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PubMed2006

N-acetylcysteine for the prevention of kidney injury in abdominal aortic surgery: a randomized, double-blind, placebo-controlled trial.

In this prospective, randomized, placebo-controlled, double-blind trial we studied the effects of IV N-acetylcysteine for prevention of renal injury in patients undergoing abdominal aortic surgery. Seventy patients without previously documented renal dysfunction were randomly allocated to receive either N-acetylcysteine (150 mg/kg mixed in 250 mL of 5% dextrose infused in 20 min, followed by an infusion of 150 mg/kg in 250 mL of 5% dextrose over 24 h) or placebo. The infusion was started after the induction of anesthesia. The primary outcome measure was renal injury as measured by the increases in urinary N-acetyl-beta-d-glucosaminidase (NAG)/creatinine ratio (indicator of renal tubular injury) and urinary albumin/creatinine ratio (indicator of glomerular injury). Renal function was assessed by measuring plasma creatinine and serum cystatin C concentrations. The urinary NAG/creatinine ratio increased significantly from baseline to before crossclamp and remained increased on day 5 in both groups. The urinary albumin/creatinine ratio increased significantly from baseline to 6 h after declamping in the N-acetylcysteine group. However, the changes in the NAG/creatinine ratio and the albumin/creatinine ratio were not significantly different between the two groups. Plasma creatinine and serum cystatin C values remained unchanged during the study period in both groups. In conclusion, N-acetylcysteine did not offer any significant protection from renal injury during elective aortic operation in patients with normal preoperative renal function, and some degree of tubular injury seems to occur before aortic crossclamp.

Acetylcysteine↗
PubMed1992

Immunohistochemical analysis of constituents of senile plaques and cerebro-vascular amyloid in aged dogs.

Immunohistochemical analysis of constituents of senile plaques and cerebro-vascular amyloid in the brain of aged dogs was performed using antisera against beta protein, cystatin C, ubiquitin, tau, and neurofilament (NF). All types of senile plaques and cerebro-vascular amyloid in aged dogs were labeled by anti-beta protein serum. Cystatin C immunoreactivity was detected in neuronal cell bodies, primitive or classical plaques, and amyloid deposited around cerebral capillaries, but not in diffuse plaques and amyloid deposited in the media tunica of cerebro-meningeal arterioles. Ubiquitin-positive granules distributed widely in both gray and white matter of aged dogs, while they were very small in number in young dogs. Swollen neurites-like materials in primitive plaques or classical plaques were immunoreactive for anti-ubiquitin serum. Tau immunostaining labeled commonly axons and several neuronal or glial cells after hydrate autoclave pretreatment. Tau-positive components were observed very rarely in the corona of classical plaques. Most of swollen neurites-like structures of primitive or classical plaques were not reactive for anti-NF serum, and only a few plaques contained small numbers of NF-positive elements.

Aging↗
PubMed2004

Prohepcidin accumulates in renal insufficiency.

BACKGROUND: The understanding of iron metabolism has increased substantially during the last decade. Several new transporters and iron regulating molecules have been described. Hepcidin, a small hepatic peptide has recently been proposed as a central mediator of dietary iron absorption. We have investigated the relationship between prohepcidin, the prohormone of hepcidin, and renal function and iron status. METHODS: Forty six patients, referred for 51Cr-EDTA clearance were included in this study. Renal function was assessed by determination of serum creatinine, creatinine clearance, serum cystatin C and serum beta-trace protein. Iron status was evaluated by determination of serum iron, transferrin, transferrin saturation and serum ferritin. All determinations were performed using commercial reagents (Roche Diagnostics, Dade Behring). Serum prohepcidin was determined using an ELISA kit. RESULTS: Serum prohepcidin was found to correlate with 51Cr-EDTA clearance (r = -0.44; p = 0.005), creatinine clearance, serum creatinine, beta-trace protein and cystatin C. No significant relationship was observed between serum prohepcidin concentrations and red cell count, hemoglobin concentration or hematocrit. No significant correlation was found in this population between prohepcidin concentrations and iron status. CONCLUSION: Increased serum prohepcidin concentrations were observed with declining kidney function. We observed no relationship between red cell indices or iron status and serum prohepcidin concentrations.

Aged↗
PubMed2006

Renal function--estimation of glomerular filtration rate.

