Objectively speaking, clinicians still know very little about fibrotic lung disease: the etiology and pathogenesis are unclear; there is still a lot of confusion about the diagnosis and judgment of the disease and its prognosis; and, importantly, there are still no therapeutic drugs that are definitively effective and have few adverse effects. However, this does not mean that clinical and scientific work has been unproductive. In fact, in the nearly 80 years since the first report of interstitial lung disease, a great deal of painstaking and meticulous work has been done to understand these diseases, and valuable evidence-based medical evidence has been accumulated. Wang Haifeng, Department of Pulmonary Diseases, The First Affiliated Hospital of Henan College of Traditional Chinese Medicine [Classification] From a single pathological criterion to a balance of clinical and pathological features In 1935, Hamman and Rich first reported a case with progressive exacerbation of dyspnea as the main manifestation, which has been considered as the first reported common type of interstitial pneumonia/idiopathic pulmonary fibrosis (IPF). In contrast, the diagnosis of acute interstitial pneumonia seems to be more reasonable at this time, due to its pathological changes, which are mainly diffuse alveolar damage. Interstitial lung diseases encompass at least 200 diseases involving the interstitial lung, and disease nomenclature and classification are constantly being adjusted as new diseases are discovered and defined as the understanding of these diseases increases. In 1969, Liebow et al. classified IIP as common interstitial pneumonia, desquamative interstitial pneumonia, lymphocytic interstitial pneumonia, giant cell interstitial pneumonia, and occlusive interstitial pneumonia. In 1998, Katzenstein and Myers adjusted the classification to common interstitial pneumonia, desquamative interstitial pneumonia, occlusive bronchiectatic interstitial pneumonia, acute interstitial pneumonia, and nonspecific interstitial pneumonia. Notably, both of these classifications are pathologic, not clinical, diagnoses. In 2002, the American Thoracic Society and the European Respiratory Society published the first “Expert Consensus”, which adjusted the IIP classification to include idiopathic pulmonary fibrosis (pathologic changes of common interstitial pneumonia), desquamative interstitial pneumonia, occlusive bronchiectasis interstitial pneumonia, lymphocytic interstitial pneumonia, cryptogenic mechanized pneumonia, and acute interstitial pneumonia. acute interstitial pneumonia (pathologic changes of diffuse alveolar damage) and nonspecific interstitial pneumonia, distinguishing for the first time between clinical and pathologic diagnoses. In September 2013, the American Journal of Respiratory and Critical Care Medicine published the latest classification of IIP: major idiopathic interstitial pneumonia, rare idiopathic interstitial pneumonia, and unclassified idiopathic interstitial pneumonia. Major idiopathic interstitial pneumonia was further divided into three categories: (1) chronic fibrotic interstitial pneumonia, including IPF and idiopathic nonspecific interstitial pneumonia; (2) smoking-associated interstitial pneumonia, including occlusive fine bronchitis with interstitial pneumonia and desquamative interstitial pneumonia; and (3) acute or subacute interstitial pneumonia, including cryptogenic mechanized pneumonia and acute interstitial pneumonia. Rarely, idiopathic interstitial pneumonia contains idiopathic lymphocytic interstitial pneumonia, idiopathic pleural pulmonary parenchymal elastosis, and some pathological changes that fail to be named clinically. Mechanism】Alveolar epithelial injury and abnormal repair are the key components The etiology and exact pathogenesis of IPF are still unclear. Since chronic inflammatory models can lead to fibrosis, inflammation was previously thought to be the main pathogenesis of these diseases, however, anti-inflammatory therapy has not achieved the expected efficacy. It is now believed that alveolar epithelial cell injury and abnormal repair are the main mechanisms leading to pulmonary fibrosis. After injury occurs, the repair process fails to complete the normal re-epithelialization process, which in turn leads to alveolar-capillary damage. This process induces cytokine production, and fibroblasts express cytokine receptors on their surface, which accumulate to the site of injury and proliferate in response to cytokines. Myofibroblasts are a class of cells with characteristics of both fibroblasts and smooth muscle cells, the origin of which remains unclear and is likely