficient mice than in WT mice. Moreover, miR-33—deficient mice had significantly higher serum HDL cholesterol levels than WT mice. These data establish a critical role for miR-33 in the regulation of ABCA 1 expression and HDL biogenesis in vivo.
Generalized pustular psoriasis is a distinct type of psoriasis characterized by recurrent febrile attacks with disseminated subcorneal pustules on generalized skin rashes. Recently, homozygous and ...compound heterozygous mutations of the IL36RN gene, which encodes the anti‐inflammatory cytokine interleukin (IL)‐36 receptor antagonist, were identified in familial and sporadic cases of various ethnicities with generalized pustular psoriasis. Here we report a 39‐year‐old Japanese male patient who had suffered from repeated attacks of generalized pustular psoriasis since infancy with intervals of several years. At presentation, erythematous lesions with a few pustules were found only on some parts of the body and controlled with topical corticosteroids. An analysis of the IL36RN gene revealed compound heterozygous mutations of c.28C>T and c.368C>T. While the former mutation causing the premature termination p.Arg10X is recurrent in Japanese cases, the latter missense mutation causing p.Thr123Met substitution is novel, but another mutation in the same position has been reported in one Japanese case. Our report further supports the presence of the Japanese‐specific hot spots in the IL36RN gene, 28C and 368C, and suggests the functional significance of Thr123. This special type of generalized pustular psoriasis caused by IL36RN mutations has been designated as deficiency for IL‐36 receptor antagonist, a new hereditary autoinflammatory disease, and its phenotypes have emerged to include other related pustular disorders, palmoplantar pustulosis, acrodermatitis continua of Hallopeau, and acute generalized exanthematous pustulosis. The genetic analysis of the cases with these diseases would be important for establishment and application of the specific treatments targeting the IL‐36 signaling.
Pancreatic injury is considered an organ-related complication in patients with coronavirus disease 2019 (COVID-19). However, it is unclear whether COVID-19 status affects pancreatic injury. This ...retrospective study aimed to determine whether COVID-19 affects the occurrence of pancreatic injuries. Consecutive patients diagnosed with sepsis admitted to the ICU between March 2020 and September 2021 were included. The primary endpoint was a pancreatic injury, which was defined as amylase or lipase levels > 3 times the upper limit of the normal range. Among the 177 patients included in the analysis, 40 (23%) were COVID-19 patients, and 54 (31%) had pancreatic injuries. Of these three patients, acute pancreatitis was diagnosed based on computed tomography. The pancreatic injury was significantly more common among COVID-19 patients (75 vs. 18%,
p
< 0.001). Multivariate analysis showed that COVID-19 and steroid use were independent risk factors for pancreatic injury (Odds Ratio (OR) 4.79 95% confidence interval (CI) 1.48–15.5,
p
= 0.009; OR 4.02 95% CI 1.42–11.4,
p
= 0.009). This study revealed that the proportion of pancreatic injury in septic patients with COVID-19 was significantly higher than in those without COVID-19. It may be difficult to diagnose pancreatitis based on amylase and lipase levels in COVID-19 patients.
MicroRNAs (miRs) are small non-protein-coding RNAs that bind to specific mRNAs and inhibit translation or promote mRNA degradation. Recent reports have indicated that miR-33, which is located within ...the intron of sterol regulatory element-binding protein (SREBP) 2, controls cholesterol homoeostasis and may be a potential therapeutic target for the treatment of atherosclerosis. Here we show that deletion of miR-33 results in marked worsening of high-fat diet-induced obesity and liver steatosis. Using miR-33(-/-)Srebf1(+/-) mice, we demonstrate that SREBP-1 is a target of miR-33 and that the mechanisms leading to obesity and liver steatosis in miR-33(-/-) mice involve enhanced expression of SREBP-1. These results elucidate a novel interaction between SREBP-1 and SREBP-2 mediated by miR-33 in vivo.