Assessment and follow-up of renal dysfunction is important in the early detection and management of chronic kidney disease. The glomerular filtration rate (GFR) is the most accurate measurement of kidney disease and is reduced before the onset of clinical symptoms. Drawbacks to the measurement of GFR include the high cost and incompatibility with routine laboratory monitoring. Serum creatinine determination is a mainstay in the routine laboratory profile of renal function. The measurement of serum cystatin C has been proposed as a more sensitive marker for GFR. According to National Kidney Foundation-K/DOQ1 clinical guidelines for chronic kidney disease, serum markers should not be used alone to assess GFR. Based on prediction equations, clinical laboratories should report an estimate of GFR, in addition to reporting the serum value. In this article, information is presented on how best to estimate GFR using prediction equations for adults and for children. Using serum creatinine concentration with the Modification of Diet in Renal Disease (MDRD) study equation offers a suitable estimation of GFR in adults. The cystatin C prediction equation with the use of a prepubertal factor seems superior to creatinine-based prediction equations in children of <14 years.

Algorithms↗
PubMedDate not supplied

[A case of recurrent cerebral hemorrhage considered to be cerebral amyloid angiopathy by cerebrospinal fluid examination].

A 73-year-old man was admitted with gait disturbance and dysarthria. He showed right-side cerebellar ataxia. Computed tomography of brain showed left thalamic bleeding. Nine months later, he was admitted again because of seizure and consciousness disturbance. He had a history of diabetes mellitus and gout for five years, but no hypertension. On physical examination the lungs and heart were normal. On neurological examination, he showed stupor,pupils and eye position were normal. He showed right hemiparesis and urinary incontinence. The deep tendon reflexes were (+) at the upper limbs and (2+) at the right knee and ankle. Blood pressure was 162/88 mmHg and glucose was 275 mg/dl. Other laboratory data were normal. Brain CT showed hemorrhage of the left frontal lobe. The cystatin C level in cerebrospinal fluid was 68 ng/ml. Therefore we suspected cystatin C deposit amyloid angiopathy. In this case, thalamic hemorrhage was initially thought to be amyloid angiopathy. In cases of cerebral hemorrhage in the elderly without hypertension, we must be considered amyloid angiopathy.

Aged↗
PubMedDate not supplied

Cysteine proteinases and their endogenous inhibitors: target proteins for prognosis, diagnosis and therapy in cancer (review).

Lysosomal cysteine proteinases, the cathepsins (Cats) belong to the papain family of proteinases, sharing a similar protein structure and mechanism of action. Subtle structural differences between these enzymes give rise to important variations in substrate specificity and specificity of inhibition by their endogenous inhibitors, the cystatins, stefins and kininogens under physiological and pathological conditions. Alterations in their expression, processing and localization have been observed at various levels in malignant human tumor tissue compared to normal and benign tissue counterparts. We have proposed that an imbalance between cathepsins and cystatins, associated with metastatic tumor cell phenotype, may facilitate tumor cell invasion and metastasis. The results of clinical investigations on cysteine cathepsins and their endogenous inhibitors in human breast, lung, brain and head and neck tumors, as well as in body fluids of ovarian, uterine, melanoma and colorectal carcinoma bearing patients, have shown that these molecules are highly predictive for the length of survival and may be used for assessment of risk of relapse and death for cancer patients. Their application for diagnosis, follow-up and the anticancer therapy has also been proposed.

Biomarkers, Tumor↗
PubMed2005

Applications of new laboratory marker assays in neurological diagnoses - a pilot study.

225 consecutive patients with different neurological diseases and 101 individuals as the control were examined between 2002-2004. Cystatin C, arginase-I, tau-protein and beta-amyloid were measured. Individuals with CNS inflammation had significantly lower Cystatin-C index (CSF/serum) values. There was no diagnostic significance of the Arginase-I assay in CSF was verified. The CSF tau-protein/beta-amyloid index was shown to be a sufficient efficacy for neurodegenerative disease diagnosis.

Amyloid beta-Peptides↗
PubMedDate not supplied

The relationship of cathepsin B and stefin A mRNA localization identifies a potentially aggressive variant of human prostate cancer within a Gleason histologic score.