to be circulating fibroblasts and/or alveolar epithelial cells. These cells produce excessive amounts of extracellular matrix such as collagen and play an important role in the process of lung fibrosis. The causes of lung injury are not known, but viruses, autoantibodies, chemical inhalation, drugs, and acidic/non-acidic gastroesophageal reflux are likely to be the main causes, and the role of oxidative-antioxidative imbalance in the development of lung injury is well supported by the literature. Familial IPF accounts for approximately 5% of patients with IPF, and studies point to an autosomal dominant disorder, suggesting that the disease is associated with genetic mutations. However, current studies of the vast majority of patients with IPF show that it has not been determined which genetic abnormalities are associated with the development of IPF. The diagnosis of interstitial lung disease requires the combined efforts of clinical, imaging, and pathologists to reach a diagnosis, and the indications for lung biopsy should be known. Different interstitial diseases may lead to similar pathological manifestations, and different lobes of the lungs of a patient may have different pathological manifestations. For example, when a patient presents pathologically with nonspecific interstitial pneumonia or mechanized pneumonia, clinicians should look for underlying etiologies, including allergic pneumonia, collagen vascular disease, or the presence of drug exposure factors, to further clarify the diagnosis. The guidelines for the diagnosis and management of IPF published in 2011 clearly state that cases with a confirmed imaging diagnosis can be diagnosed without a lung biopsy. However, the diagnosis of IIP also requires the exclusion of known causative factors such as occupational factors, inhalation factors, collagen vascular disease, and medications. The diagnostic significance of biomarkers for IIP has not been recognized, but some studies have suggested that certain biomarkers may be valuable in distinguishing IPF from non-IPF. Ohnishi and Casoni et al. found that serum levels of pulmonary surfactant-associated protein A, pulmonary surfactant-associated protein D, and DNA were higher in patients with IPF than in those without IPF. Small sample studies showed that elevated levels of pulmonary surfactant-associated protein A, pulmonary surfactant-associated protein D, KL-6, pulmonary activated chemokine, and matrix metalloproteinase 7 correlated with decreased lung function, suggesting a poor prognosis for patients. However, a large number of studies are still needed to find more valuable and specific indicators and to confirm their practical significance to truly apply biomarkers in clinical practice. The guidelines for the diagnosis and treatment of IPF released in 2011 state that there are no definite effective drugs for the treatment of IPF, and that symptomatic treatment, oxygenation, rehabilitation exercises, and prevention and treatment of complications are the available strategies. Meta-analyses of IPF treatment published in the last 2 years have focused on the efficacy of pirfenidone. It is one of the most promising clinical agents for the treatment of IPF because of its ability to slow the decline in lung function, improve survival, and be well tolerated. For non-IPF interstitial lung disease, hormones and immunosuppressants are still the main therapeutic agents, and monitoring and prevention of adverse drug reactions need to be carried out throughout the follow-up process. In contrast, secondary fibrotic lung disease requires more attention to etiologic treatment. Acute exacerbations Focus on imaging and molecular pathology As a chronic interstitial pneumonia, IPF has an insidious onset with gradual exacerbation and can also present as an acute exacerbation. Clinical manifestations of acute exacerbations of IPF include dyspnea, rapidly worsening cough, hypothermia, markedly decreased gas exchange parameters, and imaging suggestive of new exudative changes. Almost all patients with acute exacerbations of IPF have alveolar lavage fluid examinations that primarily demonstrate elevated neutrophils. The diagnosis was based on an unexplained exacerbation of IPF within 30 d, combined with imaging and excluding pulmonary infection, cardiac insufficiency, pulmonary embolism, or drug-induced acute lung injury. The pathology of acute exacerbation of IPF is characterized by diffuse alveolar injury on top of common interstitial pneumonia, and some patients also have mechanized pneumonia changes, which are similar to acute respiratory distress syndrome and acute interstitial pneumonia and need to be