Prolonged neurological symptoms such as “brain fog” and cognitive impairment have occurred after coronavirus disease 2019 (COVID-19) infection. In this report, we describe impaired consciousness ...caused by cefepime hydrochloride (CFPM) in a patient with cognitive sequalae of COVID-19. A 56-year-old male patient was diagnosed with penile abscess after COVID-19 infection, and a blood culture detected two drug-resistant
Pseudomonas aeruginosa
strains. Therefore, CFPM 2 g × twice/day was administered on day 71 after intensive care unit admission. Approximately 48 h after CFPM administration, the patient showed disturbances in consciousness. Contrast-enhanced computed tomography, magnetic resonance imaging, and spinal fluid examination revealed no obvious abnormalities. Therefore, CFPM-induced neurotoxicity was suspected. CFPM was discontinued and ceftazidime 2 g × three times/day was initiated. The patient's consciousness improved 30 h after the final administration of CFPM. Serum CFPM concentrations were 14.2, 21.7, 21.7, and 11.9 μg/mL on days 1, 2, and 3 after the initiation of CFPM and on the day after CFPM was discontinued, respectively. In conclusion
,
intensivists should pay attention to new neurological symptoms such as CFPM-induced encephalopathy in patients with prolonged neurological symptoms after COVID-19 infection.
Abnormal mechanosensing of smooth muscle cells (SMCs) resulting from the defective elastin-contractile units has been suggested to drive the formation of thoracic aortic aneurysms; however, the ...precise molecular mechanism has not been elucidated.
The aim of this study was to identify the crucial mediator(s) involved in abnormal mechanosensing and propagation of biochemical signals during the aneurysm formation and to establish a basis for a novel therapeutic strategy.
We used a mouse model of postnatal ascending aortic aneurysms ( Fbln4
; termed SMKO SMC-specific knockout), in which deletion of Fbln4 (fibulin-4) leads to disruption of the elastin-contractile units caused by a loss of elastic lamina-SMC connections. In this mouse, upregulation of Egr1 (early growth response 1) and angiotensin-converting enzyme leads to activation of Ang II (angiotensin II) signaling. Here, we showed that the matricellular protein, Thbs1 (thrombospondin-1), was highly upregulated in SMKO ascending aortas and in human thoracic aortic aneurysms. Thbs1 was induced by mechanical stretch and Ang II in SMCs, for which Egr1 was required, and reduction of Fbln4 sensitized the cells to these stimuli and led to higher expression of Egr1 and Thbs1. Deletion of Thbs1 in SMKO mice prevented the aneurysm formation in ≈80% of DKO (SMKO;Thbs1 knockout) animals and suppressed Ssh1 (slingshot-1) and cofilin dephosphorylation, leading to the formation of normal actin filaments. Furthermore, elastic lamina-SMC connections were restored in DKO aortas, and mechanical testing showed that structural and material properties of DKO aortas were markedly improved.
Thbs1 is a critical component of mechanotransduction, as well as a modulator of elastic fiber organization. Maladaptive upregulation of Thbs1 results in disruption of elastin-contractile units and dysregulation of actin cytoskeletal remodeling, contributing to the development of ascending aortic aneurysms in vivo. Thbs1 may serve as a potential therapeutic target for treating thoracic aortic aneurysms.
The high mobility group box 1 protein (HMGB1) is recognized as a prototypical endogenous danger cytokine in sepsis. We previously reported that a polyacrylonitrile (AN69ST) membrane rapidly adsorbed ...HMGB1. Herein, an in vitro hemofiltration system was designed to assess the HMGB1 adsorption capacity, adsorption sites, and adsorption mechanism of the AN69ST membrane. HMGB1 was repeatedly added seven times during hemofiltration. A rapid decrease in circulating HMGB1 was observed after every addition with no sign of saturation. Presence of HMGB1 on the filter membrane was observed on both membrane surfaces and within the bulk layer using a high concentration of HMGB1 by immunoelectron microscopy. We hypothesized that the addition of heparin to the membrane surface or filtration rate would contribute to the adsorption mechanism. We could not measure the influence of heparin and filtration. Although the membrane was too large to saturate under the μg/mL HMGB1 conditions, our results show that the AN69ST membrane has a robust absorption capacity that could be used to treat sepsis.
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