Cathepsin B (CB) is involved in degradation of extracellular matrix proteins during tumor progression in human solid organ tumors (such as colorectal, bladder, and breast cancers), including human prostate cancer. Its activities are regulated by endogenous inhibitors (such as stefins or cystatins). Increased expression of cathepsin B message, protein, and membrane association have been linked to malignancy, but there are very few studies of their mRNA expression in prostate cancer using in situ hybridization techniques. Our objective was to determine the relationship of CB and stefin A (cystatin A) mRNA localization to the Gleason grading system for histologic scores in the hope of distinguishing aggressive and less aggressive variants of prostate cancer. We used a 25-base biotinylated oligonucleotide CB cDNA antisense probe to localize CB message and a 27-base biotinylated oligonucleotide stefin A cDNA antisense probe to localize stefin A message. Prostate samples from 41 prostatectomy patients were collected along with their pre-surgery serum PSA levels and clinical stage of the disease. Sections prepared from frozen prostate tissue samples were hybridized with the CB and stefin A and control pBR 322 probes using techniques reported by Sinha et al. [1] and their distribution quantitated by an image analysis system. Prostate sections treated with RNAse before hybridization or incubated with the pBR 322 control probe showed little or no reaction products, confirming that localization of CB and stefin A probes was specific. In prostate cancer, the reaction products were found in neoplastic and invasive cells and occasionally in stromal cells. The ratios of CB to stefin A were similar in normal prostate and benign prostatic hyperplasia (BPH) whereas they varied consistently within and between Gleason histologic scores for prostate cancer. These variations showed three localization patterns; namely, prostate cancers with higher levels of CB than stefin A, lower levels of CB than stefin A, and similar levels of CB and stefin A. All three patterns and ratios for CB and stefin A were found in prostate samples (22/41) represented by the Gleason histologic score 6 tumors. In these tumors, serum PSA levels ranged from 1 to 78 ng/ml and prostate cancers showed B, C, and D clinical stages. There was no correlation of CB/stefin A ratio and serum PSA values or clinical stage in a limited number of prostate cancer cases. Our data showed that there were prostate cancer cases within Gleason histologic scores which expressed high, similar, and low levels of CB when compared to stefin A. We postulate that prostate cancer cases showing higher levels of CB compared to stefin A probably represent an aggressive variant of this cancer within any one Gleason histologic score. If this is the case, aggressive variants of prostate cancer would occur within Gleason scores 3 to 10 even though higher scores are usually considered more aggressive forms of prostate cancers. Since our study is based upon a very limited number of frozen prostate samples, we emphasize that a larger series of archival prostate cancer samples along with their survival data should be analyzed to establish any relationship of CB/stefin A ratio and aggressive variants of this cancer. Therefore, our conclusion is tentative. Our study provides a partial explanation for differences in the clinical course of prostate cancer in patients. This is the first study to show that determination of CB and stefin A mRNA ratios may lead to identification of aggressive and less aggressive variants of prostate cancer within a Gleason histologic score.

Adenocarcinoma↗
PubMed2001

3D domain swapping, protein oligomerization, and amyloid formation.

In 3D domain swapping, first described by Eisenberg, a structural element of a monomeric protein is replaced by the same element from another subunit. This process requires partial unfolding of the closed monomers that is then followed by adhesion and reconstruction of the original fold but from elements contributed by different subunits. If the interactions are reciprocal, a closed-ended dimer will be formed, but the same phenomenon has been suggested as a mechanism for the formation of open-ended polymers as well, such as those believed to exist in amyloid fibrils. There has been a rapid progress in the study of 3D domain swapping. Oligomers higher than dimers have been found, the monomer-dimer equilibrium could be controlled by mutations in the hinge element of the chain, a single protein has been shown to form more than one domain-swapped structure, and recently, the possibility of simultaneous exchange of two structural domains by a single molecule has been demonstrated. This last discovery has an important bearing on the possibility that 3D domain swapping might be indeed an amyloidogenic mechanism. Along the same lines is the discovery that a protein of proven amyloidogenic properties, human cystatin C, is capable of 3D domain swapping that leads to oligomerization. The structure of domain-swapped human cystatin C dimers explains why a naturally occurring mutant of this protein has a much higher propensity for aggregation, and also suggests how this same mechanism of 3D domain swapping could lead to an open-ended polymer that would be consistent with the cross-beta structure, which is believed to be at the heart of the molecular architecture of amyloid fibrils.

