Alpha-1-antitrypsin and the pathogenesis of emphysema

The review examines the relationship between alpha₁-antitrypsin (α ₁AT) and emphysema. Although other defects occur in subjects with alpha₁-antitrypsin deficiency, it seems likely that a reduction in inhibition due to loss of this inhibitor explains their emphysema. There is a great deal of controversy, however, concerning the role of alpha₁-antitrypsin in subjects without inherited deficiency. There is uncertainty about the presence and function of other elastase inhibitors in the peripheral lung. The function of lungα ₁AT and the presence of elastase activity are dependent upon the techniques used and this probably accounts for different results between research groups. In addition, other relevant factors such as which enzymes cause lung elastolysis, control of neutrophil chemotaxis, and mechanisms of elastin synthesis and repair are less well studied. The overall conclusion is that many aspects of the elastase/antielastase hypothesis of emphysema are poorly understood. Without further information the true role ofα ₁AT will remain largely speculative.     

β1-Antitrypsin deficiency and chronic pancreatitis

Summary ₁-Antitrypsin deficiency is a genetic disorder commonly associated with pulmonary and hepatic injury. Low serum levels of this glycoprotein result in an imbalance between circulating protease and protease inhibitors, which is thought to play a role in the development of emphysema. In recent studies, a protease-to-protease inhibitor imbalance in patients with ₁-antitrypsin deficiency was thought to be a mechanism contributing to the development of chronic pancreatitis. The heterozygous phenotype and low levels of this glycoprotein have been reported to occur more frequently in patients with chronic pancreatitis than in healthy controls. We report a patient with Pi-SS phenotype ₁-antitrypsin deficiency and chronic pancreatitis complicated by recurrent pancreatic pseudocysts and chronic abdominal pain. Our case supports the association between chronic pancreatitis and ₁-antitrypsin deficiency. Furthermore, this case provides support for the use of pancreatic stent drainage in the management of intractable abdominal pain in patients with chronic pancreatitis and a dominant stricture.     

In vivo and in vitro responses of the bovine corpus luteum after exposure to exogenous gonadotropin-releasing hormone and prostaglandin F(2α)

Administration of gonadotropin-releasing hormone (GnRH) early in the estrous cycle has been shown to cause subsequent altered luteal function. To determine whether membrane-related events may be involved in GnRH-attenuated luteal function, corpora lutea (CL) were removed from beef heifers on day seven of the estrous cycle after iv injection of GnRH or saline on day two of the cycle (n=5/group). Luteal slices were incubated with saline (control), luteinizing hormone (LH), or 8-bromo-cAMP for 2h. In vivo administration of GnRH reduced LH and cAMP-stimulated progesterone production by tissue (p<0.01), but basal progesterone production was not affected (p>0.05). Luteal adenylyl cyclase activity did not differ between saline and GnRH-treated animals (p>0.05). Then to examine if early administration of GnRH alters response of the CL to prostaglandin (PG) F_2α, beefheifers were injected with GnRH as described above (n=4/group), and then injected with PGF_2α on day eight and the CL removed 60 min later. Blood samples were collected for oxytocin (OT) analysis at frequent intervals after PGF_2α injection and for progesterone at 0 and 60 min. Induction of the early response gene c-jun or release of OT by PGF_2α was not altered by GnRH injection (p>0.05). Injection of PGF_2α decreased serum progesterone by 60 min postinjection (p<0.05), but concentrations of this steroid were unaffected by GnRH (p>0.05). Collectively, these data suggest that GnRH-induced alteration of bovine luteal function may be owing to events distal to cAMP synthesis that do not interfere with PGF_2α-induced expression of c-jun or OT release, cellular phenomena involved in luteolysis.     

