Acute lung injury and acute respiratory distress syndrome: experimental and clinical investigations

Chen, Hsing I

disease. [6] Chest radiography on admission revealed clear lung. However, 21 out of 48 cases developed severe dyspnea, hyperglycemia, leukocytosis, and decreased blood oxygen tension. Arterial pressure (AP) and heart rate (HR) fluctuation ensued. Spectral analysis of the AP and HR variabilities showed elevation in sympathetic activity at the onset of respiratory stress. Thereafter, parasympathetic drive increased with declines in AP and HR. These children died within 4 h after the onset of ARDS. Before death, chest radiography revealed severe lung infiltration. Similar to Japanese B encephalitis, destruction of the medullary depressor area caused initial sympathetic activation. Reversetranscriptase polymerase chain reaction (RT-PCR) found marked iNOS mRNA expression in the lung parenchyma, suggesting iNOS may also be involved in the pathogenesis of ARDS in patients with enterovirus 71 infection. Furthermore, we have reported ARDS in patients with leptospirosis. [18] In leptospirosis-induced ARDS, histochemical stain demonstrated spirochetes bacteria in the alveolar space. The pathology included alveolar hemorrhage, myocarditis, portal inflammation and interstitial nephritis. Antigen retrieval immunohistochemical stain disclosed iNOS expression in the alveolar type 1 cells, myocardium, hepatocytes and renal tubules. Spectral analysis of AP and HR variabilities indicated decreased sympathetic drive with increased parasympathetic activity. The changes in autonomic functions led to severe hypotension and bradycardia. Biochemical determinations suggested multiple organ damage. The pathogenesis of lung and other organ injury might also involve iNOS and NO production. [18, 29] In subjects with scrub typhus, Orientia tsutsugamushi infection caused alveolar injury. Marked iNOS expression was found in the alveolar macrophages with increase in plasma nitrate/nitrite, suggesting that NO production from the alveolar macrophages accounts for the ALI. [30] The victim from rabies was a woman bitten by a wild dog. In addition to sign of hydrophobia, hypoxia, hypercapnia, hyperglycemia and increased plasma nitrate/nitrite were observed. The woman died of alveolar hemorrhage shortly after admission. [31] Recently, we encountered five cases with long-term malignancy. These subjects displayed signs of respiratory distress following an episode of hypercalcemia. Two cases died of ARDS after the plasma calcium was increased above 6 mmol/L. Search of literatures revealed that Holmes et al. [32] reported a patient who died of ARDS following a hypercalcemia crisis caused by a parathyroid adenoma. We conducted animal experiments in whole rodent and isolated perfused rat's lungs. Our results indicated that hypercalcemia (calcium concentration > 5 mmol/L) caused severe ALI in conscious rats and isolated lungs. Immunohistochemical staining showed iNOS activity in the alveolar macrophages and epithelial cells. Reversetranscriptase polymerase chain reaction (RT-PCR) found marked increase in iNOS mRNA expression in lung parenchyma. Hypercalcemia also increased nitrate/nitrite, methyl guanidine, proinflammatory cytokines and procalcitonin. Pretreatment with calcitonin or L-N 6 (1iminoethyl)-lysine (L-Nil, an iNOS inhibitor) attenuated the hypercalcemia-induced changes. We proposed that hypercalcemia produced a sepsis-like syndrome. The ALI caused by hypercalcemia may involve NO and iNOS. [33, 34] In addition to the aforementioned animal experimentations and clinical obse