Amyloid↗
PubMed2004

Differentially expressed protein markers in human submandibular and sublingual secretions.

Proteome analysis of secretions from individual salivary glands is important for understanding the health of the oral cavity and pathogenesis of certain diseases. However, cross-contamination of submandibular (SM) and sublingual (SL) glandular secretions can occur. The close anatomic relationship of the SM and SL ductal orifices can lead to such contamination. Additionally, these glands may share common ducts. To insure the purity of SM/SL secretions for proteomic analysis, it is important to develop unique biomarkers which could be used to verify the integrity of the individual glandular saliva. In this study, a proteomics approach based on mass spectrometry and gel electrophoresis techniques was utilized to identify and verify a set of proteins (cystatin C, calgranulin B and MUC5B mucin), which are differentially expressed in SM/SL secretions. SM/SL fluids were obtained from nine healthy subjects. Cystatin C was found to be an SM-selective protein as it was found in all SM fluids but not detected in two SL fluids. MUC5B mucin and calgranulin B, on the other hand, were found to be SL-selective proteins. All SL samples contained MUC5B mucin, whereas MUC5B mucin was not detected in four SM samples. Eight of the SL samples contained calgranulin B; however, calgranulin B was absent in eight SM samples. This set of protein markers, especially calgranulin B, can be used to determine the purity of SM/SL samples, and therefore identify potential individuals who do not exhibit cross-contaminated SM/SL secretions, an important requirement for subsequent proteome analysis of pure SM and SL secretions.

Adult↗
PubMed2005

[Prevalence of secondary hyperparathyroidism (SHPT) and causal factors in adult population in Reykjavík area].

INTRODUCTION: SHPT is a consequence of decreased concentration of ionized calcium in blood, which may have many causes. The purpose of this study was to assess the prevalence and contributing factors of SHPT in an adult Icelandic population and explore the relationship between PTH and other variables which might explain age related increase in PTH. Such knowledge might be helpful in evaluating the results of PTH measurements. METHODS AND STUDY GROUP: The study group was a random sample of men and women in the Reykjavik area, 30-85 years of age. Serum PTH was measured by ECLIA (Roche Diagnostics), serum 25(OH)D by RIA (DiaSorin), and body composition by DXA. SHPT was defined as PTH >65 ng/l and ionized calcium <1.25 mmol/l. Inadequate vitamin D was defined as serum 25(OH)D 25-45 nmol/l and vitamin D deficiency <25 nmol/l, inadequate calcium intake <800 mg/day (from questionnaire) and reduced kidney function as serum cystatin-C >1.55 ng/l. The relationship between PTH and other variables was assessed by Spearman?s correlation coefficient and linear regression. RESULTS: Of 2,310 individuals invited 1,630 attended (70%), 586 men and 1,023 women. Further 21 were excluded because of primary hyperparathyroidism. Of the total group 6.6% did have SHPT, 7.7% of the women and 4.6% of men (p<0.01 by gender). Underlying causes were identified in 90% of cases, most commonly inadequate vitamin D (73%). Other important causes were obesity, inadequate calcium intake, reduced kidney function and furosemide intake. Many individuals did have more than one possible underlying cause. The concentration of PTH was found in a multivariate linear regression to be associated with age, ionized calcium, 25(OH)D, cystatin-C, smoking, and BMI, especially fat mass. Testosterone did have a weak negative relationship with PTH in men. CONCLUSIONS: Most cases of SHPT could be explained by known causes and far the commonest was inadequate vitamin D. The prevalence of SHPT in Iceland is probably higher than described elsewhere, possibly due to less sunlight exposure. These results would suggest that a greater intake of vitamin D is needed in Iceland. The relationship of PTH with body composition, especially fat mass, sex hormones and smoking, needs further evaluation.

Adult↗
PubMed2005

[Stefin A--potential application in oncological laboratory diagnosis].

This is a review of studies on stefin A, an intracellular cysteine peptidase inhibitor of cystatin superfamily. Cystatins and target cysteine peptidases, such as cathepsins B and L have been implicated in malignant progression. The biochemical characteristics of human stefin A and its functions are presented. Special attention was paid to the potential usefulness of stefin A determination in serum and tissue cytosol (ELISA test) or tissue sections (immunohistochemistry) in the oncological laboratory diagnosis.