carefully differentiated. For example, the circulating fibroblast count is significantly higher in patients with acute exacerbations of IPF, whereas there is no significant difference between acute respiratory distress syndrome and healthy controls or patients with stable IPF. A number of biomarkers associated with alveolar type II epithelial cell damage and/or proliferation, vascular endothelial cell injury, and collagen deposition are significantly elevated in patients with acute exacerbations of IPF, suggesting an association with alveolar epithelial injury and abnormal repair. Acute exacerbations can also occur in patients with non-IPF interstitial lung disease, such as nonspecific interstitial pneumonia and collagen vascular disease combined with interstitial fibrosis, with clinical, imaging, and pathologic manifestations similar to those of acute exacerbations of IPF and a poor prognosis. Mechanical ventilation is of general interest in the treatment of these patients, and some investigators have noted that invasive mechanical ventilation is not recommended unless lung transplantation is proposed in the short term. Currently, there are no definitive effective pharmacological regimens for acute exacerbations of interstitial lung disease, and the efficacy of hormones and immunosuppressive agents is limited. In clinical practice, patients with acute exacerbations of interstitial lung fibrosis are given large amounts of hormonal shock therapy, and a small number of patients do achieve some degree of clinical remission, but it is often unknown which patients may be effective at the beginning of treatment, and hormones should be reduced or stopped as soon as possible to avoid unnecessary adverse drug reactions in those who are ineffective. For the time being, lung transplantation remains the only treatment that is definitely effective, but it is difficult to implement clinically. Concomitant disease Identification of warning signs should be recognized and treated early From 1979 to the present, several studies have found that the incidence of gastroesophageal reflux is higher in patients with IPF than in normal subjects, and even higher than in asthmatics. The incidence of GERD is also significantly higher in patients with collagen vascular disease combined with interstitial lung fibrosis. The majority of patients with IPF combined with acid reflux did not exhibit typical symptoms such as heartburn, and no significant differences in pulmonary function parameters were observed. In a prospective study of 40 patients with systemic sclerosis, the incidence of acidic or non-acidic reflux was significantly higher in patients with combined pulmonary lesions, and the degree of reflux correlated with the degree of fibrotic scarring, especially central lobular fibrosis, as shown on high-resolution CT of the lungs. It is difficult to confirm the causal relationship between gastroesophageal reflux and pulmonary fibrosis because the incidence of gastroesophageal reflux in the normal population is 10%-20% and the incidence of 24-h reflux events is normal if they do not exceed 50 events, whereas fibrotic lung disease decreases lung compliance and increases negative pleural cavity pressure, which may trigger and exacerbate gastric reflux. The diagnosis of gastroesophageal reflux is often overlooked clinically because of atypical symptoms. When a patient with interstitial lung disease has chronic cough as the main manifestation, it suggests a possible combination of GERD and should be considered for appropriate treatment. The prevalence of obstructive sleep apnea in patients with IPF and the positive correlation between apnea hypoventilation index and body mass index and negative correlation with pulmonary function index suggest that early treatment of obstructive sleep apnea will be beneficial to improve patients’ quality of life and prognosis. The pathogenesis of IPF-related pulmonary hypertension is complex and not fully understood. The level of pulmonary hypertension correlates with the degree of progression of pulmonary fibrosis, i.e., in patients with secondary pulmonary hypertension, pulmonary hypertension is considered to be due to reduced vascular bed destruction and chronic hypoxic vasoconstriction; the severity of pulmonary hypertension is not proportional to the degree of pulmonary fibrosis, i.e., in patients with disproportionate pulmonary hypertension, cellular molecular mediators, imbalance of pro-angiogenic-angiogenic mediators and intermittent hypoxemia may play an important role. Patients with IPF combined with arterial hypertension have a significantly increased morbidity and mortality rate.