Chronic ‘Cryptogenic’ Liver Disease and Malignant Hepatoma in Intermediate AlpharAntitrypsin Deficiency Identified by a Pi Z-Specific Monoclonal Antibody

Using a monoclonal antibody against the Pi Z genetic variant of alpha₁-antitrypsin in an enzyme-linked immunosorbent assay, we have screened plasma samples from 857 consecutive patients with liver disease for the presence of Pi Z alpha₁-antitrypsin. Intermediate alpha₁-antitrypsin deficiency (Pi MZ and SZ) was found in 64 cases, or 7.6%, compared with an expected 4.8% (p < 0.001). The plasma alpha₁-antitrypsin level was subnormal in only 50% of them. Forty-three of the 64 heterozygotes were men, compared with 494 of 857 (58%) in the total study population (p < 0.001). At least 14 heterozygotes had cryptogenic liver disease, compared with 3 of 128 sex-and age-matched controls from the same study population (p < 0.001). Malignant hepatoma occurred in 6 heterozygotes compared with 1 control (p < 0.01), and in 13 of all 793 non-Pi Z patients (p < 0.001).     

AT<Subscript><Emphasis Type="Italic">1</Emphasis></Subscript> Receptor Blockade Prevents Cardiac Dysfunction after Myocardial Infarction in Rats

Summary Myocardial infarction (MI) can induce severe alterations of contractile function that can, in turn, lead to heart failure. In a previous study, we have demonstrated that TNF-α was involved in cardiac contractile dysfunction 7 days after coronary artery ligation in rats. Since Angiotensin II type 1 (AT₁) receptor can be involved in TNF-α production, we have investigated whether early short-term treatment with irbesartan, an AT₁ receptor blocker, is able to limit TNF-α production within the heart and to improve cardiac function and geometry following MI in rats. Male Wistar rats were subjected to permanent coronary artery ligation and received either a placebo or irbesartan (50 mg/kg/day) per os daily from day 3 to day 6 after surgery. On day 7, cardiac TNF-α was significantly reduced in MI rats receiving irbesartan (p < 0.05). Moreover, irbesartan improved residual LV end-diastolic pressure under both basal conditions and after volume overload (p < 0.01). In addition, a significant leftward shift of the pressure-volume curve in the irbesartan-treated group was found versus placebo. Finally, infarct expansion index was also significantly improved by irbesartan (p < 0.01). In conclusion, early, short-term AT₁ receptor blockade limits post-infarct cardiac TNF-α production and diminishes myocardial alterations observed 7 days after MI in the rat.     

Fecal α1-antitrypsin detection of colorectal neoplasia

Fecal ₁-antitrypsin measurement may be of value for the detection of coloreactal neoplasia and is compared with the HemoQuant test in 119 subjects with either a screen-positive Hemoccult result (N=78) or iron-deficiency anaemia (N=41). Nineteen patients were found to have coloreactal cancer, 35 had colorectal adenomatous polyps, 5 had inflammatory bowel disease, and 60 had no detected cause of occult blood loss. Of the cancer patients, 63% (12/19) were detected by fecal ₁-antitrypsin, and 63% (12/19) by HemoQuant. Of the adenomas >1 cm in diameter 33% (7/23) were detected by fecal ₁-antitrypsin and 26% (6/23) by HemoQuant. There was a poor correlation between fecal ₁-antitrypsin, and HemoQuant results for colorectal cancers (r=0.37,P>0.05), and combining the tests, the sensitivity for colorectal cancer was incerased to 84% (16/19). Fecal proteins loss, as measured using ₁-antitrypsin, appears to involve largely different mechanisms from that of blood loss from colorectal cancers.     

Increased alpha2-macroglobulin in diabetes: A hyperglycemia related phenomenon associated with reduced antithrombin III activity

Summary Increased α₂-macroglobulin (α₂M) activity and concentration, and decreased antithrombin III (ATIII) plasma concentration are reported in diabetic subjects. In diabetes an inverse correlation between ATIII activity and blood glucose, HbA₁. α₂M activity and α₂M concentration, and a direct correlation between both α₂M concentration with blood glucose and HbA₁ are found. Moreover, a direct correlation between α₂M activity and α₂M concentration fails. In both diabetic and normal subjects induced hyperglycemia increases α₂M activity and α₂M concentration reduces ATIII activity, while ATIII concentration is not affected. These data which show that hyperglycemia may increase α₂M molecule levels while altering only the biological function of ATIII, provide evidence that hyperglycemia may decrease, directly, the biological function of some proteins and may condition the levels of some risk factors for the development of diabetic complications such as α₂M. This study was presented at the 23rd Annual Meeting of the European Association for the Study of Diabetes, Leipzig, GDR, September 1987.