Cystatin A↗
PubMed1997

Cerebral amyloid angiopathy in the elderly: the clinicopathological features, pathogenesis, and risk factors.

Cerebral amyloid angiopathy (CAA) is known to be associated with intracerebral hemorrhage in the elderly. In this study we demonstrated that, among 101 cases with intracerebral hemorrhages found in 1000 consecutive autopsied cases (average age, 82.9 years) at a geriatric hospital, CAA accounted for 10.9% of them (31.0% of lobar and 14.3% of cerebellar hemorrhages). Immunohistochemically, the cerebrovascular amyloid was positive for beta/A4 peptide, and less intensely for cystatin C. The CAA-related hemorrhages were characteristically located near the cortical surface and ruptured into the subarachnoid space. No mutation of the amyloid precursor protein gene or the cystatin C gene was detected in these cases. From the observation of 500 serial sections containing amyloid-laden vessels of a patient with CAA-related hemorrhage, it was suggested that the hemorrhage occurred at microaneurysms with fibrinoid necrosis, which were found in small arteries in the cerebral cortex. The spatial distribution of CAA was closely associated with that of subpial beta/A4 peptide deposits in the brain, raising the possibility that the cerebrovascular amyloid originates from the brain parenchyma. Finally, the severity of CAA did not seem to be influenced by the inheritance of the epsilon 4 allele of the apolipoprotein E gene, which is known as a risk factor for dementia of the Alzheimer type.

Aged↗
PubMed1999

Purification, characterization, and molecular cloning of an outer layer protein of carp fertilization envelope.

An outer layer protein of carp fertilization envelope (FE), FEO-1, was purified from carp oocytes. The cDNAs encoding FEO-1 were cloned. The mature protein of FEO-1 is 21 kDa in molecular weight and contains 177 amino acid residues whose sequence has 58% identity to the outer layer protein of chick vitelline membrane. In situ hybridization and immunocytochemistry show that FEO-1 is expressed in oocytes and liver. In oocytes, FEO-1 is stored in the cortical granules. During cortical reaction, it is exocytosed to the perivitelline space and then gradually added to the outer layer of FE (FE(o)). FEO-1 first appears as discrete deposits along FE(o), then merges to form a continuous layer. The thickness of FE(o) increases as cortical reaction proceeds. In addition to FEO-1, FE(o) contains cystatin, fibroin-like substance (FLS), and cathepsin-like substance (CLS) as well. They are stored in the cortical granules and are exocytosed to FE(o) simultaneously with FEO-1 during cortical reaction. In FE(o), FEO-1 is present in monomer form and can be completely extracted by sodium dodecyl sulfate (SDS)-mercaptoethanol (MSH). On the other hand, the cystatin, FLS, and CLS present in FE(o)are cross-linked together. They are partially extracted by SDS-MSH but can be completely extracted by guanidium thiocyanate-lauroylsarcosine.

Amino Acid Sequence↗
PubMed1995

Transient appearance of CRES protein during spermatogenesis and caput epididymal sperm maturation.

In previous studies we identified an epididymal gene that exhibits homology to the cystatin family of cysteine protease inhibitors. The expression of this gene, termed CRES (cystatin-related epididymal and spermatogenic), was shown to be highly restricted to the proximal caput epididymal epithelium with less expression in the testis and no expression in the 24 other tissues examined. In this report, studies were carried out to examine CRES gene expression in the testis as well as to characterize the CRES protein in the testis and epididymis. In situ hybridization experiments revealed that within the testis CRES gene expression is stage-specific during spermatogenesis and is exclusively expressed by the round spermatids of Stages VII-VIII and the early elongating spermatids of Stages IX and X. Immunohistochemical studies demonstrated that CRES protein was transiently expressed in both the testis and epididymis. Within the testis the protein was localized to the elongating spermatids, whereas within the epididymis CRES protein was exclusively synthesized by the proximal caput epithelium and then secreted into the lumen. Surprisingly, the secreted CRES protein had completely disappeared from the epididymal lumen by the distal caput epididymidis. Western blot analysis of testicular and epididymal proteins showed that the CRES antibody specifically recognized a predominant 19 kDa CRES protein and a less abundant 14 kDa form. These observations suggest that the CRES protein performs a specialized role during sperm development and maturation.

Animals↗
PubMed1995

Carboxy-terminal truncation of oryzacystatin II by oryzacystatin-insensitive insect digestive proteinases.

The biochemical interactions between digestive proteinases of the Coleoptera pest black vine weevil (Otiorynchus sulcatus) and two plant cysteine proteinase inhibitors, oryzacystatin I (OCI) and oryzacystatin II (OCII), were assessed using gelatin-polyacrylamide gel electrophoresis, OCI-affinity chromatography, and recombinant forms of the two plant inhibitors. The insect proteinases were resolved in gelatin-containing polyacrylamide gels as five major bands, only three of them being totally or partially inactivated by OCI and OCII. The maximal inhibitory effect of both OCs at pH 5.0 was estimated at 40% and the inhibition was stable with time despite the presence of OC-insensitive proteases, indicating the stability of the OCI and OCII effects. After removing OC-sensitive proteinases from the insect crude extract by OCI-affinity chromatography, the effects of the insect cystatin-insensitive proteases on the structural integrity of the free OCs were analyzed. While OCI remained stable, OCII was subjected to limited proteolysis leading to its gradual transformation into a approximately 10.5-kDa unstable intermediate, OCIIi. As shown by the degradation pattern of a glutathione S-transferase (GST)/OCII fusion protein, the appearance of OCIIi resulted from the C-terminal truncation of OCII. Either free or linked to GST, OCIIi was as active against papain and human cathepsin H as OCII, and the initial specificities of the inhibitor for these two cysteine proteinases were conserved after cleavage. Although these observations indicate the high conformational stability of OCII near its active (inhibitory) site, they also suggest a general conformational destabilization of this inhibitor following its initial cleavage, subsequently leading to its complete hydrolysis. This apparent susceptibility of OCII to proteolytic cleavage by the insect proteinases could have major implications when planning the use of this plant cystatin for insect pest control.

Animals↗
PubMed1994

The de novo design of an antibody combining site. Crystallographic analysis of the VL domain confirms the structural model.

In a protein design approach the molecular model of an artificial antibody Fv fragment was generated with predicted complementarity to part of the known crystal structure of chicken egg-white cystatin. The model of the Fv fragment was based on the three-dimensional structure of the anti-lysozyme antibody HyHEL-10, which was modified by substituting amino acid side-chains in the complementarity-determining regions (CDRs) as well as the framework without altering the backbone. In the course of crystallization experiments with the bacterially produced Fv fragment crystals of the VL domain alone were obtained. These crystals diffracted X-rays to a resolution of 2.17 A and were shown to belong to the space group P2(1)2(1)2(1) with unit cell dimensions a = 46.89 A, b = 58.05 A, c = 83.22 A containing two VL monomers in the asymmetric unit. The crystal structure was solved by molecular replacement and refined to a crystallographic R-factor of 17.5%. The two VL monomers exhibit an asymmetric mode of association, which is different from other crystallized VL domains described before and shows the peculiar feature of an isopropanol precipitant molecule buried at the interface. Both VL structures reveal a high level of similarity to the predicted three-dimensional model. With the exception of two loop segments in the framework region that are involved in crystal packing contacts, the backbone structures of the two VL monomers in the crystal and the molecular model of the VL domain are practically identical. Although six amino acid residues had been replaced in the hypervariable regions, the CDR conformations remained conserved and only minor deviations in the orientation of some side-chains and peptide planes were detected. The crystallographic analysis of the VL domain modelled as part of a complex between an artificial Fv fragment and the small protein cystatin, deliberately chosen as antigen target, confirms the concept of distinct structural classes for CDR backbones and supports our strategy for the de novo design of an antibody combining site.

Amino Acid Sequence↗
PubMed1992

The role of the kininogens as cysteine proteinase inhibitors in local and systemic inflammation.

The contribution of the kininogens and cystatin C to the functional inhibitory capacity for cysteine proteinases of blood plasma and inflammatory secretions was estimated from ex vivo experiments. 98.5% of the inhibitory capacity of blood plasma for cathepsin L (4-5 microM) is provided by the kininogens ensuring a complete control of this enzyme even at a lowered kininogen concentration. Control of cathepsin B activity by the kininogens is incomplete and depends critically on the active concentration of cystatin C (70 nM in normal plasma), which is reduced in blood plasma of polytraumatized and septic patients and very low in epithelial lining fluid of the shock lung.

Cathepsin B↗